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Minicolumnar pathology in autism

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Abstract

To determine whether differences exist in the configuration of minicolumns between the brains of autistic and control patients. Autism is a severe and pervasive developmental disturbance of childhood characterized by disturbances in both social interactions and communication, as well as stereotyped patterns of interests, activities, and behaviors. Postmortem neuropathologic studies remain inconclusive. The authors used a computerized imaging program to measure details of cell column morphologic features in area 9 of the prefrontal cortex and areas 21 and posterior 22 (Tpt) within the temporal lobe of nine brains of autistic patients and controls. The authors found significant differences between brains of autistic patients and controls in the number of minicolumns, in the horizontal spacing that separates cell columns, and in their internal structure, that is, relative dispersion of cells. Specifically, cell columns in brains of autistic patients were more numerous, smaller, and less compact in their cellular configuration with reduced neuropil space in the periphery. In autism, there are minicolumnar abnormalities in the frontal and temporal lobes of the brain.

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... ASD is under substantial genetic influence, with a concordance rate in monozygotic twins of up to 90% (Rosenberg et al., 2009); however, identified genetic causes only explain up to 17% of cases (Sanders et al., 2015). ASD already begins in utero, affecting neurons during essential development processes such as proliferation, neuronal growth and differentiation, migration, synapse formation and network construction (e.g., Bauman & Kemper, 1985;Casanova et al., 2002). ...
... Disruption of post-natal neuron migration and/or differentiation may contribute the observed cortical anatomical disorganization reported in ASD individuals (Stoner et al., 2014) and also to reported alteration in basic functional cortical units (i.e., cortical minicolumns, Mountcastle, 1997), which have been described in ASD (Buxhoeveden et al., 2006;Casanova et al., 2002;Opris & Casanova, 2014). ...
... Disruption of post-natal neuron migration and/or differentiation may contribute to the observed cortical anatomical disorganization reported in ASD individuals (Stoner et al., 2014), and to the reported alteration in basic functional cortical units (i.e., cortical minicolumns), which have been described in ASD (Casanova et al., 2002). ...
Article
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There are currently no biomarkers for autism spectrum disorder (ASD). This neurodevelopmental condition has previously been associated with histopathological findings, including increased neuronal packing density in the amygdala, abnormal laminar cytoarchitecture and increased average neuronal density in the prefrontal cortex. The present study examined whether new brain imaging technologies could reveal in vivo, in adults with ASD, the manifestation of previously described histopathological changes. Using quantitative mapping at ultra-high field (7 Tesla), we show that we can observe microstructural alterations in the right lateral orbito-frontal cortex and the bilateral amygdala in adult individuals with ASD in vivo. These imaging alterations point to an abnormal laminar cytoarchitecture and to an increased neuronal density, similar to what has been previously described in post-mortem data in ASD. Our data demonstrate that it is possible to visualize, in vivo and at the individual level, alterations of cortical and subcortical microstructure in ASD. Future studies will be needed to extend these findings to a larger group of individuals, and evaluate their association with symptomatology as well as their specificity among the different neurodevelopmental disorders.
... Some postmortem investigations using magnetic resonance imaging (MRI) identified an abundance of white matter and some structural impairment in cell alignment and density, especially in the limbic system [23]. Atypical stimulation of the amygdala and associated structures are analyzed by functional imaging techniques in response to social stimuli in ASD-affected children [24,25]. ...
... Alterations in cortical minicolumns in layer III of the temporal and prefrontal cortex in ASD was observed in some of the research studies [56]. Minicolumns are the modular organization of neurons that span all neocortical layers of the brain and serve to arrange neurons in a defined shape and space and possess similar properties [24]. Large minicolumns are thought to play an important role in generalization, whereas small minicolumns facilitate discrimination. ...
... Large minicolumns are thought to play an important role in generalization, whereas small minicolumns facilitate discrimination. A small neuropil space at the periphery of the minicolumns in autism subjects suggests that GABAergic innervation to the minicolumn neurons interferes with the processing and differentiation of signals [24]. ...
Article
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Understanding the autistic brain and the involvement of genetic, non-genetic, and numerous signaling pathways in the etiology and pathophysiology of autism spectrum disorder (ASD) is complex, as is evident from various studies. Apart from multiple developmental disorders of the brain, autistic subjects show a few characteristics like impairment in social communications related to repetitive, restricted, or stereotypical behavior, which suggests alterations in neuronal circuits caused by defects in various signaling pathways during embryogenesis. Most of the research studies on ASD subjects and genetic models revealed the involvement of mutated genes with alterations of numerous signaling pathways like Wnt, hedgehog, and Retinoic Acid (RA). Despite significant improvement in understanding the pathogenesis and etiology of ASD, there is an increasing awareness related to it as well as a need for more in-depth research because no effective therapy has been developed to address ASD symptoms. Therefore, identifying better therapeutic interventions like “novel drugs for ASD” and biomarkers for early detection and disease condition determination are required. This review article investigated various etiological factors as well as the signaling mechanisms and their alterations to understand ASD pathophysiology. It summarizes the mechanism of signaling pathways, their significance, and implications for ASD.
... Se ha reportado alteraciones estructurales en la corteza prefrontal humana asociadas a patologías neuropsiquiátricas como por ejemplo: autismo, esquizofrenia, trastorno por déficit de atención e hiperactividad, depresión, drogadicción y trastorno obsesivocompulsivo, entre otros. (127)(128)(129)(130)(131)(132) En el autismo se ha descrito alteraciones en el tamaño de las minicolumnas corticales, densidad neuronal y tamaño celular en áreas 9 y 10 (127,128,133), en esquizofrenia se ha sugerido diversas hipótesis que en conjunto pueden explicar algunos de los signos y síntomas observados en los pacientes, por ejemplo: alteraciones genéticas (genes involucrados en el desarrollo de la corteza cerebral, transmisión glutamatérgica e inhibidores de señalización intracelular) (129,134), el funcionamiento defectuoso de los mecanismos dopaminérgicos ocasionando un exceso del neurotransmisor en el neocorteza (135)(136)(137), este último, no es el único neurotransmisor reportado en esquizofrenia, se ha sugerido que la regulación inadecuada del glutamato y Gaba aportarían elementos a la fisiopatológica de la enfermedad (138), dato corroborado por estudios de conectividad y citomorfología que demuestran que las células más afectadas en esta enfermedad son las células en candelabro, ubicadas en láminas supragranulares e intermedias de la corteza prefrontal humana (131,(139)(140)(141), dejando la inquietud de si los cambios morfológicos y por lo tanto funcionales en estas interneuronas (pobre efecto inhibitorio en el segmento inicial del axón sobre células piramidales) son la causa o la consecuencia de la patología, conociendo de antemano múltiples factores epigenéticos y genéticos involucrados en su desarrollo. ...
... Se ha reportado alteraciones estructurales en la corteza prefrontal humana asociadas a patologías neuropsiquiátricas como por ejemplo: autismo, esquizofrenia, trastorno por déficit de atención e hiperactividad, depresión, drogadicción y trastorno obsesivocompulsivo, entre otros. (127)(128)(129)(130)(131)(132) En el autismo se ha descrito alteraciones en el tamaño de las minicolumnas corticales, densidad neuronal y tamaño celular en áreas 9 y 10 (127,128,133), en esquizofrenia se ha sugerido diversas hipótesis que en conjunto pueden explicar algunos de los signos y síntomas observados en los pacientes, por ejemplo: alteraciones genéticas (genes involucrados en el desarrollo de la corteza cerebral, transmisión glutamatérgica e inhibidores de señalización intracelular) (129,134), el funcionamiento defectuoso de los mecanismos dopaminérgicos ocasionando un exceso del neurotransmisor en el neocorteza (135)(136)(137), este último, no es el único neurotransmisor reportado en esquizofrenia, se ha sugerido que la regulación inadecuada del glutamato y Gaba aportarían elementos a la fisiopatológica de la enfermedad (138), dato corroborado por estudios de conectividad y citomorfología que demuestran que las células más afectadas en esta enfermedad son las células en candelabro, ubicadas en láminas supragranulares e intermedias de la corteza prefrontal humana (131,(139)(140)(141), dejando la inquietud de si los cambios morfológicos y por lo tanto funcionales en estas interneuronas (pobre efecto inhibitorio en el segmento inicial del axón sobre células piramidales) son la causa o la consecuencia de la patología, conociendo de antemano múltiples factores epigenéticos y genéticos involucrados en su desarrollo. ...
Thesis
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The present research is a descriptive study that search to establish the morphological and cytoarchitectural organization of subpopulations of GABAergic interneurons in the cortical layers II and III of area 10 on the orbital surface of the Human Prefrontal Cortex, assessing features such as density, cortical thickness, laminar thickness, neuronal soma size, shape factor (degree of sphericity of the cell soma) and number of primary processes. Histological slides containing sections of area 10 of the two hemispheres from 5 postmortem subjects were observed. This tissue was processed with antibodies against NeuN, and calcium-binding proteins (CaBPs): Parvalbumin (PV), Calbindin (CB) and Calretinin (CR). 1646 interneurons were analyzed. We found that the human area 10 has the highest neuronal and interneuronal density in supragranular layers (II-III), although the thicknesses of supragranular and infragranular (V-VI) layers are similar. The layers II and IV have highest neuronal density, followed by layers III, V and VI; and layer I have lowest neuronal density. In relation to interneuronal density, area 10 layers II and IV have highest density, followed by layers III and V; and layers I and VI have lowest density. The CR-positive (CR+) cells subpopulation is the largest and CB-positive (CB+) cells subpopulation is the smallest. The CR+ somas are distributed uniformly throughout the six cortical layers. CB+ somas are predominant in layers II and III, scarce in layer IV and practically nonexistent in the other layers. PV-positive (PV+) somas are predominant in layers III, IV and V, followed by layers II and VI, and are practically nonexistent in layers I. Morphometric features evaluated in 1646 interneurons of layers II and III allowed distinguishing morphological differences between the three subpopulations of cortical interneurons that expressed each one of CaBPs. The PV+ cells present the largest cell bodies, with a marked tendency to spherical shape and the greatest number of the primary process; the CR+ cells have smaller somas and the least number of primary processes. CB+ cells have an intermediate number of primary processes between CR+ and PV+ cells, but its soma shape and size are similar to CR+ cells. In both cortical layers studied (II and III) morphological variations in interneurons were observed: the soma size of interneurons increase from layer II to layer III (for the interneuronal subpopulations); the PV+ cells of layers III showed less number of primary processes than the ones located in layer II. None of the morphometric features considered in this study presented interhemispheric asymmetries. The agglomerative hierarchical clustering analysis allowed the identification of eight subgroups of GABAergic interneurons in supragranular layers of human area 10 differentiated by the morphological features considered, and Besides by their laminar location and the expression of a CaBP type. The results of this analysis were consistent with the descriptive data, the correlation analysis and the data reported by others authors in the literature about these cell populations in others cortical areas.
... Autism spectrum disorders (ASD) are neurodegenerative disorders that are mainly diagnosed based on the behaviors of children, whose symptoms include de cit to develop normal social interaction with other people, impaired development of communicative ability, lack of imaginative ability, and repetitive, stereotyped movements (Casanova et al. 2002). Some changes occur in the anatomy and physiology of brain, such as overgrowth of the frontal cortex during the prenatal period in ASD (Casanova et al. 2002;Talkowski et al. 2012). ...
... Autism spectrum disorders (ASD) are neurodegenerative disorders that are mainly diagnosed based on the behaviors of children, whose symptoms include de cit to develop normal social interaction with other people, impaired development of communicative ability, lack of imaginative ability, and repetitive, stereotyped movements (Casanova et al. 2002). Some changes occur in the anatomy and physiology of brain, such as overgrowth of the frontal cortex during the prenatal period in ASD (Casanova et al. 2002;Talkowski et al. 2012). On the other side, underdeveloped parts in cognitive areas affect decision making, communication and language (Talkowski et al. 2012). ...
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Though the prevalence of autism spectrum disorder (ASD) is increasing day by day, there is still a lack of a proper way to diagnose or prevent ASD. There is no study carried out in the Bangladeshi children with ASD to evaluate the association of Transferrin ( TF ) and Transcription Factor 4 ( TCF4 ) genetic polymorphisms. This genetic association study was designed to explore the association of rs1867503 polymorphism of TF and rs9951150 polymorphism of TCF4 genes with ASD. We collected blood from 96 children with ASD and 118 healthy children of very similar age differences. Genotyping of these SNPs was performed by the PCR-RFLP method. SPSS (version 16) was used to estimate the odds ratio (OR) and their 95% confidence intervals (CI). The frequency of mutant allele G for rs1867503 and rs9951150 polymorphisms was found 48% and 44%, respectively. In our analysis, both TF and TCF4 polymorphisms showed an increased risk for the development of ASD. AG heterozygote, GG mutant homozygote, AG+GG combined genotype, and G mutant allele of TF rs1867503 showed a significantly elevated risk of ASD development (OR=3.18, p =0.0003; OR=2.62, p =0.0128; OR=2.98, p =0.0002; and OR=1.94, p =0.001, respectively). Likewise, AG heterozygote, GG mutant homozygote, AG+GG combined genotype, and G minor allele of TCF4 rs9951150 also showed a significantly elevated risk of ASD development (OR=2.92, p =0.0007; OR=2.36, p =0.0273; OR=2.72, p =0.0005; and OR=1.92; p =0.0014, respectively). Our results indicate that TF rs1867503 and TCF4 rs9951150 polymorphisms are strongly associated with the development of ASD in Bangladeshi children.
... Neocortex formation termed neocorticalization, brain parcellation, lateralization, and gyrification are affected by the addition of supernumerary minicolumns within the neocortex (Casanova & Christopher, 2008). Because these minicolumns are widespread and high in numbers, abnormalities in their basic ontogenetic pattern, referred to as minicolumnopathies, provide incredibly significant alterations in the functioning of the brain; these minicolumnopathies change brain volume, gray-over-white matter ratio and gyrification (Casanova et al., 2002). In dyslexia, a minicolumnopathy may be present (Casanova et al., 2002) as functional magnetic resonance imaging (fMRI) studies suggest that people with dyslexia have reduced brain volume, decreased gyrification and abnormal lateralization (Casanova et al., 2010). ...
... Because these minicolumns are widespread and high in numbers, abnormalities in their basic ontogenetic pattern, referred to as minicolumnopathies, provide incredibly significant alterations in the functioning of the brain; these minicolumnopathies change brain volume, gray-over-white matter ratio and gyrification (Casanova et al., 2002). In dyslexia, a minicolumnopathy may be present (Casanova et al., 2002) as functional magnetic resonance imaging (fMRI) studies suggest that people with dyslexia have reduced brain volume, decreased gyrification and abnormal lateralization (Casanova et al., 2010). Further, the white matter depth of people with dyslexia is more extensive than usual owing to lower levels of cortex folding (Casanova et al., 2010). ...
Article
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Multiscale entropy analysis (MSE) is a novel entropy-based approach for measuring dynamical complexity in physiological systems over a range of temporal scales. MSE has been successfully applied in the literature when measuring autism traits, Alzheimer’s, and schizophrenia. However, until now, there has been no research on MSE applied to children with dyslexia. In this study, we have applied MSE analysis to the EEG data of an experimental group consisting of children with dyslexia as well as a control group consisting of typically developing children and compared the results. The experimental group comprised 16 participants with dyslexia who visited Ankara University Medical Faculty Child Neurology Department, and the control group comprised 20 age-matched typically developing children with no reading or writing problems. MSE was calculated for one continuous 60-s epoch for each experimental and control group’s EEG session data. The experimental group showed significantly lower complexity at the lowest temporal scale and the medium temporal scales than the typically developing group. Moreover, the experimental group received 60 neurofeedback and multi-sensory learning sessions, each lasting 30 min, with Auto Train Brain. Post-treatment, the experimental group’s lower complexity increased to the typically developing group’s levels at lower and medium temporal scales in all channels.
... In the current analysis, the heterogeneous network with K = 1000 was regarded as a typical developmental model, and homogeneous networks with K = 0.001 and 1 were assumed to be possible ASD-like models. Second, as there are biological studies that showed that the brains of individuals with ASD have a greater number of cortical minicolumns (i.e., structures that constitute basic functional assemblies of neurons) 32,33 , the influence of an increased number of lower-level neurons on the performance of the models was also evaluated in this study. To investigate the influences of the parameter K and the number of lower-level neurons on the model performance, the four representative network structures in Table 1 were subjected to the analysis described earlier. ...
... However, we believe that we have succeeded in showing a decreasing tendency of the model's generalization ability for excessively large functional networks. This trend, demonstrated computationally in this study, is consistent with biologically confirmed findings that ASD patients have larger brains 38 , more minicolumns 32,33 , and an excitatory/inhibitory imbalance 39 . ...
Article
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The mechanism underlying the emergence of emotional categories from visual facial expression information during the developmental process is largely unknown. Therefore, this study proposes a system-level explanation for understanding the facial emotion recognition process and its alteration in autism spectrum disorder (ASD) from the perspective of predictive processing theory. Predictive processing for facial emotion recognition was implemented as a hierarchical recurrent neural network (RNN). The RNNs were trained to predict the dynamic changes of facial expression movies for six basic emotions without explicit emotion labels as a developmental learning process, and were evaluated by the performance of recognizing unseen facial expressions for the test phase. In addition, the causal relationship between the network characteristics assumed in ASD and ASD-like cognition was investigated. After the developmental learning process, emotional clusters emerged in the natural course of self-organization in higher-level neurons, even though emotional labels were not explicitly instructed. In addition, the network successfully recognized unseen test facial sequences by adjusting higher-level activity through the process of minimizing precision-weighted prediction error. In contrast, the network simulating altered intrinsic neural excitability demonstrated reduced generalization capability and impaired emotional clustering in higher-level neurons. Consistent with previous findings from human behavioral studies, an excessive precision estimation of noisy details underlies this ASD-like cognition. These results support the idea that impaired facial emotion recognition in ASD can be explained by altered predictive processing, and provide possible insight for investigating the neurophysiological basis of affective contact.
... Evidence from functional magnetic resonance imaging (fMRI), electroencephalographic (EEG), and event-related potential (ERP) studies outline that error monitoring is a function of the dorsolateral prefrontal cortex (DLPFC) and the medial frontal cortex (MFC), including the supplementary eye fields, rostral cingulate motor area, and dorsal anterior cingulate cortex (ACC) (reviewed in Ridderinkhof et al. 2004). A series of neuropathological studies in autism suggest the presence of significant minicolumnar abnormalities in brain regions related to error monitoring, specifically in the DLPFC, the MFC, and the ACC (Casanova 2005(Casanova ,2007Casanova et al. 2006aCasanova et al. , b, 2003. ...
... Our preliminary studies indicate that minicolumns are reduced in size and increased in number in the autistic brain, especially the prefrontal cortex (Casanova et al. 2002a(Casanova et al. , b, 2006a. More specifically, minicolumns in the brains of autistic patients are narrower and contain less peripheral, neuropil space (Casanova et al. 2006a;Casanova 2005). The lack of a 'buffer zone' normally afforded by lateral inhibition and appropriate neuropil space may adversely affect the functional distinctiveness of minicolumnar activation, and could result in isolated islands of coordinated excitatory activity (i.e., possible seizure foci). ...
Chapter
Error monitoring and correction is one of the executive functions and is important for effective goal-directed behavior. Deficient executive functioning, including reduced error monitoring ability, is one of the typical features of such neurodevelopmental disorders as autism spectrum disorder (ASD), probably related to perseverative responding, stereotyped repetitive behaviors, and an inability to accurately monitor ongoing behavior. Our prior studies of behavioral and event-related potential (ERP) measures during performance on visual oddball tasks in high-functioning autistic children showed that despite only minor differences in reaction times (RT) children with autism committed significantly more errors. The chapter reviews behavioral (reaction time, accuracy, rate of omission and commission errors, post-error reaction time slowing) error monitoring in children with ASD and response-locked event-related potentials (ERP), in particular, the error-related negativity (ERN) and error-related positivity (Pe) recorded at the fronto-central EEG sites. The ERN reflects early error detection processes, whereas the Pe has been associated with later conscious error evaluation and attention reallocation. Our prior studies showed significant differences of behavioral and ERN indices between children with ASD and with ADHD as well as with typical developing peers. The goal of our chapter is to review effects of slow frequency repetitive TMS (rTMS) over dorsolateral prefrontal cortex (DLPFC) in high-functioning children with ASD on behavioral and electrocortical measures found in a series of studies conducted by our group. Our results show significant post-TMS differences in the response-locked ERPs such as ERN, as well as behavioral response-monitoring measures indicative of improved error monitoring and correction function. Our review suggests that TMS has the potential to become a viable therapeutic tool in ASD treatment and may play an important role in improving the quality of life of many children with the disorder. The chapter provides rationale to use ERN and Pe, along with behavioral performance measures as functional outcome measures, to assess the effectiveness of neuromodulation (e.g., rTMS and rTMS combined with neurofeedback) in children with autism, and thus, may have important practical implications.
... There is evidence that GABAergic interneuron growth and connections in the prefrontal and temporal cortices are altered in ASD (84), which could lead to E/I imbalance (85). In post-mortem brain samples of ASD cases, it was found that neocortical minicolumns, elemental modular microcircuits made up of excitatory pyramidal neurons surrounded by GABAergic inhibitory neurons, were reduced, which could results in inhibitory circuits disruption (84,86). ...
... There is evidence that GABAergic interneuron growth and connections in the prefrontal and temporal cortices are altered in ASD (84), which could lead to E/I imbalance (85). In post-mortem brain samples of ASD cases, it was found that neocortical minicolumns, elemental modular microcircuits made up of excitatory pyramidal neurons surrounded by GABAergic inhibitory neurons, were reduced, which could results in inhibitory circuits disruption (84,86). ...
Article
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Electroencephalography (EEG) can further out our understanding of autistic spectrum disorders (ASD) neurophysiology. Epilepsy and ASD comorbidity range between 5 and 46%, but its temporal relationship, causal mechanisms and interplay with intellectual disability are still unknown. Epileptiform discharges with or without seizures go as high as 60%, and associate with epileptic encephalopathies, conceptual term suggesting that epileptic activity can lead to cognitive and behavioral impairment beyond the underlying pathology. Seizures and ASD may be the result of similar mechanisms, such as abnormalities in GABAergic fibers or GABA receptor function. Epilepsy and ASD are caused by a number of genetic disorders and variations that induce such dysregulation. Similarly, initial epilepsy may influence synaptic plasticity and cortical connection, predisposing a growing brain to cognitive delays and behavioral abnormalities. The quantitative EEG techniques could be a useful tool in detecting and possibly measuring dysfunctions in specific brain regions and neuronal regulation in ASD. Power spectra analysis reveals a U-shaped pattern of power abnormalities, with excess power in the low and high frequency bands. These might be the consequence of a complicated network of neurochemical changes affecting the inhibitory GABAergic interneurons and their regulation of excitatory activity in pyramidal cells. EEG coherence studies of functional connectivity found general local over-connectivity and long-range under-connectivity between different brain areas. GABAergic interneuron growth and connections are presumably impaired in the prefrontal and temporal cortices in ASD, which is important for excitatory/inhibitory balance. Recent advances in quantitative EEG data analysis and well-known epilepsy ASD co-morbidity consistently indicate a role of aberrant GABAergic transmission that has consequences on neuronal organization and connectivity especially in the frontal cortex.
... While many hypotheses have been proposed to explain the sensory alterations in ASD, the current prevailing hypothesis is that of abnormal GABA mediated neurotransmission [59][60][61] . With specific regard to difficulties with amplitude and frequency discrimination in the current study, postmortem comparisons of the brains of adults with and without ASD have found that that the brains of adults with ASD had fewer lateral inhibitory connections between cortical minicolumns 62 . Given that lateral inhibition via GABAergic interneurons between cortical minicolumns is fundamental for appropriate discrimination of sensory input 63 , our finding of specific difficulties with tactile discrimination in children with ASD is consistent with the broad idea of atypical GABA inhibition in ASD. ...
Article
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Alterations of tactile processing have long been identified in autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). However, the extent to which these alterations are disorder-specific, rather than disorder-general, and how they relate to the core symptoms of each disorder, remains unclear. We measured and compared tactile detection, discrimination, and order judgment thresholds between a large sample of children with ASD, ADHD, ASD + ADHD combined and typically developing controls. The pattern of results suggested that while difficulties with tactile detection and order judgement were more common in children with ADHD, difficulties with tactile discrimination were more common in children with ASD. Interestingly, in our subsequent correlation analyses between tactile perception and disorder-specific clinical symptoms, tactile detection and order judgment correlated exclusively with the core symptoms of ADHD, while tactile discrimination correlated exclusively with the symptoms of ASD. When taken together, these results suggest that disorder-specific alterations of lower-level sensory processes exist and are specifically related to higher-level clinical symptoms of each disorder.
... These authors discussed the possibility that increased spine densities may result from deficient postnatal culling of connections and may thus have downstream effects on the interplay of excitation and inhibition in local microcircuits, which may be in line with recent connectome modelling studies (44,83). Other reports have shown focal 'patches' of disorganized cortical layers in ASD (84) and emphasized altered columnar arrangement, again with prominent findings in temporal and frontal cortices (85,86). ...
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Autism is a common neurodevelopmental condition characterized by substantial phenotypic heterogeneity, which hinders diagnosis, research, and intervention. A leading example can be found in marked imbalances in language and perceptual skills, where deficits in one domain often co-exist with normal or even superior performance in the other domain. The current work capitalized on multiple data analytics including data-driven subtyping and dimensional approaches to quantify cognitive imbalances in multi-site datasets of individuals diagnosed with autism spectrum disorder (ASD) and neurotypical controls, and assessed structural and functional brain network substrates. Studying cognitive dimensions as well as multimodal neuroimaging signatures in 155 ASD and 151 neurotypical individuals, we observed robust evidence for a structure-function substrate of cognitive imbalances in ASD. Specifically, ASD presented with marked imbalances in cognitive profiles relative to neurotypical controls, characterized by verbal to non-verbal intelligence discrepancy. Different analytical approaches including subtyping and dimensional regression methods converged in showing that these imbalances were reflected in atypical cortical thickening and functional integration of language networks, alongside sensory and higher cognitive networks. Phenotypic findings could be replicated in an independent sample of 325 ASD and 569 neurotypical controls. Although verbal and non-verbal intelligence are currently considered as specifiers unrelated to the categorical diagnosis of autism, our results show that intelligence disparities are accentuated in ASD and relate to a consistent structure-function substrate affecting multiple brain networks. Our findings motivate the incorporation of cognitive imbalances in future autism research, which may help to parse the phenotypic heterogeneity of autism and potentially inform intervention-oriented subtyping.
... Adolescents with ASD also show age-dependent alterations in the connectivity between the frontal lobe and parietal region [24], which supports the notion that ASD is a dynamic developmental syndrome. Some of these anatomical abnormalities have been associated with extensive changes in myelination, excessive oxidative stress [25], glial activation [26], minicolumn pathology [27], abnormal neurogenesis, and neuronal migration [28,29]. Because the cerebral size in patients with ASD often correlates with functional deficits [30,31], these changes in the brain-growth pattern seem to be crucial to understand the symptomatology and etiology of ASD. ...
Article
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Autism Spectrum Disorder (ASD) is an early neurodevelopmental disorder that involves deficits in interpersonal communication, social interaction, and repetitive behaviors. Although ASD pathophysiology is still uncertain, alterations in the abnormal development of the frontal lobe, limbic areas, and putamen generate an imbalance between inhibition and excitation of neuronal activity. Interestingly, recent findings suggest that a disruption in neuronal connectivity is associated with neural alterations in white matter production and myelination in diverse brain regions of patients with ASD. This review is aimed to summarize the most recent evidence that supports the notion that abnormalities in the oligodendrocyte generation and axonal myelination in specific brain regions are involved in the pathophysiology of ASD. Fundamental molecular mediators of these pathological processes are also examined. Determining the role of alterations in oligodendrogenesis and myelination is a fundamental step to understand the pathophysiology of ASD and identify possible therapeutic targets.
... Furthermore, it could be helpful to understand as early as possible whether children with non-verbal or minimally verbal ASD have a CAS on the basis of neuroanatomical brain configuration, given the difficulty of directly testing these children. Grey matter volume increase is one of the most consistent structural findings in ASD, and it is particularly striking in younger children [20], thus supporting the early brain overgrowth of ASD related to abnormal cortical development and expansion [38,39]. It is of interest that the cortical volumes' increase found in our ASD children versus TD is mainly distributed in fronto-temporal lobes, known to be crucial for socio-communicative skills development [40]. ...
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Autism Spectrum Disorder (ASD) and Childhood Apraxia of Speech (CAS) are developmental disorders with distinct diagnostic criteria and different epidemiology. However, a common genetic background as well as overlapping clinical features between ASD and CAS have been recently reported. To date, brain structural language-related abnormalities have been detected in both the conditions, but no study directly compared young children with ASD, CAS and typical development (TD). In the current work, we aim: (i) to test the hypothesis that ASD and CAS display neurostructural differences in comparison with TD through morphometric Magnetic Resonance Imaging (MRI)-based measures (ASD vs. TD and CAS vs. TD); (ii) to investigate early possible disease-specific brain structural patterns in the two clinical groups (ASD vs. CAS); (iii) to evaluate predictive power of machine-learning (ML) techniques in differentiating the three samples (ASD, CAS, TD). We retrospectively analyzed the T1-weighted brain MRI scans of 68 children (age range: 34-74 months) grouped into three cohorts: (1) 26 children with ASD (mean age ± standard deviation: 56 ± 11 months); (2) 24 children with CAS (57 ± 10 months); (3) 18 children with TD (55 ± 13 months). Furthermore, a ML analysis based on a linear-kernel Support Vector Machine (SVM) was performed. All but one brain structures displayed significant higher volumes in both ASD and CAS children than TD peers. Specifically, ASD alterations involved fronto-temporal regions together with basal ganglia and cerebellum, while CAS alterations are more focused and shifted to frontal regions, suggesting a possible speech-related anomalies distribution. Caudate, superior temporal and hippocampus volumes directly distinguished the two conditions in terms of greater values in ASD compared to CAS. The ML analysis identified significant differences in brain features between ASD and TD children, whereas only some trends in the ML classification capability were detected in CAS as compared to TD peers. Similarly, the MRI structural underpinnings of two clinical groups were not significantly different when evaluated with linear-kernel SVM. Our results may represent the first step towards understanding shared and specific neural substrate in ASD and CAS conditions, which subsequently may contribute to early differential diagnosis and tailoring specific early intervention.
... For instance, the high rates of CFD and MCA in rare autism syndromes are strongly suggestive of a common biology despite genotypic variation. Despite the dearth of obvious brain malformations reported in our autism dataset, the high prevalence of microscopic dysplastic foci in idiopathic autism tends to validate this point [13,15,32,33]. ...
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Background Linking genotype to phenotype is a major aim of genetics research, yet many complex conditions continue to hide their underlying biochemical mechanisms. Recent research provides evidence that relevant gene-phenotype associations are discoverable in the study of intellectual disability (ID). Here we expand on that work, identifying distinctive gene interaction modules with unique enrichment patterns reflective of associated clinical features in ID. Methods Two hundred twelve forms of monogenic ID were curated according to comorbidities with autism and epilepsy. These groups were further subdivided according to secondary clinical symptoms of complex versus simple facial dysmorphia and neurodegenerative-like features due to their clinical prominence, modest symptom overlap, and probable etiological divergence. An aggregate gene interaction ID network for these phenotype subgroups was discovered using via a public database of known gene interactions: protein-protein, genetic, and mRNA coexpression. Additional annotation resources (Gene Ontology, Human Phenotype Ontology, TRANSFAC/JASPAR, and KEGG/WikiPathways) were utilized to assess functional and phenotypic enrichment modules within the full ID network. Results Phenotypic analysis revealed high rates of complex facial dysmorphia in ID with comorbid autism. In contrast, neurodegenerative-like features were overrepresented in ID with epilepsy. Network analysis subsequently showed that gene groups divided according to clinical features of interest resulted in distinctive interaction clusters, with unique functional enrichments according to module. Conclusions These data suggest that specific comorbid and secondary clinical features in ID are predictive of underlying genotype. In summary, ID form unique clusters, which are comprised of individual conditions with remarkable genotypic and phenotypic overlap.
... Kaplan, M., Edelson, S. M., & Seip, J. L. (1998) Our research group proposed that low frequency transcranial magnetic stimulation (rTMS) may affect lateral inhibition in minicolumns and improve executive functions and behavioral symptoms of autism spectrum disorder (ASD). This hypothesis was based on Casanova's "minicolumnopathy" theory of autism (Casanova 2005(Casanova , 2007Casanova et al., 2003) and its rationale is described in more detail in a recent publication (Casanova et al., 2015) and several chapters . Our proposal aimed at establishing an early stage trial of rTMS in children with autism was awarded a NIH Eureka R01 grant and the study resulted in numerous publications reporting positive outcomes for this neuromodulation approach Casanova et al., 2012;Sokhadze et al., 2009Sokhadze et al., , 2010Sokhadze et al., , 2012Sokhadze et al., , 2014bSokhadze et al., , 2016aSokhadze et al., , 2017Wang et al., 2016a). ...
... ASD is a complex, multifactorial disorder characterised by social, behavioural and language impairments evident from an early age. Although the aetiology of ASD remains unknown, neuropathological studies have identified cortical alterations including laminar and columnar disorganisation and increased neuronal density in frontal, temporal and cingulate cortices (Bailey et al. 1998;Casanova et al. 2002;Stoner et al. 2014;Uppal et al. 2014). Early evidence from MRI studies suggested that head growth is accelerated in ASD during infancy but differences appear to dissipate with age (Courchesne et al. 2001;Ecker et al. 2015). ...
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The structural organisation of the brain can be characterised as a hierarchical ensemble of segregated modules linked by densely interconnected hub regions that facilitate distributed functional interactions. Disturbances to this network may be an important marker of abnormal development. Recently, several neurodevelopmental disorders, including autism spectrum disorder (ASD), have been framed as disorders of connectivity but the full nature and timing of these disturbances remain unclear. In this study, we use non-negative matrix factorisation, a data-driven, multivariate approach, to model the structural network architecture of the brain as a set of superposed subnetworks, or network components. In an openly available dataset of 196 subjects scanned between 5 to 85 years we identify a set of robust and reliable subnetworks that develop in tandem with age and reflect both anatomically local and long-range, network hub connections. In a second experiment, we compare network components in a cohort of 51 high-functioning ASD adolescents to a group of age-matched controls. We identify a specific subnetwork representing an increase in local connection strength in the cingulate cortex in ASD (t=3.44, p<0.001). This work highlights possible long-term implications of alterations to the developmental trajectories of specific cortical subnetworks.
... For example, results from histological (Avino & Hutsler, 2010) and in vivo neuroimaging studies (Andrews et al., 2017;Bezgin, Lewis, & Evans, 2018;Hong, Valk, Di Martino, Milham, & Bernhardt, 2018;Mann et al., 2018) suggest that the GWM boundary is less well defined in ASD. This indistinct boundary is potentially due to an abnormal cell patterning at the GWM transition zone (Avino & Hutsler, 2010), with an excess of interstitial neurons distributed among the cortico-cortical U-fibers of the superficial white matter (Avino & Hutsler, 2010;Bailey et al., 1998;Casanova, Buxhoeveden, Switala, & Roy, 2002;Hutsler, Love, & Zhang, 2007;Simms, Kemper, Timbie, Bauman, & Blatt, 2009;Wegiel et al., 2010), which may result from deviations in fetal neuronal proliferation or decreased developmental apoptosis (Avino & Hutsler, 2010;Chun & Shatz, 1989; for a review, see McFadden & Minshew, 2013). Moreover, abnormalities at and around the GWM boundary have been inferred from a reduced graywhite matter tissue contrast (GWC) in ASD, which may be driven by increased T1-weighted signal intensity within the gray matter (Andrews et al., 2017). ...
Article
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Autism spectrum disorder (ASD) is a highly complex neurodevelopmental condition that is accompanied by neuroanatomical differences on the macroscopic and microscopic level. Findings from histological, genetic, and more recently in vivo neuroimaging studies converge in suggesting that neuroanatomical abnormalities, specifically around the gray‐white matter (GWM) boundary, represent a crucial feature of ASD. However, no research has yet characterized the GWM boundary in ASD based on measures of diffusion. Here, we registered diffusion tensor imaging data to the structural T1‐weighted images of 92 adults with ASD and 92 matched neurotypical controls in order to examine between‐group differences and group‐by‐sex interactions in fractional anisotropy and mean diffusivity sampled at the GWM boundary, and at different sampling depths within the superficial white and into the gray matter. As hypothesized, we observed atypical diffusion at and around the GWM boundary in ASD, with between‐group differences and group‐by‐sex interactions depending on tissue class and sampling depth. Furthermore, we identified that altered diffusion at the GWM boundary partially (i.e., ~50%) overlapped with atypical gray‐white matter tissue contrast in ASD. Our study thus replicates and extends previous work highlighting the GWM boundary as a crucial target of neuropathology in ASD, and guides future work elucidating etiological mechanisms. Full-text is available at: https://onlinelibrary.wiley.com/doi/full/10.1002/hbm.25237
... En personas con autismo se ha observado que estas minicolumnas son más pequeñas, más numerosas y están más cercanas las unas de las otras en el lóbulo frontal y temporal. Además, las neuronas que las componen están más separadas de lo normal (Casanova, Buxhoeveden, Switala & Roy, 2002a. Estas observaciones también se han recogido respecto a personas con síndrome de Asperger (Casanova, Buxhoeveden, Switala & Roy, 2002b). ...
Thesis
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Based on the distinction between "hot" and "cool" executive functions (Zelazo & Müller, 2002), a research line that aims to study the relationship between executive functions related to emotions (―hot") and socio-emotional deficits observed in ASD, began. The main objective of this study is to analyze the psychopathological correlates of emotional deficits in ASD. This work arises in this theoretical framework and aims to study socioemotional deficits in adults with autism, in relation to both "hot" and ―cool‖ executive dysfunctions, social maturity, autistic traits and comorbid psychopathology, specifying which variables influence or explain the perception of emotions in Autism Spectrum Disorders. Four experiments were designed, linked to the 4 general objectives of the research: 1. Confirm the presence of emotional perception deficits in adults with ASD, compared to the control group (no TEA). 2. Confirm the presence of deficits in executive functions attributed to the ASD group, compared to the control group (no TEA). 3. Specify which variables influence, or explain, the perception of emotions in adults with autism, in order to find out the nature of emotional deficits in people with autism. 4. Establish if certain emotional permeability exists in the experimental group (TEA), through a task of emotion induction.
... The peripheral neuropil space surrounds the minicolumn core and contains GABAergic interneurons, which are thought to protect the minicolumn by excessive excitatory inputs of neighboring minicolumns with repercussions on excitatory/inhibitory balance. This mechanism may in part explain the decreased seizure threshold seen in patients with autism [80,81]. A reduction in GABAergic inhibitory activity would be responsible for the high incidence of seizures and for hypersensitivity which is typical of patients with autism [82]. ...
Article
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Autism spectrum disorder is characterized by neurological, psychiatric and medical comorbidities-some conditions co-occur so frequently that comorbidity in autism is the rule rather than the exception. The most common autism co-occurring conditions are intellectual disability, language disorders, attention-deficit hyperactivity disorder, epilepsy, gastrointestinal problems, sleep disorders, anxiety, depression, obsessive-compulsive disorder, psychotic disorders, oppositional defiant disorder, and eating disorders. They are well known and studied. Migraine is the most common brain disease in the world, but surprisingly only a few studies investigate the comorbidity between autism and migraine. The aim of this narrative review is to explore the literature reports about the comorbidity between autism and migraine and to investigate the common neurotransmitter, immune, anatomical and genetic abnormalities at the base of these two conditions.
... However, there is evidence that the development and connection of GABAergic interneurons are interrupted in the frontal and temporal cortex of patients with ASD [58] leading to an excitatory/inhibitory imbalance [59]. Moreover, in patients with ASD, the minicolumns in layer III of the neocortex are increased in number but more "narrow", due to a reduction in the dendritic space [60], and this anomalous organization of minicolumns could determine a deficit of fibers and GABAergic tone [61]. ...
Article
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A large body of literature reports the higher prevalence of epilepsy in subjects with Autism Spectrum Disorder (ASD) compared to the general population. Similarly, several studies report an increased rate of Subclinical Electroencephalographic Abnormalities (SEAs) in seizure-free patients with ASD rather than healthy controls, although with varying percentages. SEAs include both several epileptiform discharges and different non-epileptiform electroencephalographic abnormalities. They are more frequently associated with lower intellectual functioning, more serious dysfunctional behaviors, and they are often sign of severer forms of autism. However, SEAs clinical implications remain controversial, and they could represent an epiphenomenon of the neurochemical alterations of autism etiology. This paper provides an overview of the major research findings with two main purposes: to better delineate the state-of-the-art about EEG abnormalities in ASD and to find evidence for or against appropriateness of SEAs pharmacological treatment in ASD.
... De nombreuses anomalies structurales sont retrouvées dans l'autisme, notamment au niveau des (Casanova, Buxhoeveden, Switala, & Roy, 2002), compte tenu des anomalies des interneurones inhibiteurs GABAergiques. Les stimulations ne restent pas à l'intérieur de ces minicolonnes, mais migrent vers des mini-colonnes proches qui amplifient leur effet (Levitt, Eagleson, & Powell, 2004). ...
Thesis
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Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by difficulties in social communication with restricted and repetitive behaviors, and cerebral abnormalities. The first project of this work shows abnormal resting-state brain connectivity using electroencephalography that can account for the multimodal integration difficulties that directly impact introspection processes. In the second project, we confirm autobiographical memory (ABM) atypicality in ASD adolescents, with an atypical sensory profile, but also the existence of a positive effect of prompting and visual cues during recall. Beyond, our work highlights the importance of the creation of ABM rehabilitation, realized in the third project. Preliminary results show a beneficial effect on the social identity of adolescents with autism. ABM is, therefore, very relevant to study in autism, integrating a unique and ecological multimodal dimension, and an interesting tool of rehabilitation.
... The more consistent findings were reported for the prefrontal cortex, the fusiform gyrus, the fronto-insular and cingulate cortices, the hippocampus, the amygdala and the cerebellum. Casanova and colleagues found minicolumn abnormalities in autism (Casanova et al. 2002(Casanova et al. , 2006; see also Varghese et al. 2017). The amygdala appears to be enlarged in children but not in adolescents with autism (Sparks et al. 2002;Schumann et al. 2004;Schumann and Amaral 2006). ...
Chapter
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The term “limbic” was first used in 1664 by Thomas Willis to describe the cortical structures on the medial side of the cerebral hemisphere, surrounding the brain stem. Two centuries later, Paul Broca noticed that the cingulate gyrus and the parahippocampal gyrus form a border (limbus) around the corpus callosum and the brain stem. Broca subdivided his grand lobe limbique into inner (the hippocampus) and outer (the cingulate and parahippocampal gyri) rings. During the last decades of the nineteenth century and the first decades of the twentieth century, it was generally believed that most if not all structures of Broca’s limbic lobe were dominated by olfactory input and therefore form part of the rhinencephalon. In 1937, James Papez proposed that these structures are involved in a closed circuit. The circuit of Papez includes projections from the hippocampus via the fornix to the mamillary body and then via the mamillothalamic tract of Vicq d’Azyr to the anterior thalamic nucleus, from here to the cingulate gyrus, and as last step from the cingulate gyrus back to the hippocampus. Papez suggested that his circuit formed the anatomical basis for emotions. In 1952, Paul MacLean included the circuit of Papez with the amygdala and the hypothalamus into his limbic system, supposed to be responsible for emotional behaviour (the “visceral” or “emotional” brain). Lennart Heimer promoted an expanded version of the classic limbic lobe of Broca, which contains all non-isocortical parts of the cerebral hemisphere together with the laterobasal-cortical amygdaloid complex, with several output channels in the basal forebrain. Thus defined, the limbic lobe contains all of the major cortical and amygdaloid structures known to be especially important for emotional and behavioural functions. Experimental studies in the early 1970s identified the output channels of the limbic lobe in the basal forebrain as the ventral striatopallidal system, the extended amygdala and the basal nucleus of Meynert.
... In the ACC, decreased neuronal size and cell packing have been reported in layers I-III [Simms, Kemper, Timbie, Bauman, & Blatt, 2009] as well as a reduction in pyramidal cell size in layer V and a correlation between Von Economo neurons and ASD severity [Uppal et al., 2014]. Even when neuronal abnormalities have not been identified, there have been findings of columnar or laminar disorganization in cortical regions [Casanova, Buxhoeveden, Switala, & Roy, 2002;Trutzer, García-Cabezas, & Zikopoulos, 2019]. It is possible that ASD neuronal pathology is the result of widely heterogeneous brain regional disconnections. ...
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Evidence for putative pathophysiological mechanisms of autism spectrum disorder (ASD), including peripheral inflammation, blood–brain barrier disruption, white matter alterations, and abnormal synaptic overgrowth, indicate a possible involvement of neuroinflammation in the disorder. Neuroinflammation plays a role in the development and maintenance of the dendritic spines involved in glutamatergic and GABAergic neurotransmission, and also influences blood–brain permeability. Cytokines released from microglia can impact the length, location or organization of dendritic spines on excitatory and inhibitory cells as well as recruit and impact glial cell function around the neurons. In this study, gene expression levels of anti‐ and pro‐inflammatory signaling molecules, as well as oligodendrocyte and astrocyte marker proteins, were measured in both gray and white matter tissue in the anterior cingulate cortex from ASD and age‐matched typically developing (TD) control brain donors, ranging from ages 4 to 37 years. Expression levels of the pro‐inflammatory gene, HLA‐DR, were significantly reduced in gray matter and expression levels of the anti‐inflammatory gene MRC1 were significantly elevated in white matter from ASD donors as compared to TD donors, but neither retained statistical significance after correction for multiple comparisons. Modest trends toward differences in expression levels were also observed for the pro‐inflammatory (CD68, IL1β) and anti‐inflammatory genes (IGF1, IGF1R) comparing ASD donors to TD donors. The direction of gene expression changes comparing ASD to TD donors did not reveal consistent findings implicating an elevated pro‐ or anti‐inflammatory state in ASD. However, altered expression of pro‐ and anti‐inflammatory gene expression indicates some involvement of neuroinflammation in ASD. Lay Summary The anterior cingulate cortex is an integral brain region in modulating social behaviors including nonverbal communication. The study found that inflammatory gene expression levels were altered in this brain region. We hypothesize that the inflammatory changes in this area could impact neuronal function. The finding has future implications in using these molecular markers to identify potential environmental exposures and distinct cell differences in autism. © 2020 International Society for Autism Research, Wiley Periodicals, Inc.
... In addition, in postmortem brain samples of ASD cases, a reduction was found of neocortical minicolumns, elemental modular microcircuits made up of excitatory pyramidal neurons surrounded by GABAergic inhibitory neurons, which could result in inhibitory circuits disruption [49]. Defects in GABAergic signaling, especially shifting the E/I balance toward excitatory transmission, may thereby explain some of the characteristics of oscillatory impairment in ASD with wide behavioral and cognitive dimensions [50]. ...
Article
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Intermittent photic stimulation (IPS) is a useful technique in electroencephalography (EEG) to investigate the neurophysiological anomalies of brain activity. Although not an active task, IPS has also been explored in ASD; it is thought to capture local potential oscillators at specific frequencies and perhaps tap into rhythmic activity in a way that general resting-state recordings cannot. Previous studies suggest that individuals with ASD showed photic driving reactivity predominantly at lower frequencies of stimulation. In our study we used IPS to measure rhythmic oscillatory activity in a sample of 81 ASD children. We found a significant correlation linking ASD children with photic driving activation only at low frequencies (δθ band) and increased severity of “restricted behavior”. This suggests that ASD children with higher severity of restricted behaviors could have a hypersynchronous θ power and an impaired resonance synchronization at middle-ranged frequencies (α). Furthermore, we found some evidence of hemispherical oscillatory asymmetry linked particularly to behavioral impairments. This result is in line with the EEG pattern model indicating a “U-shaped profile” of electrophysiological power alterations with excess power in low- and high-frequency bands and a reduction of power in the middle-ranged frequencies. IPS technique in electroencephalography is confirmed to reveal EEG biomarkers in autistic children, with a focus on spectral power, coherence, and hemisphere asymmetries.
... These include a role for cortical inhibitory interneurons in maintaining alpha oscillations (Lorincz et al. 2009), a role for thalamic "pacemaker" neurons (e.g., see Anderson and Sears 1964;Jahnsen and Llinás 1984;Steriade and Deschenes 1984), and an influence of the mGluR1a subtype of the metabotropic glutamate receptor located postsynaptically to corticothalamic fibers (Hughes et al. 2002). Studies investigating the above in individuals with ASD report abnormalities in all the above systems including an imbalance of excitatory (e.g., glutamatergic) and inhibitory (e.g., GABAergic) activity in inhibitory interneuron and pyramidal cell cortical networks (Casanova et al. 2002;Levitt et al. 2004), as well as studies reporting abnormal thalamic structure and connectivity in ASD (Hardan et al. 2006(Hardan et al. , 2008Nair et al. 2013;Tsatsanis et al. 2003). Studies examining associations between other brain measures (such as diffusion measures) and PAF are needed. ...
Article
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Associations between age, resting-state (RS) peak-alpha-frequency (PAF = frequency showing largest amplitude alpha activity), and thalamic volume (thalamus thought to modulate alpha activity) were examined to understand differences in RS alpha activity between children with autism spectrum disorder (ASD) and typically-developing children (TDC) noted in prior studies. RS MEG and structural-MRI data were obtained from 51 ASD and 70 TDC 6- to 18-year-old males. PAF and thalamic volume maturation were observed in TDC but not ASD. Although PAF was associated with right thalamic volume in TDC (R2 = 0.12, p = 0.01) but not ASD (R2 = 0.01, p = 0.35), this group difference was not large enough to reach significance. Findings thus showed unusual maturation of brain function and structure in ASD as well as an across-group thalamic contribution to alpha rhythms.
... For example, results from histological (Avino & Hutsler, 2010) and in vivo neuroimaging studies (Andrews et al., 2017;Bezgin, Lewis, & Evans, 2018;Hong, Valk, Di Martino, Milham, & Bernhardt, 2018;Mann et al., 2018) suggest that the GWM boundary is less well defined in ASD. This indistinct boundary is potentially due to an abnormal cell patterning at the GWM transition zone (Avino & Hutsler, 2010), with an excess of interstitial neurons distributed among the cortico-cortical U-fibers of the superficial white matter (Avino & Hutsler, 2010;Bailey et al., 1998;Casanova, Buxhoeveden, Switala, & Roy, 2002;Hutsler, Love, & Zhang, 2007;Simms, Kemper, Timbie, Bauman, & Blatt, 2009;Wegiel et al., 2010), which may result from deviations in fetal neuronal proliferation or decreased developmental apoptosis (Avino & Hutsler, 2010;Chun & Shatz, 1989; for a review, see McFadden & Minshew, 2013). Moreover, abnormalities at and around the GWM boundary have been inferred from a reduced graywhite matter tissue contrast (GWC) in ASD, which may be driven by increased T1-weighted signal intensity within the gray matter (Andrews et al., 2017). ...
... In particular, alpha desynchronization may be linked to increased neural excitability/decreased neural inhibition (6). Previous studies in ASD reported abnormal cortical inhibitory interneurons (79,80) and altered glutamatergic levels (81,82), associated with atypical sensory processing in ASD (73, 83). The excitation/inhibition imbalance increases neural noise in ASD and may lead to atypical sensory processing and under-responsiveness to behaviorally relevant stimuli in participants with ASD (72). ...
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Background Autism spectrum disorder (ASD) is associated with atypical neural activity in resting-state. Most of the studies have focused on abnormalities in alpha-frequency, as a marker of ASD dysfunctions. However, few have explored alpha synchronization, with a specific interest in resting-state networks: the default mode network (DMN), the sensorimotor network (SMN), and the dorsal attention network (DAN). These functional connectivity analyses provide relevant insight into the neurophysiological correlates of multimodal integration in ASD. Methods Using the high temporal resolution of EEG, the present study investigates the functional connectivity in the alpha band within and between the DMN, SMN, and the DAN. We examined eyes-closed EEG alpha lagged phase synchronization, using standardized Low-Resolution Brain Electromagnetic Tomography (sLORETA) in 29 participants with ASD and 38 age,- sex- and IQ-matched typically developing (TD) controls. Results We observed reduced functional connectivity in the ASD group relative to TD controls, within and between the DMN, the SMN, and the DAN. We identified three hubs of dysconnectivity in ASD: the posterior cingulate cortex, the precuneus, and the medial frontal gyrus. These three regions also presented decreased current source density in the alpha band. Conclusion These results may account for impairments in multimodal - sensory and internal information - integration frequently observed in ASD. Underconnectivity potentially involves difficulties switching between this externally oriented attention and internally oriented thoughts and, more broadly, may impact embodied cognition.
... The ability to discriminate stimuli relies on the ability to separate spatially distinct signals, which has been linked to GABA-mediated lateral inhibition (Puts et al., 2011(Puts et al., , 2017Sapey-Triomphe et al., 2019;Tommerdahl et al., 2010). Thus, elevated thresholds observed in our study could be explained, at least in part, by reduced GABAergic inhibition in early childhood autism, likely due to altered local circuitry (Casanova et al., 2003;Casanova et al., 2002). This Wang Y. et al., 2017). ...
Article
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We assessed different aspects of tactile perception in young children (3–6 years) with autism. Autistic and neurotypical children completed vibrotactile tasks assessing reaction time, amplitude discrimination (sequential and simultaneous) and temporal discrimination (temporal order judgment and duration discrimination). Autistic children had elevated and more variable reaction times, suggesting slower perceptual-motor processing speed and/or greater distractibility. Children with autism also showed higher amplitude discrimination and temporal order judgement thresholds compared to neurotypical children. Tactile perceptual metrics did not associate with social or tactile sensitivities measured by parent-reports. Altered tactile behavioral responses appear in early childhood, can be quantified but appear dissociated from sensitivity. This implies these measures are complementary, but not necessarily related, phenomena of atypical tactile perception in autism.
... This may influence neuronal networks, and consequently explain the enlarged volumes in ASD during two to four years of age. For instance, greater density of minicolumns and smaller width between these minicolumns in the frontal lobe have been observed more frequently in autistic than N-ASD post-mortem cases older than four years of age [41,42]. Minicolumns are locally connected neuronal networks with radial neuronal projections that function as an essential cortical information processing unit [43]. ...
Article
Frontal lobe volume has been extensively researched in individuals with Autism spectrum disorder (ASD), though findings are yet to be summarised to explain the developmental trends of frontal lobe volume. The aim of the present study is to consolidate all existing frontal lobe volume and age data of autistic individuals below 30 years of age, and compare this data to non-autistic (N-ASD) controls. Following a systematic review, frontal lobe volume data were obtained from seven papers. Raw data, or the means and standard deviations of frontal lobe volume, and age, were obtained from the studies giving 372 autistic and 190 N-ASD participants. Data were plotted and analysed. Findings revealed that regression lines of fit for ASD (R2L⁢i⁢n⁢e⁢a⁢r = 0.33; R2Q⁢u⁢a⁢d⁢r⁢a⁢t⁢i⁢c = 0.52) and N-ASD (R2L⁢i⁢n⁢e⁢a⁢r = 0.14; R2Q⁢u⁢a⁢d⁢r⁢a⁢t⁢i⁢c = 0.39) were significantly different by diagnosis (linear p = 0.002, quadratic p = 0.02) with quadratic models providing significantly better fit within ASD (p < 0.001) and N-ASD (p < 0.001). Additional analyses revealed that frontal lobe volume was greater in autistic individuals than N-ASD between two and four years (F(1,31) = 12.965, p < 0.005, η2 = 0.291). In the present study, there were distinct developmental trends for frontal lobe volume between ASD and N-ASD.
... In ASD subjects, several studies identified a combination of atypical structural and functional features in these areas. Structurally, cortical and subcortical measurements in ASD postmortem brain tissue, primarily in frontal and temporal cortices and the amygdala, described an aberrant organization, such as small cell size and increased packing density [49,50], white matter volume increase [51], decreased cortical thickness [52], and more numerous and narrower minicolumns [53]. Functionally, a growing number of studies used fMRI to examine changes in intrinsic functional connectivity (FC) of specific Figure 1. ...
Article
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Autism spectrum disorders (ASD) are pervasive neurodevelopmental disorders that include a variety of forms and clinical phenotypes. This heterogeneity complicates the clinical and experimental approaches to ASD etiology and pathophysiology. To date, a unifying theory of these diseases is still missing. Nevertheless, the intense work of researchers and clinicians in the last decades has identified some ASD hallmarks and the primary brain areas involved. Not surprisingly, the areas that are part of the so-called “social brain”, and those strictly connected to them, were found to be crucial, such as the prefrontal cortex, amygdala, hippocampus, limbic system, and dopaminergic pathways. With the recent acknowledgment of the cerebellar contribution to cognitive functions and the social brain, its involvement in ASD has become unmistakable, though its extent is still to be elucidated. In most cases, significant advances were made possible by recent technological developments in structural/functional assessment of the human brain and by using mouse models of ASD. Mouse models are an invaluable tool to get insights into the molecular and cellular counterparts of the disease, acting on the specific genetic background generating ASD-like phenotype. Given the multifaceted nature of ASD and related studies, it is often difficult to navigate the literature and limit the huge content to specific questions. This review fulfills the need for an organized, clear, and state-of-the-art perspective on cerebellar involvement in ASD, from its connections to the social brain areas (which are the primary sites of ASD impairments) to the use of monogenic mouse models.
... On the one hand, the brains of ASD children pay similar attention to all stimuli at the same time, causing a flood of information in the brain; on the other hand, they must actively abandon some irrelevant information during post-processing, which becomes a bottleneck of information processing. Functional neuroimaging studies have shown that when ASD children participate in social activities, their brains tend to rely on primary senses to process information, and lack higher-order processing as that of ordinary brains , Casanova et al. 2002, Critchley et al. 2000, Pierce et al. 2001, Schultz et al. 2000. If a newly born child relies on an overactive sensory processing system that is extremely low in screening ability, high-order cognitive processes will be suppressed by the large number of stimuli in the surroundings (Belmonte and Yurgelun-Todd 2003). ...
... Histological studies have suggested several potential cellular substrates associated with connectome miswiring of autism, including altered cortical lamination 94-97 and columnar 98,99 , together with atypical neuronal migration that can result in cortical blurring 95,100 and changes in spine density of cortical projection neurons 101,102 . Such cellular changes may impact the functional organization of cortical microcircuits in autism, a possibility supported by molecular studies in animals 4,[22][23][24][25]103,104 . ...
Article
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The pathophysiology of autism has been suggested to involve a combination of both macroscale connectome miswiring and microcircuit anomalies. Here, we combine connectome-wide manifold learning with biophysical simulation models to understand associations between global network perturbations and microcircuit dysfunctions in autism. We studied neuroimaging and phenotypic data in 47 individuals with autism and 37 typically developing controls obtained from the Autism Brain Imaging Data Exchange initiative. Our analysis establishes significant differences in structural connectome organization in individuals with autism relative to controls, with strong between-group effects in low-level somatosensory regions and moderate effects in high-level association cortices. Computational models reveal that the degree of macroscale anomalies is related to atypical increases of recurrent excitation/inhibition, as well as subcortical inputs into cortical microcircuits, especially in sensory and motor areas. Transcriptomic association analysis based on postmortem datasets identifies genes expressed in cortical and thalamic areas from childhood to young adulthood. Finally, supervised machine learning finds that the macroscale perturbations are associated with symptom severity scores on the Autism Diagnostic Observation Schedule. Together, our analyses suggest that atypical subcortico-cortical interactions are associated with both microcircuit and macroscale connectome differences in autism. Autism is increasingly recognized to impact multiple scales of neural organization. Here, the authors show alterations in individuals with autism relative to typically developing controls, with findings particularly pointing to atypically organized subcortical-cortical networks.
... Autism spectrum disorder (MIM 209850) comprises a heterogeneous group of early onset neurodevelopmental diseases characterized by impairments in social-communicative skills and repetitive behaviors (APA, 2013) that affects at least 1.5% of the population worldwide (Christensen et al., 2016). The most consistent neuropathological findings in patients with ASD include increased cortical surface area during early childhood (Miles et al., 2000;Hazlett et al., 2011) and reduced number of Purkinje cells in the cerebellum (Allen, 2005) possibly due to abnormal progenitor cell neurogenesis, altered cortical organization (presence of heterotopias and more frequent and narrower minicolumns) suggestive of abnormal neuronal migration (Casanova et al., 2002;Whitney et al., 2008;Stoner et al., 2014), and increased cortical dendritic spine densities possibly due to defective synapse elimination during brain development (Hutsler and Zhang, 2010;Tang et al., 2014). Recent molecular genetic studies have identified a specific cause for ASD in almost 30% of the cases, while in the remaining cases the underlying pathogenic mechanisms may involve complex genetic and environmental risk factors (Bourgeron, 2015). ...
Article
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Current evidence indicates that certain immune molecules such as components of the complement system are directly involved in neurobiological processes related to brain development, including neurogenesis, neuronal migration, synaptic remodeling, and response to prenatal or early postnatal brain insults. Consequently, complement system dysfunction has been increasingly implicated in disorders of neurodevelopmental origin, such as schizophrenia, autism spectrum disorder (ASD) and Rett syndrome. However, the mechanistic evidence for a causal relationship between impaired complement regulation and these disorders varies depending on the disease involved. Also, it is still unclear to what extent altered complement expression plays a role in these disorders through inflammation-independent or -dependent mechanisms. Furthermore, pathogenic mutations in specific complement components have been implicated in the etiology of 3MC syndrome, a rare autosomal recessive developmental disorder. The aims of this review are to discuss the current knowledge on the roles of the complement system in sculpting brain architecture and function during normal development as well as after specific inflammatory insults, such as maternal immune activation (MIA) during pregnancy, and to evaluate the existing evidence associating aberrant complement with developmental brain disorders.
... Finally, a diffusion tensor imaging (DTI) study would inform our understanding of structural connectivity between the amygdala and the prefrontal cortex and its relationship to 5-HTTLPR genotype. Such research may highlight the relevance of the present finding to the differences in cortical connection size and number observed between ASD and TD individuals linked to serotonin (Casanova et al., 2002;Janušonis et al., 2004). ...
Thesis
Appropriate emotion regulation is a necessary mechanism for social development. The amygdala is a brain structure involved in emotion perception and processing whereas the ventral prefrontal cortex (vPFC) has been linked to the regulation of amygdala activity. The purpose of this dissertation is to investigate the functional correlates of developmental and genetic aspects in the amygdala -vPFC network. Chapter 2 of this dissertation focuses on the effects of white matter integrity on amygdala activation in response to emotional faces. We conducted diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI) analyses in a sample consisting of typically developing (TD) adolescents and young adults. This chapter reports three main findings. First, participant age predicted amygdala activation in response to faces in general, but not in the comparison of specific faces. Specifically, younger subjects exhibited greater amygdala activation than older subjects. Second, white matter integrity increased with age in our cross-sectional sample of adolescents and young adults. Third, higher white matter integrity was related to lower amygdala activation in response to both fearful and sad faces compared to neutral faces, but not to happy vs. neutral faces. Chapter 3 investigated the contribution of 5-HTTLPR variant genotype on amygdala- vPFC functional connectivity in adolescents with autism spectrum disorder (ASD). We hypothesized a diagnosis (ASD vs. TD) by genotype (low vs. higher expressing serotonin transporter gene variant) interaction on amygdala-vPFC connectivity. We expected greater connectivity in individuals with ASD and low expressing 5-HTTLPR genotypes, in response to emotional faces (fearful, happy, and sad) compared to neutral faces. Individuals in the low expressing ASD group showed significantly greater connectivity than the ASD higher expressing group and both TD groups in response to happy relative to neutral faces. The interaction was not observed in response to sad and fearful faces.With the use of fMRI, DTI, and genetic work, the present dissertation contributes to the understanding of emotion regulation development in typically developing individuals as well as in individuals with ASD.
... They also presented strong evidence for an association between that reverberation and various clinical features in patients (e.g., delusions, anhedonia-asociality). Impaired inhibition has been strongly associated with autism [30][31][32][33][34]. A question that arises naturally is, therefore, whether circular inferences are present in ASD, and whether they would then be of the same nature as in schizophrenia (e.g., sensory vs prior reverberation). ...
Article
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Autism spectrum disorders have been proposed to arise from impairments in the probabilistic integration of prior knowledge with sensory inputs. Circular inference is one such possible impairment, in which excitation-to-inhibition imbalances in the cerebral cortex cause the reverberation and amplification of prior beliefs and sensory information. Recent empirical work has associated circular inference with the clinical dimensions of schizophrenia. Inhibition impairments have also been observed in autism, suggesting that signal reverberation might be present in that condition as well. In this study, we collected data from 21 participants with self-reported diagnoses of autism spectrum disorders and 155 participants with a broad range of autistic traits in an online probabilistic decision-making task (the fisher task). We used previously established Bayesian models to investigate possible associations between autistic traits or autism and circular inference. There was no correlation between prior or likelihood reverberation and autistic traits across the whole sample. Similarly, no differences in any of the circular inference model parameters were found between autistic participants and those with no diagnosis. Furthermore, participants incorporated information from both priors and likelihoods in their decisions, with no relationship between their weights and psychiatric traits, contrary to what common theories for both autism and schizophrenia would suggest. These findings suggest that there is no increased signal reverberation in autism, despite the known presence of excitation-to-inhibition imbalances. They can be used to further contrast and refine the Bayesian theories of schizophrenia and autism, revealing a divergence in the computational mechanisms underlying the two conditions.
Article
Despite decades of research, the brain basis of aberrant face processing in autism spectrum disorder (ASD) remains a topic of debate. The mid‐fusiform sulcus (MFS), a minor feature of the ventral occipitotemporal cortex, provides new directions for studying face processing. The MFS closely aligns with face‐selective cortical patches and other structural and functional divisions of the fusiform gyrus; however, it has received little attention in clinical populations. We collected structural MRI data from 54 individuals with ASD and 61 age‐and‐IQ‐matched controls ages 8 to 40 years. The MFS was identified on cortical surface reconstructions via 4 trained raters and classified into known surface patterns. Mean MFS gray matter volume (GMV), cortical surface area (SA), cortical thickness (CT), and standard deviation of CT (CT SD) were extracted. Effects of diagnosis, age, and hemisphere on MFS surface presentation and morphometry were assessed via multinomial logistic regression and mixed effects general linear modeling, respectively. The MFS was reliably identified in 97% of hemispheres examined. Macroanatomical patterns and age‐related decreases in MFS GMV and CT were similar between groups. CT SD was greater in the left hemisphere in ASD. Participants' ability to interpret emotions and mental states from facial features was significantly negatively correlated with MFS CT and CT SD. Overall, the MFS is a stable feature of the fusiform gyrus in ASD and CT related measures appear to be sensitive to diagnosis and behavior. These results can inform future investigations of face processing and structure–function relationships in populations with social deficits. Lay Summary A small structural feature of the brain related to seeing faces (the mid‐fusiform sulcus; MFS) appears similar in autism spectrum disorder (ASD) and neurotypical development; however, the thickness of this structure on the left side of the brain is more variable in ASD. People who are better at judging mental states from another person's eyes tend to have thinner and less variable MFS. This feature may teach us more about face processing and how brain structure influences function in ASD.
Article
Resumen Antecedentes En pacientes con autismo se han descrito anomalías estructurales cerebrales, pero los estudios realizados son de pequeño tamaño y contradictorios. Quisimos identificar qué regiones cerebrales de los pacientes con autismo pueden considerarse diferentes de las de los controles sanos. Métodos Se realizó una búsqueda sistemática de estudios de resonancia magnética del tamaño de diversas regiones cerebrales. Se recogieron datos y se combinaron por medio de un metaanálisis de efectos aleatorios. Se investigaron los efectos sobre la variabilidad de la edad y del CI por medio de meta-regresión. Resultados El cerebro completo, los hemisferios cerebrales, el cerebelo y el núcleo caudado tenían mayor volumen, pero el área del cuerpo calloso estaba reducida. La edad y el CI modificaron los lóbulos del vérmix cerebeloso VI-VII, y la edad, la amígdala. Conclusiones El autismo podría deberse a anomalías de regiones específicas del cerebro y a una falta de integración global debida al aumento de tamaño del cerebro. Los resultados contradictorios en la literatura se deben en parte a la edad y al CI de las poblaciones del estudio. Algunas regiones muestran alteraciones de las trayectorias de crecimiento.
Article
Background Autism spectrum disorder (ASD) is a common neurodevelopmental diagnosis showing substantial phenotypic heterogeneity. A leading example can be found in verbal and nonverbal cognitive skills, which vary from elevated to impaired compared with neurotypical individuals. Moreover, deficits in verbal profiles often coexist with normal or superior performance in the nonverbal domain. Methods To study brain substrates underlying cognitive imbalance in ASD, we capitalized categorical and dimensional IQ profiling as well as multimodal neuroimaging. Results IQ analyses revealed a marked verbal to nonverbal IQ imbalance in ASD across 2 datasets (Dataset-1: 155 ASD, 151 controls; Dataset-2: 270 ASD, 490 controls). Neuroimaging analysis in Dataset-1 revealed a structure–function substrate of cognitive imbalance, characterized by atypical cortical thickening and altered functional integration of language networks alongside sensory and higher cognitive areas. Conclusion Although verbal and nonverbal intelligence have been considered as specifiers unrelated to autism diagnosis, our results indicate that intelligence disparities are accentuated in ASD and reflected by a consistent structure–function substrate affecting multiple brain networks. Our findings motivate the incorporation of cognitive imbalances in future autism research, which may help to parse the phenotypic heterogeneity and inform intervention-oriented subtyping in ASD.
Thesis
Le problème de la pharmacorésistance est un phénomène courant en médecine et qui n’épargne pas la psychiatrie. Au même titre qu’on parle « d’épilepsie résistante », on parle de « dépression ou de schizophrénie résistante ». L’autisme est une situation un peu différente dans la mesure où il n’existe pas de traitement de référence pour les troubles du neurodéveloppement. Ces trois troubles, néanmoins, constituent des enjeux majeurs de santé publique tant du point de vue économique que sociétal, avec d’importantes répercussions fonctionnelles pour les patients. Après nous être interrogés dans une première partie sur la définition même de la pharmacorésistance dans la dépression, la schizophrénie et l’autisme et sur les mécanismes physiopathologiques possiblement impliqués dans leur genèse, nous avons recherché ce qui pouvait être commun à ces troubles. Cette démarche nous a permis de comprendre comment optimiser leurs traitements. Différentes techniques d’optimisation des traitements sont à la disposition des cliniciens et incluent la potentialisation des médicaments entre eux ou encore la potentialisation des médicaments par des techniques de neurostimulation (l’électroconvulsivothérapie, ECT, la stimulation magnétique transcrânienne répétitive, rTMS, ou la stimulation transcrânienne à courant continu, tDCS). Dans une seconde partie de ce travail, nous avons étudié différentes approches d’optimisation des traitements : l’utilisation de la clozapine dans les troubles du comportement à type d’agressivité dans l’autisme ; l’utilisation de la tDCS dans les troubles des fonctions exécutives toujours dans l’autisme ; la potentialisation de la clozapine par l’ECT dans la schizophrénie résistante et enfin la potentialisation de l’ECT par la rTMS dans la dépression résistante. Les résultats encourageants que nous avons obtenus nous amènent à réfléchir sur les mécanismes d’action de ces techniques de potentialisation, notamment l’ECT et sur l’élaboration de protocoles nous permettant de confirmer nos résultats.
Chapter
Autism spectrum disorders (ASDs) are complex neuro-developmental disorders. They demonstrate pervasive deficits in social communication, restricted and repetitive behaviors, cognitive impairments, etc. Most often individuals with ASDs are often considered “non-verbal” and they require comprehensive intervention to improve their functional communication skills. Augmentative and alternative communication (AAC) was always viewed as a “last resort” for people with complex communication needs when all other interventions failed to achieve the potential benefit. However, with growing evidence, AAC has been implemented even in children with communication difficulties to augment spoken language development. Thus, this chapter aims to discuss the characteristics of ASD, to describe the need for AAC intervention in children with ASD, challenges and practices of AAC in ASD, to review implementation of aided AAC systems for children with ASD in different contexts, to indicate the gaps and future prospective in AAC intervention for people with ASDs.
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A bstract Both macroscale connectome miswiring and microcircuit anomalies have been suggested to play a role in the pathophysiology of autism. However, an overarching framework that consolidates these macro and microscale perspectives of the condition is lacking. Here, we combined connectome-wide manifold learning and biophysical simulation models to understand associations between global network perturbations and microcircuit dysfunctions in autism. Our analysis established that autism showed significant differences in structural connectome organization relative to neurotypical controls, with strong effects in low-level somatosensory regions and moderate effects in high-level association cortices. Computational models revealed that the degree of macroscale anomalies was related to atypical increases of subcortical inputs into cortical microcircuits, especially in sensory and motor areas. Transcriptomic decoding and developmental gene enrichment analyses provided biological context and pointed to genes expressed in cortical and thalamic areas during childhood and adolescence. Supervised machine learning showed the macroscale perturbations predicted socio-cognitive symptoms and repetitive behaviors. Our analyses provide convergent support that atypical subcortico-cortical interactions may contribute to both microcircuit and macroscale connectome anomalies in autism.
Article
Post-mortem studies allow for the direct investigation of brain tissue in those with autism and related disorders. Several review articles have focused on aspects of post-mortem abnormalities but none has brought together the entire post-mortem literature. Here, we systematically review the evidence from post-mortem studies of autism, and of related disorders that present with autistic features. The literature consists of a small body of studies with small sample sizes, but several remarkably consistent findings are evident. Cortical layering is largely undisturbed, but there are consistent reductions in minicolumn numbers and aberrant myelination. Transcriptomics repeatedly implicate abberant synaptic, metabolic, proliferation, apoptosis and immune pathways. Sufficient replicated evidence is available to implicate non-coding RNA, aberrant epigenetic profiles, GABAergic, glutamatergic and glial dysfunction in autism pathogenesis. Overall, the cerebellum and frontal cortex are most consistently implicated, sometimes revealing distinct region-specific alterations. The literature on related disorders such as Rett syndrome, Fragile X and copy number variations (CNVs) predisposing to autism is particularly small and inconclusive. Larger studies, matched for gender, developmental stage, co-morbidities and drug treatment are required.
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Full-text available
Autism spectrum disorders have been proposed to arise from impairments in the probabilistic integration of prior knowledge with sensory inputs. Circular inference is one such possible impairment, in which excitation-to-inhibition imbalances in the cerebral cortex cause the reverberation and amplification of prior beliefs and sensory information. Recent empirical work has associated circular inference with the clinical dimensions of schizophrenia. Inhibition impairments have also been observed in autism, suggesting that signal reverberation might be present in that condition as well. In this study, we collected data from 21 participants with diagnosed autism spectrum disorders and 155 participants with a broad range of autistic traits in an online probabilistic decision-making task (the fisher task). We used previously established Bayesian models to investigate possible associations between autism or autistic traits and circular inference. No differences in prior or likelihood reverberation were found between autistic participants and those with no diagnosis. Similarly, there was no correlation between any of the circular inference model parameters and autistic traits across the whole sample. Furthermore, participants incorporated information from both priors and likelihoods in their decisions, with no relationship between their weights and psychiatric traits, contrary to what common theories for both autism and schizophrenia would suggest. These findings suggest that there is no increased signal reverberation in autism, despite the known presence of excitation-to-inhibition imbalances. They can be used to further contrast and refine the Bayesian theories of schizophrenia and autism, revealing a divergence in the computational mechanisms underlying the two conditions.
Article
Despite decades of research, the brain basis of aberrant face processing in autism spectrum disorder (ASD) remains a topic of debate. The mid-fusiform sulcus (MFS), a minor feature of the ventral occipitotemporal cortex, provides new directions for studying face processing. The MFS closely aligns with face-selective cortical patches and other structural and functional divisions of the fusiform gyrus; however, it has received little attention in clinical populations. We collected structural MRI data from 54 individuals with ASD and 61 age-and-IQ-matched controls ages 8 to 40 years. The MFS was identified on cortical surface reconstructions via 4 trained raters and classified into known surface patterns. Mean MFS gray matter volume (GMV), cortical surface area (SA), cortical thickness (CT), and standard deviation of CT (CT SD) were extracted. Effects of diagnosis, age, and hemisphere on MFS surface presentation and morphometry were assessed via multinomial logistic regression and mixed effects general linear modeling, respectively. The MFS was reliably identified in 97% of hemispheres examined. Macroanatomical patterns and age-related decreases in MFS GMV and CT were similar between groups. CT SD was greater in the left hemisphere in ASD. Participants' ability to interpret emotions and mental states from facial features was significantly negatively correlated with MFS CT and CT SD. Overall, the MFS is a stable feature of the fusiform gyrus in ASD and CT related measures appear to be sensitive to diagnosis and behavior. These results can inform future investigations of face processing and structure-function relationships in populations with social deficits. Autism Res 2020, 00: 1-12. Lay Summary: A small structural feature of the brain related to seeing faces (the mid-fusiform sulcus; MFS) appears similar in autism spectrum disorder (ASD) and neurotypical development; however, the thickness of this structure on the left side of the brain is more variable in ASD. People who are better at judging mental states from another person's eyes tend to have thinner and less variable MFS. This feature may teach us more about face processing and how brain structure influences function in ASD.
Article
Despite growing knowledge about autism spectrum disorder (ASD), research findings have not been translated into curative treatment. At present, most therapeutic interventions provide for symptomatic treatment. Outcomes of interventions are judged by subjective endpoints (e.g., behavioral assessments) which alongside the highly heterogeneous nature of ASD account for wide variability in the effectiveness of treatments. Transcranial magnetic stimulation (TMS) is one of the first treatments that targets a putative core pathological feature of autism, specifically the cortical inhibitory imbalance that alters gamma frequency synchronization. Studies show that low frequency TMS over the dorsolateral prefrontal cortex (DLPC) of individuals with ASD decreases the power of gamma activity and increases the difference between gamma responses to target and non-target stimuli. TMS improves executive function skills related to self-monitoring behaviors and the ability to apply corrective actions. These improvements manifest themselves as a reduction of stimulus bound behaviors and diminished sympathetic arousal. Results become more significant with increasing number of sessions and bear synergism when used along with neurofeedback. When applied at low frequencies in individuals with ASD, TMS appears to be safe and to improve multiple patient-oriented outcomes. Future studies should be conducted in large populations to establish predictors of outcomes (e.g., genetic profiling), length of persistence of benefits, and utility of booster sessions.
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Prior studies have used functional neuroimaging to demonstrate that the organization of the autistic brain is different from that of the non-autistic brain. Similarly, patients with epilepsy have also shown cortical reorganization. We present a case study that provides direct confirmation of disorganized sensorimotor distribution in a patient with autism spectrum disorder and epilepsy. To our knowledge, this is the first time cortical mapping directly showing abnormal cortical organization in a patient with autism spectrum disorder and epilepsy has been reported in the literature.
Article
Autism Spectrum Disorder (ASD) is a highly heterogeneous neurodevelopmental disorder characterized by deficits in social communication and by patterns of restricted interests and/or repetitive behaviors. The Simons Foundation Autism Research Initiative’s Human Gene and CNV Modules now list over 1,000 genes implicated in ASD and over 2,000 copy number variant loci reported in individuals with ASD. Given this ever-growing list of genetic changes associated with ASD, it has become evident that there is likely not a single genetic cause of this disorder nor a single neurobiological basis of this disorder. Instead, it is likely that many different neurobiological perturbations (which may represent subtypes of ASD) can result in the set of behavioral symptoms that we called ASD. One such of possible subtype of ASD may be associated with dopamine dysfunction. Precise regulation of synaptic dopamine (DA) is required for reward processing and behavioral learning, behaviors which are disrupted in ASD. Here we review evidence for DA dysfunction in ASD and in animal models of ASD. Further, we propose that these studies provide a scaffold for scientists and clinicians to consider subcategorizing the ASD diagnosis based on the genetic changes, neurobiological difference, and behavioral features identified in individuals with ASD.
Article
The mechanistic underpinnings of autism remain a subject of debate and controversy. Why do individuals with autism share an overlapping set of atypical behaviors and symptoms, despite having different genetic and environmental risk factors? A major challenge in developing new therapies for autism has been the inability to identify convergent neural phenotypes that could explain the common set of symptoms that result in the diagnosis. Although no striking macroscopic neuropathological changes have been identified in autism, there is growing evidence that inhibitory interneurons (INs) play an important role in its neural basis. In this Review, we evaluate and interpret this evidence, focusing on recent findings showing reduced density and activity of the parvalbumin class of INs. We discuss the need for additional studies that investigate how genes and the environment interact to change the developmental trajectory of INs, permanently altering their numbers, connectivity and circuit engagement. This Review discusses evidence from human studies and mouse models that cortical interneurons are involved in the pathophysiology of autism and that parvalbumin cell hypofunction may be a primary driver of circuit dysfunction in autism.
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This study proposes a Computer-Aided Diagnostic (CAD) system to diagnose subjects with autism spectrum disorder (ASD). The CAD system identifies morphological anomalies within the brain regions of ASD subjects. Cortical features are scored according to their contribution in diagnosing a subject to be ASD or typically developed (TD) based on a trained machine-learning (ML) model. This approach opens the hope for developing a new CAD system for early personalized diagnosis of ASD. We propose a framework to extract the cerebral cortex from structural MRI as well as identifying the altered areas in the cerebral cortex. This framework consists of the following five main steps: (i) extraction of cerebral cortex from structural MRI; (ii) cortical parcellation to a standard atlas; (iii) identifying ASD associated cortical markers; (iv) adjusting feature values according to sex and age; (v) building tailored neuro-atlases to identify ASD; and (vi) artificial neural networks (NN) are trained to classify ASD. The system is tested on the Autism Brain Imaging Data Exchange (ABIDE I) sites achieving an average balanced accuracy score of 97±2%. This paper demonstrates the ability to develop an objective CAD system using structure MRI and tailored neuro-atlases describing specific developmental patterns of the brain in autism.
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The cerebral cortex is divisible into a number of cytoarchitectonic areas, but developmental mechanisms that regulate their number and size remain unknown. Here we provide evidence that reducing the population of selected thalamic fibers projecting into the primary visual cortex (area 17) of monkeys during midgestation induces the formation of a novel cytoarchitectonic area situated along the border of and embedded within area 17. This region, termed area X, differs cytoarchitectonically from both area 17 and the adjacent secondary visual cortex (area 18). We propose that an aberrant combination of thalamic and cortical connections acting on a portion of prospective area 17 deprived of its normal thalamic input may result in formation of a hybrid cortex. Our results support the protomap hypothesis of cortical parcellation and suggest how during evolution new cytoarchitectonic regions may arise by cell-cell interactions that depend on a unique combination of intrinsic properties of cortical neurons and afferent fibers.
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In the human primary and secondary auditory cortices the neuron somata are arranged in distinct columnar clusters. Measurements on their diameters and the intervals between them yield significant hemispherical differences, having in all cases greater values in the left hemisphere. Computer-assisted tracings of Golgi-impregnated dendritic trees of 300 neurons show the expected types. An analysis of the columnar structure of the dendritic trees indicates varying degrees of specificity in collecting information from their surroundings. An analysis of their tangential extent shows that in the primary cortices a greater extent in the left hemisphere effectively cancels the differences in columnar widths and intervals, allowing for a similar dendritic connectivity among columns in both hemispheres. In the secondary cortex this connectivity is greater on the right side.
Article
The modular organization of nervous systems is a widely documented principle of design for both vertebrate and invertebrate brains of which the columnar organization of the neocortex is an example. The classical cytoarchitectural areas of the neocortex are composed of smaller units, local neural circuits repeated iteratively within each area. Modules may vary in cell type and number, in internal and external connectivity, and in mode of neuronal processing between different large entities; within any single large entity they have a basic similarity of internal design and operation. Modules are most commonly grouped into entities by sets of dominating external connections. This unifying factor is most obvious for the heterotypical sensory and motor areas of the neocortex. Columnar defining factors in homotypical areas are generated, in part, within the cortex itself. The set of all modules composing such an entity may be fractionated into different modular subsets by different extrinsic connections. Linkages between them and subsets in other large entities form distributed systems. The neighborhood relations between connected subsets of modules in different entities result in nested distributed systems that serve distributed functions. A cortical area defined in classical cytoarchitectural terms may belong to more than one and sometimes to several distributed systems. Columns in cytoarchitectural areas located at some distance from one another, but with some common properties, may be linked by long-range, intracortical connections.
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More than 20,000 autopsy reports from several general hospitals were surveyed for the purpose of selecting brains without a pathological lesion that had been weighed in the fresh condition. From this number, 2,773 males and 1,963 females were chosen for whom body weight, body height, and cause of death had been recorded. The data were segregated into 23 age groups ranging from birth to 86+ years and subjected to statistical evaluation. Overall, the brain weights in males were greater than in females by 9.8%. The largest increases in brain weights in both sexes occurred during the first 3 years of life, when the value quadruples over that at birth, while during the subsequent 15 years the brain weight barely quintuples over that at birth. Progressive decline in brain weight begins at about 45 to 50 years of age and reaches its lowest values after age 86 years, by which time the mean brain weight has decreased by about 11% relative to the maximum brain weight attained in young adults (about 19 years of age). Computed regression lines for brain weights versus body heights and body weights and for ratios of brain weights to body heights and weights versus age groups show clearly differential rates of change in brain weights which are less affected by sex.
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In the parietal cortex of the rat, sections cut tangentially show that profiles of medium and large apical dendrites are grouped into clusters. The number of apical dendrites in each cluster is variable and the usual separation between individual clusters is about 50 μ. Despite these variations the pattern does not appear to be random. Reconstructions from one micron serial sections show that neurons giving rise to the ascending dendrites forming clusters are located at different levels in layer V. The cell bodies of these neurons are arranged vertically below their dendrites and show a tendency to form groups. All of the neurons have apical dendrites that ascend through the cortex with a few secondary branches occurring close to the base. The principal secondary branching begins in layer III and spreads obliquely up through layer I. Furthermore, beginning in the inferior region of layer III apical dendrites are added to the clusters at their peripheries. These are from layer III pyramids. It is clear that the superior aspects of the cluster arrangements must intermingle with those of the neurons in adjacent clusters. The neuropil surrounding the dendrites forming clusters appears to contain a few smaller dendrites. Small unmyelinated axons are the most frequent component of the surrounding neuropil and these form terminals which synapse on the spines and trunks of the clustered dendrites. There is no obvious function that can be ascribed to the clusters other than they may form a component of the columnar organization in cortex described in part by physiological techniques.
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The superior temporal region (STR) in the rhesus monkey includes the circular sulcus (Cis), the supratemporal plane (STP), and the superior temporal gyrus (STG). Rostrally the STR is continuous with the periallocortices of the prepyriform and anterior insular regions; caudally it borders the isocortices of the inferior parietal lobule and the superior temporal sulcus. The STR contains 12 cytoarchitectonic areas: four fields on the Cis, four on the STP, and four on the STG. The sulcal fields (root fields) are adjacent to the insula and resemble it in the possession of a relatively strong layer V; the STP fields (core fields) are characterized by well-developed layer IV; and the STG fields (belt fields) exhibit strong differentiation of layer III. In each line of fields the more rostral ones show relative prominence of the deeper layers, with increasing prominence of the superficial layers occurring caudad in a stepwise fashion. Analysis of the connectional organization of the fields within the STR suggests an assembly of four rostrocaudal stages, each composed of one field from each line–a root, a core, and a belt field. There is a specific arrangement of connections among the fields of a given stage and between fields in adjacent stages. Projections directed caudally from one field to another field in the adjacent stage arise in layers V and VI and terminate in the superficial layers (mainly layer I). Projections directed to a field in a rostrally adjacent stage arise from layer III neurons and terminate in layers III and IV, usually in columns. There is also a laminar specificity between fields lying within a given stage.
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Structural asymmetries between the hemispheres are found in the human brain. Asymmetries in the auditory regions and in the Sylvian fissures are present even in the fetus. The Sylvian asymmetries may have existed in Neanderthal man and are found consistently in some apes. They may relate to right-left differences infunction. Thus, the striking auditory asymmetries could underlie language lateralization. The asymmetries in the frontal and occipital lobes and the lateral ventricles are correlated with hand preference. Anatomical asymmetries may help to explain the range of human talents, recovery from acquired disorders of language function, certain childhood learning disabilities, some dementing illnesses of middle life, and the evidence for behavioral lateralization in nonhuman primates.
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The auditory regions in four normal brains were mapped and the full extent of the cytoarchitectonic subdivisions was measured for the presence of right-left asymmetries. It was found that asymmetries similar to those found in the planum temporale (left commonly larger than right) are also seen in auditory cytoarchitectonic area Tpt, and area of probable importance for language function. There is a strong positive correlation between the planum asymmetry and the asymmetry of Tpt. It is concluded that the previously described planum asymmetries probably reflect asymmetries in an auditory cytoarchitectonic area and therefore may represent, at least in part, the anatomic substrate for language lateralization.
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Immunocytochemical methods were used to study 28,000 mol. wt calbindin and tachykinin immunoreactivity in the monkey cerebral cortex. Calbindin and tachykinin immunoreactivity give rise to a generally different pattern of staining of cell bodies and terminal-like puncta. However, the staining of long, vertically-oriented bundles of processes—identical to classical double bouquet cell axonal arborizations— is the most prominent feature of the pattern of both calbindin- and tachykinin-immunoreactive staining. These bundles form a widespread and regular columnar system descending from layer II to layers III-V. The bundles are most evident in layer III where, in tangential sections, they have a density of 7–15 bundles/10,000 μm2 with a center-to-center spacing of 15–30 μm.
Article
Since its initial description in 1943,1 autism has been primarily conceptualized as a behavioral disorder, and for many years it was believed to be the result of parental and environmental influences. With heightened clinical interest in the disorder, coincident with advances in medical technology, however, evidence for an underlying neurologic basis for autism has become increasingly apparent. HISTORICAL NEUROPATHOLOGIC PERSPECTIVE Based largely on the constellation of symptoms that characterize the disorder, various anatomical sites within the brain have been suggested as a possible primary source of pathology in autism. Suspected regions have included the medial temporal lobe,2-5 the thalamic nuclei,6 the basal ganglia,7 and the vestibular system.8 Computed tomographic imaging studies have shown inconsistent findings.9-14 More recently, however, magnetic resonance imaging studies have described abnormalities in portions of the cerebellum and posterior fossa.15-17 Direct microscopic examination of the autistic brain has, until recently, yielded little information. Aarkrog18 reported "slight thickening of the arterioles, slight connective tissue increase in the leptomeninges, and some cell increase" in a frontal lobe biopsy performed on an autistic patient. Later, in 1976, 33 cases of childhood psychosis were reviewed by Darby.19 Although he suggested a possible correlation between limbic system lesions and the affective symptomatology of autism, no consistent neuropathologic findings were found. In 1980, Williams et al20 studied sections of brain from four patients with autistic-like behavior; looking primarily for cell loss and gliosis, they failed to find any consistent abnormalities. MICROSCOPIC NEUROANATOMIC OBSERVATIONS In 1984, anatomic abnormalities were reported in the brain of a 29-year-old man with well-documented autism; the technique of whole brain serial section was used, and the patient was studied in comparison with an identically processed age- and sex-matched control subject.21,22
Article
Early infantile autism is a behaviorally defined syndrome that is often associated with abnormalities on neurologic examination and seizures. We report on the brain of a 29-year-old autistic man as compared with that of an age- and sex-matched normal control, using gapless sections of whole brain. Abnormalities were found in the hippocampus, subiculum, entorhinal cortex, septal nuclei, mamillary body, selected nuclei of the amygdala, neocerebellar cortex, roof nuclei of the cerebellum, and inferior olivary nucleus.
Article
IN 1943 KANNER,~ describing the clinical features of 11 cases, delineated a syndrome of childhood which he called ‘early infantile autism’. More recently EISENBERG and KANNER~ have summarized the early findings, enumerating 5 characteristic features of the syndrome : (a) the inability to relate to people ‘from the beginning of life’; (b) failure to use language in order to communicate; (c) an obsession for maintaining sameness; (d) preoccupation with objects; (e) evidence of ‘good cognitive potentialities’. In the same paper these authors go on to say: “in the light of experience with a ten-fold increase in clinical material, we would now isolate these two pathognomic features, both of which must be present: extreme self-isolation and the obsessive insistence on the preservation of sameness, features that may be regarded as primary. . . . ” The aims of the present study are (i) to describe and quantify the ‘free-field’ behaviour of such a group of children; (ii) to present an analysis of their electroencephalograms including some preliminary telemetry data; and (iii) to suggest a possible neurophysiological hypothesis to account for the two sets of findings. The patients studied were ten children, nine boys and one girl whose average age was 3 years 10 months. The criteria for their inclusion in the study were (i) that in each case the diagnosis of autism should have been made independently by at least two clinicians; and (ii) that none of the patients should have evidence of anatomical cerebral damage. The possibility of misclassification is an ever present hazard in all research employing nosological entities. Having decided, however, to accept the diagnosis of autism made by the two clinicians, it was strictly adhered to, despite any possible reservations on the part of the writers. In retrospect, it appears that all children manifested the first four of the diagnostic signs listed by EISENBERG and KANNER (idem) including the two ‘primary’ features. It is debatable whether all children showed evidence of ‘good cognitive potentialities’. This however is the most difficult feature to assess, since these children are largely
Article
To compare the size and pattern of the terminal distribution of corticocortical projections in two primate species with brains of different size, tritiated amino acids were injected into the prefrontal cortex of New World squirrel monkeys (Saimiri sciureus) and Old World rhesus monkeys (Macaca mulatta), and their brains were processed for light microscopic autoradiography. In both species, prefrontal efferents are directed to a number of cortical targets in the same and opposite hemispheres, where in coronal sections, they generally terminate as radially oriented columns. In the rhesus monkey, the median width of the columns in transverse sections is 685 micrometers. In squirrel monkey, corresponding columns have a median with of 555 micrometers. Considering that the volume of the neocortex in rhesus monkey is approximately 4.5 x larger than that of squirrel monkey, the dimensions of cortical columns in the two species are surprisingly similar. This finding suggests that phylogenetic expansion in cortical surface area is accompanied by an increase in the number, rather than the width of afferent fiber columns. The increase in number of modular units may be relevant to the increasing computational and information processing capacity of the cerebral cortex in the course of evolution.
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A new cytoarchitectonic study of the human auditory cortex was undertaken in the light of recent knowledge concerning the architecture, fiber connectivity, and physiology of this region in the monkey. The survey of three normative human brains (six hemispheres) processed in whole-brain serial sections disclosed a cytoarchitectonic organization of the cortical auditory region similar to that in the macaque. Unlike the monkey, auditory-related cortex was found in parietal operculum and inferior parietal lobule. Similarities in cortical architectonics between human and monkey brains may provide a rationale for the application of knowledge concerning animal physiology and connectivity to man.
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The calculation of volume fractions in nervous tissue is a method often used in neuroanatomy. In ontogenetic studies and problems concerning aging, as well as after experimental procedures, volume fractions are calculated in order to quantify the results. Grey level index (GLI) and grey cell coefficient (GCC) are different parameters correlated to the volume density of cellular elements in nervous tissue. The grey cell coefficient (GCC) is defined as the volume fraction of cellular elements in a griseum (grey matter area) and is estimated by a basic stereological method (point counting) from observations in two dimensions. The grey level index (GLI), measured with an automatic image analyzer, is the areal proportion of projected profiles of all stained elements within a volume given by the area of the measuring field and the thickness of section. GLI and GCC are compared in specimens obtained by a special histological procedure, and a method to estimate volume fractions by means of GLI-measurement is described.
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The more than 1000-fold increase in the cortical surface without a comparable increase in its thickness during mammalian evolution is explained in the context of the radial-unit hypothesis of cortical development. According to the proposed model, cortical expansion is the result of changes in proliferation kinetics that increase the number of radial columnar units without changing the number of neurons within each unit significantly. Thus, mutation of a regulatory gene(s) that controls the timing and ratio of symmetric and asymmetric modes of cell divisions in the proliferative zone, coupled with radial constraints in the distribution of migrating neurons, could create an expanded cortical plate with enhanced capacity for establishing new patterns of connectivity that are validated through natural selection.
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The human prefrontal cortex can be divided into structurally and functionally distinct cytoarchitectonic areas, but the extent of individual variation in the position, size, and shape of these areas is unknown. Using criteria described in the preceding companion article (Rajkowska and Goldman-Rakic, 1995), as well as visual inspection, we have mapped areas 9 and 46 in the frontal lobe of seven postmortem human brains, and completely reconstructed these dorsolateral regions in five of the seven cases. The lateral reconstructions in these five cases were analyzed and superimposed on the lateral view of the Talairach and Tournoux (1988) coordinate system in such a way as to render both the variability and the regions of overlap for the two prefrontal areas in the five different brains. Based on this exercise, we developed a set of conservative Talairach coordinates to define area 9 and 46. Area 9 is located on the dorsal, lateral, and dorsomedial surfaces of the frontal lobe extending along the middle third of the superior frontal gyrus and adjacent portions of the middle frontal gyrus in all cases examined. Area 46 lies on the dorsolateral convexity and is either partially or completely surrounded by area 9. It is consistently found on one or more convolutions of the middle frontal gyrus. The superior border of area 46 with adjacent cortex is also variable within the middle and superior frontal sulci, as is the inferior border within the upper wall of the inferior frontal sulcus. The genuine variability in the morphology of the human frontal lobe indicated by our findings suggests that the differences among the classical maps of Brodmann, von Economo and Koskinas, and Sarkissov and others may have been due to normal variation among the brains they analyzed. Such variation may underlie individual differences in the visuospatial and cognitive capacities subserved by these areas.
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The classical cytoarchitectonic maps of human prefrontal areas produced by various cartographers in the early part of this century, though similar in gross topography, differ from one another in their descriptions of the size, shape, and precise location of specific regions within the frontal promontory. The current advances in human neurobiology stimulated us to reinvestigate the cytoarchrtecture of the human prefrontal cortex, beginning with areas 9 and 46, to establish a set of objective cytometric criteria for identification of these areas. Nissl-stained and Galh/as-stained celloidin-embedded sections were prepared from the left hemispheres of 17 human subjects 23–73 years old, without history of neurological disease. In eight cases, light microscopic observations were supplemented by morphometric data collected on a research microscope equipped with differential interference contrast optics and interfaced to a TV monitor with video mixing equipment and a microcomputer. We used the three-dimensional counting method of Williams and Rakic (1988) to measure (1) total cortical and relative laminar thickness, (2) neuronal packing density per 0.001 mm³ in individual cortical layers, and (3) sizes of neuronal somata in selected cortical layers. Light microscopic analysis confirmed that the cortical layers are more differentiated in area 46 than in area 9, particularly at the borders of layer IV. Layers III and V exhibit clearer sublamination in area 9, while layer IV is also somewhat wider in area 46 than in area 9 (9.3% vs 6.4% of cortical thickness); the overall thickness of the cortex is the same in both areas. Cytometric analysis revealed that layer IV neurons of area 46 are more densely packed than those in area 9 (55.38 ± 726 vs 45.80 ± 4.45 neurons/0.001 mm³), as are neurons in the supragranular layers II and III combined (53.51 ± 6.33 vs 45.69 ± 3.81 neurons/0.001 mm³). Finally, neurons in area 46 are more homogeneous in size than those in area 9. Differences in myeloarchitecture are also evident each area contains numerous, well-stained radial striae and two pronounced bands of horizontal fibers, but in general, area 46 is less myelinated than area 9. Objective cytometric methods can clearly distinguish two adjacent areas within the human prefrontal lobe. These findings may prove useful in the areal parcellation of the human cerebral cortex as well as provide a baseline for analysis of pathological changes in neurological and psychiatric disorders such as a schizophrenia, Huntington's or Alzheimer's diseases.
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The spatial organization of human cingulate (areas 24b, 23b, and 31) and pericingulate (areas 7 and 19) cortex was examined by using an image analyzer to measure characteristics of vertically oriented, translaminar columns of neurons in the cerebral cortex. Columns of 30-50 microns in diameter are hypothesized to be a general feature of cortical organization, but no quantitative analysis of different human cortical areas has been performed. Our results prove for the first time that a columnar organization was detectable in every area examined. The average width of cell columns was approximately 40 microns separated by a neuropil-rich fascicle of the same dimension. Because differences in the expression of a columnar organization were seen, the degree of columnization was subsequently expressed by a verticality index (VI) revealing specific changes in its dimension depending on the architectonic area. The VI was calculated by a linear combination of three variables derived from the measurement of cell density profiles in Nissl-stained sections at right angles to vertically oriented cell columns. Variables included the amplitude of profile peaks, the standard deviation of the width of those profile peaks, and the standard deviation of the distances between profile peaks. The index of verticality describes the deviation of a distinct area and layer from the mean degree of vertical organization of all cortical areas and layers examined. Thus, different degrees of columnar organization can be quantitatively described by the verticality index and can be used as criteria to characterize architectonic areas.
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Cytoarchitectonic area TA1 (von Economo) in the cortex of the planum temporale within the Sylvian fissure, which is auditory association cortex and documented to be part of the neural substrate of language functions, was studied quantitatively in the brain specimens of five women and four men (mean age of 50 year). All cases were documented to be medically and cognitively normal, and consistently right-handed. We investigated the possibility that the difference in brain size between men and women is reflected in differences in the numerical density of neurons in area TA1, an area associated with morphologic and psychological sex differences. Neuron counts were made directly through cell differentiation under the microscope from Nissl-stained sections. Cortical depth, the number of neurons through the depth of cortex under 1 mm2 of cortical surface (Nc), and the number of neurons per unit volume (Nv) were obtained for the total cortex and for each of the six layers in each hemisphere. For total cortex in both hemispheres, depth and Nc were similar, but Nv was greater by 11% in women, with no overlap of scores between the sexes. The sex difference in Nv was attributable to layers II and IV; in contrast, Nv did not differ between the sexes in layers III, V, and VI. This is the first report of such a sex difference in human cortex. The results suggest that the cortical functional unit has a different ratio of input and output components in men and women which could have implications for the sex differences in cognition and behavior. Due to the small sample size and the homogeneity of the cases studied, generalizability of the results requires replication by other studies. In addition, cytoarchitectonic mapping indicated that area TA1 also occurs in the vertical posterior wall of the Sylvian fissure, providing evidence that anatomical definition of the planum temporale should include the posterior vertical wall of the superior temporal gyrus.
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In this article we describe some functional properties of the model of a somatosensory cortical macrocolumn--the segregate--described in the preceding companion article. These functional properties emerged in the model network in the course of stimulus-driven self-organization of its afferent connections under control of short-range inhibitory and longer-range excitatory lateral interactions among its minicolumns. In general, self-organization leads the model network to develop complex, nonlinear functional properties, and makes its neurons sensitive to the shape and temporal features of peripheral stimuli. The properties acquired reproduce some of the known properties of somatosensory and visual cortical networks. In particular, it is shown that, even though the network is exposed only to stationary point stimuli during self-organization, neurons in the model still acquire the ability to discriminate the direction of a moving stimulus, as well as the orientation of a stationary bar stimulus. Different stimulus directions and orientations are represented by different neurons in the model network, and the maps of neurons having these preferences have many properties in common with real cortical maps. In addition, we demonstrate the model network's ability to discriminate among spatially complex stimuli, such as letters of the alphabet. The parallels between the emergent structural and functional properties of the model network and the properties of sensory neocortex suggest that the model captures some of the basic mechanisms by which sensory cortical modules develop and maintain their elegantly detailed and appreciable information-processing capabilities.
Article
This series of two articles develops a hypothesis on the modular organization of somatosensory cortex. The hypothesis is built around two functional entities: the segregate, a discrete somatosensory cortical macrocolumn approximately 0.5 mm in diameter, and the minicolumn, a smaller column approximately 0.05 mm in diameter, 40-80 of which make up a segregate. The hypothesis proposes that during perinatal development, minicolumns, acting via their short-range inhibitory and longer-range excitatory lateral connections, play an important role in the selection of thalamic connections to neighboring minicolumns. More specifically, the thalamic connections to each minicolumn are shaped by the interaction of that minicolumn primarily with those neighbors that belong to the same segregate. The outcome of this within-segregate self-organizational process is that (1) the minicolumns in a segregate acquire a complex but orderly pattern of afferent connections; (2) this connectional pattern, along with lateral inhibition, gives the minicolumns diverse receptive fields, arranged in a shuffled but orderly manner; and, most importantly, (3) the minicolumns and the segregate as a whole acquire a variety of stimulus feature-extracting properties. A computer-based model of a segregate is developed to show that under conditions found in the developing cerebral cortex, the thalamocortical connections within a segregate readily form complex patterns as proposed by the hypothesis. Furthermore, the connectional patterns developed by the model segregate, its receptive field organization, and its feature-extracting properties (the latter are described in the following article) reproduce many experimentally observed features of real cortical networks.
Article
The distribution of stimulus-evoked 14C-2-deoxyglucose (2DG) labeling in primary somatosensory cortex (SI) of monkey (Macaca fascicularis) and cat was investigated. Reconstructions of the global pattern of labeling reveal that discrete skin stimuli evoke activity within an extensive region of SI, and that the activation pattern typically consists of multiple, elongated regions of above-background labeling ("modules," typically 0.5-1.0 mm wide, and 1-4 mm long). Evidence obtained using recently developed methods (Tommerdahl, 1989) for quantitative analysis of 2DG activity patterns is shown to be consistent with the idea (Whitsel et al., 1991) that SI modules typically are bounded by zones dominated by stimulus-evoked inhibition. The labeling pattern within individual 2DG modules in SI of both cats and monkeys is analyzed quantitatively (in the frequency domain). Within-module spatial activation patterns are demonstrated to be periodic, consisting of radially oriented profiles of above-background labeling separated from each other by less strongly labeled radial profiles. The spectral characteristics of within-module 2DG labeling change systematically with location along the module's long axis: spatial frequencies between 18 and 35 cycles/mm are prominent in the labeling that occupies both the middle and upper layers at central locations in the module, but are a less obvious component of the labeling in both the middle and upper layers at locations remote to the module center. Since the radially oriented periodic variation both (1) in 2DG labeling in regions of SI outside modules and (2) in optical density in images of Nissl-stained sections of SI consists predominantly of spatial frequencies in the range of 18-35 cycles/mm, it is concluded that the radial profiles of labeling within individual 2DG modules correspond to groupings of minicolumns distinguishable from their neighbors on the basis of labeling intensity. The findings raise the possibility that highly structured, within-module spatial patterns of SI minicolumnar activation encode information about the physical properties of tactile stimuli.
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Autism is a behaviorally defined syndrome in which neuropathological abnormalities have been identified in the limbic system and cerebellum. The morphology of hippocampal neurons in two cases of infantile autism was studied and compared to age-matched controls. CA4 neurons in autistic children were smaller in perikaryon area and dendritic branching of both CA4 and CA1 neurons was less than in controls. These findings are consistent with previous studies and suggest a curtailment in maturation in the pathogenesis of autism.
Article
In addition to the horizontal bands of myelinated axons that produce the line of Gennari and the inner band of Baillarger, the macaque primary visual cortex contains prominent vertical bundles of myelinated axons. In tangential sections through layer IVC, these axon bundles are regularly arranged. They have a mean center-to-center spacing of about 23 μm, and each one contains an average of 34 (S.D. ± 13) myelinated axons. These bundles seem to be largely composed of efferent fibers, because in material in which pyramidal cells have been labelled in layer II/III and in layers IVA and IVB the axons of these neurons descend towards the white matter in bundles. However, it is doubtful whether all of the descending myelinated axons from the superficial layers emerge from the cortex, since counts show that the bundles contain maximum numbers of myelinated axons at the level of layer IVC, and that in layers V and VI their number is reduced by about 30%. Perhaps some of the axons enter the line of Baillarger, in layer V.
Article
The modular organization of nervous systems is a widely documented principle of design for both vertebrate and invertebrate brains of which the columnar organization of the neocortex is an example. The classical cytoarchitectural areas of the neocortex are composed of smaller units, local neural circuits repeated iteratively within each area. Modules may vary in cell type and number, in internal and external connectivity, and in mode of neuronal processing between different large entities; within any single large entity they have a basic similarity of internal design and operation. Modules are most commonly grouped into entities by sets of dominating external connections. This unifying factor is most obvious for the heterotypical sensory and motor areas of the neocortex. Columnar defining factors in homotypical areas are generated, in part, within the cortex itself. The set of all modules composing such an entity may be fractionated into different modular subsets by different extrinsic connections. Linkages between them and subsets in other large entities form distributed systems. The neighborhood relations between connected subsets of modules in different entities result in nested distributed systems that serve distributed functions. A cortical area defined in classical cytoarchitectural terms may belong to more than one and sometimes to several distributed systems. Columns in cytoarchitectural areas located at some distance from one another, but with some common properties, may be linked by long-range, intracortical connections.
Article
Auditory cortex of macaque monkeys can be divided into a core of primary or primary-like areas located on the lower bank of the lateral sulcus, a surrounding narrow belt of associated fields, and a parabelt region just lateral to the belt on the superior temporal gyrus. We determined patterns of ipsilateral cortical connections of the parabelt region by placing injections of four to seven distinguishable tracers in each of five monkeys. Results were related to architectonic subdivisions of auditory cortex in brain sections cut parallel to the surface of artificially flattened cortex (four cases) or cut in the coronal plane (one case). An auditory core was clearly apparent in these sections as a 16- to 20-mm rostrocaudally elongated oval, several millimeters from the lip of the sulcus, that stained darkly for parvalbumin, myelin, and acetylcholinesterase. These features were most pronounced caudally in the cortex assigned to auditory area I, only slightly reduced in the rostral area, and most reduced in the narrower rostral extension we define as the rostrotemporal area. A narrow band of cortex surrounding the core stained more moderately for parvalbumin, acetylcholinesterase, and myelin. Two regions of the caudal belt, the caudomedial area, and the mediolateral area, stained more darkly, especially for parvalbumin. Rostromedial and medial rostrotemporal, regions of the medial belt stained more lightly for parvalbumin than the caudomedial area or the lateral belt. The parabelt region stained less darkly than the core and belt fields. Injections confined to the parabelt region labeled few neurons in the core, but large numbers in parts of the belt, the parabelt, and adjacent portions of the temporal lobe. Injections that encroached on the belt labeled large numbers of neurons in the core and helped define the width of the belt. Caudal injections in the parabelt labeled caudal portions of the belt, rostral injections labeled rostral portions, and both caudal and rostral injections labeled neurons in the rostromedial area of the medial belt. These observations support the concept of dividing the auditory cortex into core, belt, and parabelt; provide evidence for including the rostral area in the core; suggest the existence of as many as seven or eight belt fields; provide evidence for at least two subdivisions of the parabelt; and identify regions of the temporal lobe involved in auditory processing.
Article
The auditory cortex of macaque monkeys contains a core of primary-like areas surrounded by a narrow belt of associated fields that encompass much of the superior temporal plane in these animals. Adjacent to the lateral belt on the superior temporal gyrus is a parabelt region that contains at least two subdivisions (rostral and caudal). In a previous study (Hackett et al. [1998] J. Comp. Neurol. 394:475-495), we determined that the parabelt has topographic connections with the belt areas surrounding the core, but minimal connections with the core itself. In this study, we describe the thalamocortical connections of the parabelt auditory cortex based on multiple injections of neuronal tracers into this region in each of five macaque monkeys. Injections confined to the parabelt labeled large numbers of neurons in the dorsal (MGd) and magnocellular (MGm) divisions of the medial geniculate complex (MGC), suprageniculate (Sg), limitans (Lim), and medial pulvinar (PM) nuclei. Only when injections encroached on the lateral belt cortex were substantial numbers of labeled neurons found in the ventral (MGv) division of the MGC, consistent with the absence of significant connections between the parabelt and core fields. The rostrocaudal topography of the parabelt region was maintained in the thalamocortical connections, supporting the parcellation of this region of cortex. The results suggest that the parabelt region represents a third level of auditory cortical processing, which is not influenced by direct inputs from primary cortical or subcortical auditory structures.
Article
In the present study, we determined connections of three newly defined regions of auditory cortex with regions of the frontal lobe, and how two of these regions in the frontal lobe interconnect and connect to other portions of frontal cortex and the temporal lobe in macaque monkeys. We conceptualize auditory cortex as including a core of primary areas, a surrounding belt of auditory areas, a lateral parabelt of two divisions, and adjoining regions of temporal cortex with parabelt connections. Injections of sever