Neuronal migration disorders

Neuronal migration disorders are a category of developmental brain disorders leading to cortical dysplasia. This group of disorders is characterized by defective movement of neurons from the place of origin along the lining of the lateral ventricle, to the eventual place of residence in the correct laminar position within the cerebral cortex. As a result of defective migration, affected individuals typically display mental retardation and epilepsy. Although patients with the more severe forms of these disorders often present during infancy, patients may present at any age from newborn to adulthood. The migration defect may be generalized or focal, and may be disturbed at any of several stages, leading to several distinct radiographical and clinical presentations. The human phenotypes suggests that there are at least four distinct and clinically-important steps in cortical neuronal migration, and the identification of the responsible genes suggests that multiple cellular processes are critical for correct neuronal positioning.     

Cellular abnormalities and synaptic plasticity in seizure disorders of the immature nervous system

The nervous system has an enhanced capacity to generate seizures during a restricted phase of postnatal development. Studies in animals and particularly in in vitro brain slices from hippocampus and neocortex have been instrumental in furthering an understanding of the underlying processes. Developmental alterations in glutaminergic excitatory synaptic transmission appear to play a key role in the enhanced seizure susceptible of rodents during the second and third week of life. Prior to this period, the number of excitatory synapses is relatively low. The scarcity of connections and the inability of the existing synapses to release glutamate when activated at high frequencies likely contribute importantly to the resistance of neonates to seizures. However, at the beginning of week 2, a dramatic outgrowth of excitatory synapses occurs, and these synapses are able to faithfully follow activation at high frequencies. These changes, coupled with the prolonged nature of synaptic potentials in early life, likely contribute to the ease of seizure generation. After this time, seizure susceptibility declines, patterns of local synaptic connectivity remodel, and some synapses are pruned. Concurrently, the duration of excitatory postsynaptic potentials shortens due at least in part to a switch in the subunit composition of postsynaptic receptors. Other studies have examined the mechanisms underlying chronic epilepsy initiated in early life. Models of both cortical dysplasia and recurrent early-life seizures suggest that alterations in the normal development of excitatory synaptic transmission can contribute importantly to chronic epileptic conditions. In the recurrent early-life seizure model, abnormal use-dependent selection of subpopulations of excitatory synapses may play a role. In experimental cortical dysplasia, alterations in the molecular composition of postsynaptic receptor are observed that favor subunit combinations characteristic of infancy.     

The specialized structure of human language cortex: pyramidal cell size asymmetries within auditory and language-associated regions of the temporal lobes

Functional lateralization of language within the cerebral cortex has long driven the search for structural asymmetries that might underlie language asymmetries. Most examinations of structural asymmetry have focused upon the gross size and shape of cortical regions in and around language areas. In the last 20 years several labs have begun to document microanatomical asymmetries in the structure of language-associated cortical regions. Such microanatomic results provide useful constraints and clues to our understanding of the biological bases of language specialization in the cortex. In a previous study we documented asymmetries in the size of a specific class of pyramidal cells in the superficial cortical layers. The present work uses a nonspecific stain for cell bodies to demonstrate the presence of an asymmetry in layer III pyramidal cell sizes within auditory, secondary auditory and language-associated regions of the temporal lobes. Specifically, the left hemisphere contains a greater number of the largest pyramidal cells, those that are thought to be the origin of long-range cortico-cortical connections. These results are discussed in the context of cortical columns and how such an asymmetry might alter cortical processing. These findings, in conjunction with other asymmetries in cortical organization that have been documented within several labs, clearly demonstrate that the columnar and connective structure of auditory and language cortex in the left hemisphere is distinct from homotopic regions in the contralateral hemisphere.     

Exploring face perception in disorders of development: Evidence from Williams syndrome and autism

Individuals with Williams syndrome (WS) and autism are characterized by different social phenotypes but have been said to show similar atypicalities of face‐processing style. Although the structural encoding of faces may be similarly atypical in these two developmental disorders, there are clear differences in overall face skills. The inclusion of both populations in the same study can address how the profile of face skills varies across disorders. The current paper explored the processing of identity, eye‐gaze, lip‐reading, and expressions of emotion using the same participants across face domains. The tasks had previously been used to make claims of a modular structure to face perception in typical development. Participants with WS (N=15) and autism (N=20) could be dissociated from each other, and from individuals with general developmental delay, in the domains of eye‐gaze and expression processing. Individuals with WS were stronger at these skills than individuals with autism. Even if the structural encoding of faces appears similarly atypical in these groups, the overall profile of face skills, as well as the underlying architecture of face perception, varies greatly. The research provides insights into typical and atypical models of face perception in WS and autism.     

Self-Determination and Empowerment: A Feminist Standpoint Analysis of Talk about Disability

In this paper we offer a feminist analysis of talk about self-determination and empowerment in the context of disability, focusing on the case of developmental disabilities. We find strains of the same patterns feminist epistemologists have argued shape the organization of formal knowledge from the standpoint of the privileged. At the extreme, people with developmental disabilities appear as objects without selves, outside of the context of interpersonal and social structural relationships that constrain who they can be by defining them as other, often in multiple and interacting ways. Empowerment, from the dominant standpoint, becomes an abstract attribute or condition; something a person has or does not have. Taking the standpoint of women and other marginalized people offers a view of self-determination as a person's development of his or her self. Empowerment becomes a potential characteristic of a social relationship, one that facilitates the development of someone's self. The most empowering relationships are mutual, recognizing and building on the diverse contributions and needs of participants in ways that seek to minimize inequalities over time. The reason some of us are self-determining is that we are in interpersonal and social structural relationships that empower us. To construct interpersonal and social structural relationships that empower people with developmental disabilities requires challenging the way dominant conceptualizations of independence and productivity also express the standpoint of the privileged. The standpoint of women allows all of us to talk more of how we connect with and facilitate one another's developing selves within communities.     

Children like dense neighborhoods: Orthographic neighborhood density effects in novel readers

Previous evidence with English beginning readers suggests that some orthographic effects, such as the orthographic neighborhood density effects, could be stronger for children than for adults. Particularly, children respond more accurately to words with many orthographic neighbors than to words with few neighbors. The magnitude of the effects for children is much higher than for adults, and some researchers have proposed that these effects could be progressively modulated according to reading expertise. The present paper explores in depth how children from 1st to 6th grade perform a lexical decision with words that are from dense or sparse orthographic neighborhoods, attending not only to accuracy measures, but also to response latencies, through a computer-controlled task. Our results reveal that children (like adults) show clear neighborhood density effects, and that these effects do not seem to depend on reading expertise. Contrarily to previous claims, the present work shows that orthographic neighborhood effects are not progressively modulated by reading skill. Further, these data strongly support the idea of a general language-independent preference for using the lexical route instead of grapheme-to-phoneme conversions, even in beginning readers. The implications of these results for developmental models in reading and for models in visual word recognition and orthographic encoding are discussed.     

Spoken Language Outcomes after Hemispherectomy: Factoring in Etiology

We analyzed postsurgery linguistic outcomes of 43 hemispherectomy patients operated on at UCLA. We rated spoken language (Spoken Language Rank, SLR) on a scale from 0 (no language) to 6 (mature grammar) and examined the effects of side of resection/damage, age at surgery/seizure onset, seizure control postsurgery, and etiology on language development. Etiology was defined as developmental (cortical dysplasia and prenatal stroke) and acquired pathology (Rasmussen's encephalitis and postnatal stroke). We found that clinical variables were predictive of language outcomes only when they were considered within distinct etiology groups. Specifically, children with developmental etiologies had lower SLRs than those with acquired pathologies (p =.0006); age factors correlated positively with higher SLRs only for children with acquired etiologies (p =.0006); right-sided resections led to higher SLRs only for the acquired group (p =.0008); and postsurgery seizure control correlated positively with SLR only for those with developmental etiologies (p =.0047). We argue that the variables considered are not independent predictors of spoken language outcome posthemispherectomy but should be viewed instead as characteristics of etiology.     

Gaze detection and the cortical processing of faces: Evidence from infants and adults

Abstract

Faces, as a class of objects, have been studied extensively in order to understand how the human visual system recognizes and represents objects. In this paper we studied the ontogeny of the ability to perceive gaze direction. We bring together both developmental research and neurophysiological and neuropsychological research in order to address this issue. In two experiments we explored the developmental time course of the ability to discriminate between direct and averted gaze, a task thought to involve cortical information processing of faces. We found that (a) infants as young as four months could discriminate between direct and averted gaze, (b) this ability was not due to the development of low-level visual processes, and (c) younger infants did not show reliable evidence of gaze discrimination. In an additional experiment we tested adults to study the effect of face context on the ability to discriminate gaze direction. Adult subjects were more sensitive in this discrimination when the eyes were in the context of an upright face than when the eyes were in either an inverted face or in a scrambled face. Taken together, these results suggest that the mechanisms underlying gaze detection may be mediated by cortical circuits also involved in other aspects of face recognition.     

Development of the Brain’s Functional Network Architecture

A full understanding of the development of the brain’s functional network architecture requires not only an understanding of developmental changes in neural processing in individual brain regions but also an understanding of changes in inter-regional interactions. Resting state functional connectivity MRI (rs-fcMRI) is increasingly being used to study functional interactions between brain regions in both adults and children. We briefly review methods used to study functional interactions and networks with rs-fcMRI and how these methods have been used to define developmental changes in network functional connectivity. The developmental rs-fcMRI studies to date have found two general properties. First, regional interactions change from being predominately anatomically local in children to interactions spanning longer cortical distances in young adults. Second, this developmental change in functional connectivity occurs, in general, via mechanisms of segregation of local regions and integration of distant regions into disparate subnetworks.     

Structural and functional MRI- findings in children and adolescents with antisocial behavior

BACKGROUND: The developmental course of children with conduct disorder (CD) is heterogeneous. Especially children who exhibit symptoms early in their lifetimes are characterized by a negative outcome. Neurobiological aspects of CD have been investigated in these children but little is known about structural and functional brain aberrations. METHODS: We describe the developmental taxonomy of children with CD and focus on those with the early onset subtype. Structural MRI data of these children and antisocial adults are recapitulated. The impact of investigating neurobiological underpinnings of antisocial behavior and how this might contribute to future forensic and psychiatric assessments is discussed. RESULTS/ CONCLUSION: Children display similar structural aberrations of fronto-limbic structures to adults with antisocial behavior, and amygdala dysfunction might be closely related to dysregulated emotions. Though the investigation of biological factors in antisocial subjects has made great progress in recent years, today MRI is still a rather complex, expensive and indistinct method for forensic assessment.     

Language Organization and Reorganization in Epilepsy

The vast majority of healthy individuals are left hemisphere dominant for language; however, individuals with left hemisphere epilepsy have a higher likelihood of atypical language organization. The cerebral organization of language in epilepsy has been studied with invasive procedures such as Wada testing and electrical cortical stimulation mapping (ESM), and more recently, with noninvasive neuroimaging techniques such as functional magnetic resonance imaging (fMRI). Investigators have used these techniques to explore the influence of unique clinical features inherent in epilepsy that might contribute to the reorganization of language, such as location of seizure onset, age of seizure onset, and extent of interictal epileptiform activity. In this paper, we review the contribution of these and other clinical variables to the lateralization and localization of language in epilepsy, and how these patient-related variables affect the results from these three different, yet complementary methodologies. Unlike the abrupt language changes that occur following acute brain injury with disruption of established language circuits, converging evidence suggests that the chronic nature of epileptic activity can result in a developmental shift of language from the left to the right hemisphere or re-routing of language pathways from traditional to non-traditional areas within the dominant left hemisphere. Clinical variables have been shown to contribute to cerebral language reorganization in the setting of chronic seizure disorders, yet such factors have not been reliable predictors of altered language networks in individual patients, underscoring the need for language lateralization and localization procedures when definitive identification of language cortex is necessary for clinical care.     

Serotonin in autism and pediatric epilepsies

Serotonergic abnormalities have been reported in both autism and epilepsy. This association may provide insights into underlying mechanisms of these disorders because serotonin plays an important neurotrophic role during brain development--and there is evidence for abnormal cortical development in both autism and some forms of epilepsy. This review explores the hypothesis that an early disturbance in the serotonin system affects cortical development and the development of thalamocortical innervation, and is a potential mechanism, common to autism and pediatric epilepsies associated with cortical dysplasia. An argument is made that cortical malformation leads to abnormalities of thalamocortical connectivity, and that serotonin plays a critical role in this process. Finally, a role for altered metabolism of the serotonin precursur, tryptophan, in both epilepsy and autism is discussed.     

The organization of thinking: What functional brain imaging reveals about the neuroarchitecture of complex cognition

Recent findings in brain imaging, particularly in fMRI, are beginning to reveal some of the fundamental properties of the organization of the cortical systems that underpin complex cognition. We propose an emerging set of operating principles that govern this organization, characterizing the system as a set of collaborating cortical centers that operate as a large-scale cortical network. Two of the network’s critical features are that it is resource constrained and dynamically configured, with resource constraints and demands dynamically shaping the network topology. The operating principles are embodied in a cognitive neuroarchitecture, 4CAPS, consisting of a number of interacting computational centers that correspond to activating cortical areas. Each 4CAPS center is a hybrid production system, possessing both symbolic and connectionist attributes. We describe 4CAPS models of sentence comprehension, spatial problem solving, and complex multitasking and compare the accounts of these models with brain activation and behavioral results. Finally, we compare 4CAPS with other proposed neuroarchitectures.     

The molecular basis of cognitive deficits in pervasive developmental disorders

Persons with pervasive developmental disorders (PDD) exhibit a range of cognitive deficits that hamper their quality of life, including difficulties involving communication, sociability, and perspective-taking. In recent years, a variety of studies in mice that model genetic syndromes with a high risk of PDD have provided insights into the underlying molecular mechanisms associated with these disorders. What is less appreciated is how the molecular anomalies affect neuronal and circuit function to give rise to the cognitive deficits associated with PDD. In this review, we describe genetic mutations that cause PDD and discuss how they alter fundamental social and cognitive processes. We then describe efforts to correct cognitive impairments associated with these disorders and identify areas of further inquiry in the search for molecular targets for therapeutics for PDD.     

Neural Network Models and Mechanisms of Strategy Development

The focus of this paper is mechanisms that may be responsible for intellectual and developmental differences in the cognitive strategies of typical and atypical children, including those with mental retardation. The discussion of these mechanisms is based on behavioral experiments on external memory strategies and on a set of neural network models designed for these tasks. Following the review of the external memory research, the rationale for using neural network models, how they have been used in other research, and their specific application to intellectual and developmental differences in external memory, including the results of several simulations, are reviewed. This is followed by a discussion of the mechanisms of intellectual differences and developmental change included in the models and some challenges for this type of modeling. Neural network modeling is discussed as an asset to research on cognitive development.     

Perfectionism in Pediatric Anxiety and Depressive Disorders

Although perfectionism has been identified as a factor in many psychiatric disorders across the life span, it is relatively understudied in pediatric anxiety and depressive disorders. Furthermore, there exists little cohesion among previous research, restricting the conclusions that can be made across studies. In this review, research associating perfectionism with pediatric anxiety and depression is examined and a framework is presented synthesizing research to date. We focus on detailing the current understanding of how perfectionism develops and interacts with other developmental features characteristic of anxiety and depression in children and potential pathways that result in anxiety and depressive disorders. This includes: how perfectionism is measured in children, comparisons with relevant adult literature, the development of perfectionism in children and adolescents, mediators and moderators of the link between perfectionism and anxiety and depression, and the role of perfectionism in treatment and prevention of these disorders. We also present research detailing perfectionism across cultures. Findings from these studies are beginning to implicate perfectionism as an underlying process that may contribute broadly to the development of anxiety and depression in a pediatric population. Throughout the review, difficulties, limitations, and gaps in the current understanding are presented while offering suggestions for future research.     

The psychoanalytic vision of Hans Loewald

Hans Loewald is a comprehensive and original theorist on a par with any major post-Freudian thinker, yet neither his ideas nor his person have become the basis for a Loewaldian school or approach, and he is not as well known as other innovators of comparable quality. In this paper the author attempts to characterize the scope and depth of Loewald's theory-his vision of the psyche and psychic life, or metapsychology, his characterization of the psychoanalytic process, and his vision of the clinical and human goals of psychoanalysis. She suggests that Loewald holds in all of these realms, and without apparent contradiction, a doubled-emphatically ego-psychological and emphatically object-relational-perspective, and an equal commitment to both the first topography and the structural theory. His views throughout are undergirded by a bi-directional developmental view that centers on differentiation and integration. The paper includes brief reflections on how to assess psychoanalytic theories, like Loewald's, developed before empirical research that seems to challenge them.     

Orthographic analogies and reading development

Given the interest in the use of orthographic analogies in skilled reading, the role of analogies in reading development has received surprisingly little attention. The experiments presented here examine three important developmental issues: whether beginning readers can make orthographic analogies, how the consistency of spelling-sound relations affects this ability, and whether orthographic analogies are used in reading prose. It is concluded that orthographic analogies have an important role to play in reading development, and some suggestions are offered as to why this may be so.