Morphology in autism spectrum disorders:local processing bias and language

We conducted a detailed study of a case of linguistic talent in the context of autism spectrum disorder, specifically Asperger syndrome. I.A. displays language strengths at the level of morphology and syntax. Yet, despite this grammar advantage, processing of figurative language and inferencing based on context presents a problem for him. The morphology advantage for I.A. is consistent with the weak central coherence (WCC) account of autism. From this account, the presence of a local processing bias is evident in the ways in which autistic individuals solve common problems, such as assessing similarities between objects and finding common patterns, and may therefore provide an advantage in some cognitive tasks compared to typical individuals. We extend the WCC account to language and provide evidence for a connection between the local processing bias and the acquisition of morphology and grammar.

An overview of psychological and neurobiological mechanisms by which early negative experiences increase risk of mood disorders

Objective: Early life experiences are associated with severe and long-lasting effects on behavioural and emotional functioning, which in turn are thought to increase the risk for unipolar depression and other disorders of affect regulation. The neurobiological and psychological mechanisms through which adverse early life experiences confer risk are poorly understood. Method: Alterations in brain structure and function in limbic and prefrontal cortical regions have been linked to early negative experiences and to mood disorders. Results: There are a number of psychological domains that may be dysfunctional in people with mood disorders, and which, if the dysfunction occurs prior to onset of mood symptoms, may signify a risk factor for depression. Cognitive dysfunction has been examined in patients with mood disorders, with some suggestion that changes in cognitive function may antedate the onset of mood symptoms, and may be exacerbated in those who experienced early negative trauma. Social cognition, including emotion comprehension, theory of mind and empathy, represent under-studied domains of psychological function that may be negatively influenced by early adverse experience. Temperament and personality factors may also leave people vulnerable to mood instability. Conclusion: This review summarizes the evidence for dysfunction in each of these domains for people with mood disorders.

Visual hallucinations in the psychosis spectrum and comparative information from neurodegenerative disorders and eye disease

Much of the research on visual hallucinations (VHs) has been conducted in the context of eye disease and neurodegenerative conditions, but little is known about these phenomena in psychiatric and nonclinical populations. The purpose of this article is to bring together current knowledge regarding VHs in the psychosis phenotype and contrast this data with the literature drawn from neurodegenerative disorders and eye disease. The evidence challenges the traditional views that VHs are atypical or uncommon in psychosis. The weighted mean for VHs is 27% in schizophrenia, 15% in affective psychosis, and 7.3% in the general community. VHs are linked to a more severe psychopathological profile and less favorable outcome in psychosis and neurodegenerative conditions. VHs typically co-occur with auditory hallucinations, suggesting a common etiological cause. VHs in psychosis are also remarkably complex, negative in content, and are interpreted to have personal relevance. The cognitive mechanisms of VHs in psychosis have rarely been investigated, but existing studies point to source-monitoring deficits and distortions in top-down mechanisms, although evidence for visual processing deficits, which feature strongly in the organic literature, is lacking. Brain imaging studies point to the activation of visual cortex during hallucinations on a background of structural and connectivity changes within wider brain networks. The relationship between VHs in psychosis, eye disease, and neurodegeneration remains unclear, although the pattern of similarities and differences described in this review suggests that comparative studies may have potentially important clinical and theoretical implications. © 2014 The Author.

Atypical connectivity in autistic spectrum disorders

Autism is a developmental disorder that is currently defined in terms of a triad of impairments in social interaction, communication, and behavioural flexibility. Psychological models have focussed on deficits in high level social and cognitive processes, such as ‘weak central coherence’ and deficits in ‘theory of mind’. Converging evidence from different fields of neuroscience research indicates that the underlying neural dysfunction is associated with atypical patterns of cortical connectivity (Rippon et al., 2007). This arises very early in development and results in sensory, perceptual and cognitive deficits at a much earlier and more fundamental level than previously suggested, but with cascading effects on higher level psychological and social processes. Earlier research in this sphere has focussed mainly on patterns of underconnectivity in distributed cortical networks underpinning process such as language and executive function. (Just et al., 2007). Such research mainly utilises imaging techniques with high spatial resolution. This paper focuses on evidence associated with local over-connectivity, evident in more low level and transitory processes and hence more easily measurable with techniques with high temporal resolution, such as MEG and EEG. Results are described which provide evidence of such local over-connectivity, characterised by atypical results in the gamma frequency range (Brown et al., 2005) together with discussions about the future directions of such research and its implications for remediation.

Retinal vascular dysfunction relates to cognitive impairment in Alzheimer's disease

Cerebral vascular dysregulation has been increasingly implicated as a risk factor in the development of Alzheimer disease (AD)1; however, because of the difficulties associated with assessing and visualizing the cerebral vasculature directly, the ability to detect such dysregulation, noninvasively, is currently limited.2 Consequently, one concept that is being increasingly explored is the possibility of using the eye as a "window to the brain"; this approach has reasonable scientific validity as the retinal and brain vessels share a large number of embryological, anatomic, and functional similarities.2 Indeed, previous research has demonstrated a correlation between cognition and the geometry of the retinal vessels in elderly people.3 The aim of this pilot study, therefore, was to explore whether microvascular functional anomalies are evident at the retinal level in mild AD patients and to determine whether these anomalies relate to the degree of concurrent cognitive deficit..

Comparative quantitative study of ‘signature’ pathological lesions in the hippocampus and adjacent gyri of 12 neurodegenerative disorders

The hippocampus (HC) and adjacent gyri are implicated in dementia in several neurodegenerative disorders. To compare HC pathology among disorders, densities of ‘signature’ pathological lesions were measured at a standard location in eight brain regions of 12 disorders. Principal components analysis of the data suggested that the disorders could be divided into three groups: (1) Alzheimer’s disease (AD), Down’s syndrome (DS), sporadic Creutzfeldt–Jakob disease, and variant Creutzfeldt–Jakob disease in which either β-amyloid (Aβ) or prion protein deposits were distributed in all sectors of the HC and adjacent gyri, with high densities being recorded in the parahippocampal gyrus and subiculum; (2) Pick’s disease, sporadic frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions, and neuronal intermediate filament inclusion disease in which relatively high densities of neuronal cytoplasmic inclusions were present in the dentate gyrus (DG) granule cells; and (3) Parkinson’s disease dementia, dementia with Lewy bodies, progressive supranuclear palsy, corticobasal degeneration, and multiple system atrophy in which densities of signature lesions were relatively low. Variation in density of signature lesions in DG granule cells and CA1 were the most important sources of neuropathological variation among disorders. Hence, HC and adjacent gyri are differentially affected in dementia reflecting either variation in vulnerability of hippocampal neurons to specific molecular pathologies or in the spread of pathological proteins to the HC. Information regarding the distribution of pathology could ultimately help to explain variations in different cognitive domains, such as memory, observed in various disorders.

Developing multidimensional metrics for evaluating paediatric neurodevelopmental disorders

Healthy brain functioning depends on efficient communication of information between brain regions, forming complex networks. By quantifying synchronisation between brain regions, a functionally connected brain network can be articulated. In neurodevelopmental disorders, where diagnosis is based on measures of behaviour and tasks, a measure of the underlying biological mechanisms holds promise as a potential clinical tool. Graph theory provides a tool for investigating the neural correlates of neuropsychiatric disorders, where there is disruption of efficient communication within and between brain networks. This research aimed to use recent conceptualisation of graph theory, along with measures of behaviour and cognitive functioning, to increase understanding of the neurobiological risk factors of atypical development. Using magnetoencephalography to investigate frequency-specific temporal dynamics at rest, the research aimed to identify potential biological markers derived from sensor-level whole-brain functional connectivity. Whilst graph theory has proved valuable for insight into network efficiency, its application is hampered by two limitations. First, its measures have hardly been validated in MEG studies, and second, graph measures have been shown to depend on methodological assumptions that restrict direct network comparisons. The first experimental study (Chapter 3) addressed the first limitation by examining the reproducibility of graph-based functional connectivity and network parameters in healthy adult volunteers. Subsequent chapters addressed the second limitation through adapted minimum spanning tree (a network analysis approach that allows for unbiased group comparisons) along with graph network tools that had been shown in Chapter 3 to be highly reproducible. Network topologies were modelled in healthy development (Chapter 4), and atypical neurodevelopment (Chapters 5 and 6). The results provided support to the proposition that measures of network organisation, derived from sensor-space MEG data, offer insights helping to unravel the biological basis of typical brain maturation and neurodevelopmental conditions, with the possibility of future clinical utility.

Family and group cognitive behavior therapy: Evaluation of treatment outcome and treatment specificity

This dissertation examined the efficacy of family cognitive behavior treatment (FCBT) and group cognitive behavior treatment (GBCT) for reducing anxiety disorders in children and adolescents using several approaches: clinical significant change, equivalence testing, and analyses of variance. It also examined treatment specificity in terms of targeting family/parents (in FCBT) and peers/group (in GCBT) contextual variables using two main approaches: analyses of variance and structural equation modeling (SEM). The sample consisted of 143 children and their parents who presented to the Child Anxiety and Phobia Program housed within the Child and Family Psychosocial Research Center at Florida International University. Diagnostic interviews and questionnaires were administered to assess youth anxiety. Questionnaires were administered to assess child and parent views of family/parents and peers/group contextual variables. In terms of clinical significant change, results indicated that 84.6% of youth in FCBT and 71.2% of youth in GBCT no longer met diagnostic criteria for their primary/targeted anxiety disorder. In addition, results from analyses of variance indicated that FCBT and GCBT were both efficacious in reducing anxiety disorders in youth across both child and parent ratings. Results using both analyses of variance and structural equation modeling also indicated that there was no meaningful treatment specificity between FCBT and GCBT in terms of either family/parents or peers/group contextual variables. That is, child social skills improved in GCBT in which these skills were targeted and in FCBT in which these skills were not targeted; parenting skills improved in FCBT in which these skills were targeted and in GCBT in which these skills were not targeted. Clinical implications and future research recommendations are discussed.

Human Synaptic Plasticity Gene Expression Profile and Dendritic Spine Density Changes in HIV-Infected Human CNS Cells: Role in HIV-Associated Neurocognitive Disorders (HAND)

HIV-associated neurocognitive disorders (HAND) is characterized by development of cognitive, behavioral and motor abnormalities, and occur in approximately 50% of HIV infected individuals. Our current understanding of HAND emanates mainly from HIV-1 subtype B (clade B), which is prevalent in USA and Western countries. However very little information is available on neuropathogenesis of HIV-1 subtype C (clade C) that exists in Sub-Saharan Africa and Asia. Therefore, studies to identify specific neuropathogenic mechanisms associated with HAND are worth pursuing to dissect the mechanisms underlying this modulation and to prevent HAND particularly in clade B infection. In this study, we have investigated 84 key human synaptic plasticity genes differential expression profile in clade B and clade C infected primary human astrocytes by using RT2 Profile PCR Array human Synaptic Plasticity kit. Among these, 31 and 21 synaptic genes were significantly (≥3 fold) down-regulated and 5 genes were significantly (≥3 fold) up-regulated in clade B and clade C infected cells, respectively compared to the uninfected control astrocytes. In flow-cytometry analysis, down-regulation of postsynaptic density and dendrite spine morphology regulatory proteins (ARC, NMDAR1 and GRM1) was confirmed in both clade B and C infected primary human astrocytes and SK-N-MC neuroblastoma cells. Further, spine density and dendrite morphology changes by confocal microscopic analysis indicates significantly decreased spine density, loss of spines and decreased dendrite diameter, total dendrite and spine area in clade B infected SK-N-MC neuroblastoma cells compared to uninfected and clade C infected cells. We have also observed that, in clade B infected astrocytes, induction of apoptosis was significantly higher than in the clade C infected astrocytes. In conclusion, this study suggests that down-regulation of synaptic plasticity genes, decreased dendritic spine density and induction of apoptosis in astrocytes may contribute to the severe neuropathogenesis in clade B infection.

Understanding the genetic basis of phenotype variability in individuals with neurocognitive disorders

Thesis (Ph.D.)--University of Washington, 2016-06