The usefulness of spatial pattern analysis in understanding the pathogenesis of neurodegenerative disorders, with particular reference to plaque formation in Alzheimer's disease

Discrete, microscopic lesions are developed in the brain in a number of neurodegenerative diseases. These lesions may not be randomly distributed in the tissue but exhibit a spatial pattern, i.e., a departure from randomness towards regularlity or clustering. The spatial pattern of a lesion may reflect its development in relation to other brain lesions or to neuroanatomical structures. Hence, a study of spatial pattern may help to elucidate the pathogenesis of a lesion. A number of statistical methods can be used to study the spatial patterns of brain lesions. They range from simple tests of whether the distribution of a lesion departs from random to more complex methods which can detect clustering and the size, distribution and spacing of clusters. This paper reviews the uses and limitations of these methods as applied to neurodegenerative disorders, and in particular to senile plaque formation in Alzheimer's disease.

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.

Development of a passive MEG stimulus for measurement of the binaural masking level difference

The ability to hear a target signal over background noise is an important aspect of efficient hearing in everyday situations. This mechanism depends on binaural hearing whenever there are differences in the inter-aural timing of inputs from the noise and the signal. Impairments in binaural hearing may underlie some auditory processing disorders, for example temporal-lobe epilepsies. The binaural masking level difference (BMLD) measures the advantage in detecting a tone whose inter-aural phase differs from that of the masking noise. BMLD’s are typically estimated psychophysically, but this is challenging in children or those with cognitive impairments. The aim of this doctorate is to design a passive measure of BMLD using magnetoencephalography (MEG) and test this in adults, children and patients with different types of epilepsy. The stimulus consists of Gaussian background noise with 500-Hz tones presented binaurally either in-phase or 180° out-of-phase between the ears. Source modelling provides the N1m amplitude for the in-phase and out-of-phase tones, representing the extent of signal perception over background noise. The passive BMLD stimulus is successfully used as a measure of binaural hearing capabilities in participants who would otherwise be unable to undertake a psychophysical task.

Work disability and depressive disorders:impact on the European population

OBJECTIVE: Our aim was to study the impact of depressive disorders on work disability to discover the determinants of depression for work disability in the European countries. DESIGN: The sample was composed of 31,126 individuals from 29 countries included in the 2002 World Health Survey of the World Health Organization. National representative samples of countries from all regions of Europe and with different levels of economic development and health coverage were selected. RESULTS: Estimates of people not working because of ill health did not differ among European countries in relation to levels of economic development or health coverage. Significant determinants of people with diagnosis of depression not working because of ill health (reference category) versus working were age (odds ratio = 0.97), female sex (odds ratio = 1.71), education (odds ratio = 1.11), marital status (being unmarried indicating less probability), lowest income level, and comorbidity with angina pectoris (odds ratio = 0.51). Moreover, according to previous studies, we found some determinants (comorbidity with other diseases, young age, and unemployment) impacting on health status. CONCLUSIONS: Depression is a substantial cause of work disability and it is a complex phenomenon that involves many variables. Investigation into this relationship should improve, focusing on the role of determinants.

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.

Anxiety sensitivity in children and the development of panic and anxiety in adolescents: A prospective study

Research with adult samples has identified a cognitive risk factor for the development of panic and other anxiety disorders in the concept of anxiety sensitivity. The research to date on anxiety sensitivity in children, using the Childhood Anxiety Sensitivity Index (CASI), suggests that the CASI may help to garner knowledge regarding the development of anxiety sensitivity and also help to understand the development of panic attacks, panic disorder and other anxiety disorders in youth. To examine the development of anxiety sensitivity and its relation to panic in youth, data were collected on 44 children in 1998 who were administered the CASI in 1991. Results indicated that children whose CASI scores increased from Time 1 to Time 2 were significantly more likely to report experiencing panic attacks than children whose CASI scores decreased from Time 1 to Time 2. Specifically, 64% (9/14) of children whose CASI scores increased from Time 1 to Time 2 reported having one or more panic attacks versus 36% (5/14) reported having none. Moreover, 72% (21/29) of children whose CASI scores decreased from Time 1 to Time 2 reported no panic attacks. These results suggest that childhood may be the time when anxiety sensitivity as a risk factor for panic and panic disorder is developing. Results are discussed in terms of their relevance for understanding the development of panic and the need for further research to determine the generalizability of these findings in larger samples of children followed over different time spans. ^

Endothelin receptor B and neural crest derived melanocyte development

Neural Crest cells (NCC) constitute a unique embryonic cell population that arises between the prospective epidermis and the dorsal aspect of the neural tube of vertebrates. NCC migrate ventromedially and dorsolaterally throughout the developing embryo giving rise to the peripheral nervous system constituents and melanocytes that ultimately reside in the skin and hair follicles respectively. Mice and humans with mutations in the Endothelin receptor b (Ednrb) gene manifest strikingly similar phenotypes characterized by hypopigmentation, hearing loss and megacolon these are due to absence of melanocytes in the skin and inner ear and lack of enteric ganglia in the distal part of the gut, respectively. Piebald lethal mice and humans with Hirschsprung's disease or Waardenburg syndrome carry different mutations in the Ednrb gene. The major goals of this project were to determine whether the action of Ednrb in NCC is required prior to commitment of these cells to the melanocytic lineage and to investigate its potential participation in the actual process of commitment. In order to achieve these goals transgenic mice that express Ednrb under two different regulatory elements were created. The first, Dct-Ednrb, expresses Ednrb under the control of the DOPAchrome tautomerase (Dct) promoter to direct expression to already committed melanocyte precursors. The second, Nes-Ednrb, expresses Ednrb under the regulation of the human nestin gene second enhancer to direct expression to pre-migratory NCC. Crosses of the Dct-Ednrb mouse with piebald lethal showed that the transgene was capable of rescuing the hypopigmentation phenotype of the later. This result indicates that the action of Ednrb after NCC commit to the melanocytic lineage is sufficient for normal melanocyte development. The Dct-Ednrb was further crossed with two other hypopigmentation mutants that carry mutations in the transcription factors Sox10 and Pax3. The transgene rescued the phenotype of the Sox10 mutant only. This suggests that Ednrb interacts with Sox10 but not with Pax3 during melanocyte development. The Nes-Ednrb mice developed a hypopigmentation phenotype that was augmented when crossed with piebald lethal or lethal spotting (mutation in Edn3, the ligand for Ednrb) mice but was rescued by over expression of Edn3. These results suggest that alterations in Ednrb expression early in development affect melanocyte development. This study provides novel information necessary to better understand the early embryonic development of NCC, clarifies specific interactions between different melanogenic genes and, could eventually help in the implementation of therapies for human pigmentary genetic disorders. ^

Parental involvement and group cognitive behavioral treatment for anxiety disorders in children and adolescents: Treatment specificity and mediation effects of parent and peer variables

Phobic and anxiety disorders are one of the most common, if not the most common and debilitating psychopathological conditions found among children and adolescents. As a result, a treatment research literature has accumulated showing the efficacy of cognitive behavioral treatment (CBT) for reducing anxiety disorders in youth. This dissertation study compared a CBT with parent and child (i.e., PCBT) and child group CBT (i.e., GCBT). These two treatment approaches were compared due to the recognition that a child’s context has an effect on the development, course, and outcome of childhood psychopathology and functional status. The specific aims of this dissertation were to examine treatment specificity and mediation effects of parent and peer contextual variables. The sample consisted of 183 youth and their mothers. Research questions were analyzed using analysis of variance for treatment outcome, and structural equation modeling, accounting for clustering effects, for treatment specificity and mediation effects. Results indicated that both PCBT and GCBT produced positive treatment outcomes across all indices of change (i.e., clinically significant improvement, anxiety symptom reduction) and across all informants (i.e., youths and parents) with no significant differences between treatment conditions. Results also showed partial treatment specific effects of positive peer relationships in GCBT. PCBT also showed partial treatment specific effects of parental psychological control. Mediation effects were only observed in GCBT; positive peer interactions mediated treatment response. The results support the use CBT with parents and peers for treating childhood anxiety. The findings’ implications are further discussed in terms of the need to conduct further meditational treatment outcome designs in order to continue to advance theory and research in child and anxiety treatment.

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.

The effectiveness of explicit individualized phonemic awareness instruction by a speech -language pathologist to preschool children with phonological speech disorders

This study investigated the effects of an explicit individualized phonemic awareness intervention administered by a speech-language pathologist to 4 prekindergarten children with phonological speech sound disorders. Research has demonstrated that children with moderate-severe expressive phonological disorders are at-risk for poor literacy development because they often concurrently exhibit weaknesses in the development of phonological awareness skills (Rvachew, Ohberg, Grawburg, & Heyding, 2003).^ The research design chosen for this study was a single subject multiple probe design across subjects. After stable baseline measures, the participants received explicit instruction in each of the three phases separately and sequentially. Dependent measures included same-day tests for Phase I (Phoneme Identity), Phase II (Phoneme Blending), and Phase III (Phoneme Segmentation), and generalization and maintenance tests for all three phases.^ All 4 participants made substantial progress in all three phases. These skills were maintained during weekly and biweekly maintenance measures. Generalization measures indicated that the participants demonstrated some increases in their mean total number of correct responses in Phase II and Phase III baseline while the participants were in Phase I intervention, and more substantial increases in Phase III baseline while the participants were in Phase II intervention. Increased generalization from Phases II to III could likely be explained due to the response similarities in those two skills (Cooper, Heron, & Heward, 2007).^ Based upon the findings of this study, speech-language pathologists should evaluate phonological awareness in the children in their caseloads prior to kindergarten entry, and should allocate time during speech therapy to enhance phonological awareness and letter knowledge to support the development of both skills concurrently. Also, classroom teachers should collaborate with speech-language pathologists to identify at-risk students in their classrooms and successfully implement evidence-based phonemic awareness instruction. Future research should repeat this study including larger groups of children, children with combined speech and language delays, children of different ages, and ESOL students.^