Neogenin: A multi-functional receptor regulating diverse developmental processes

Neogenin, a close relative of the axon guidance receptor Deleted in Colorectal Cancer (DCC), has been shown to be a receptor for members of the Netrin and Repulsive Guidance Molecule (RGM) families. While Netrin-l-Neogenin interactions result in a chernoattractive axon guidance response, the interaction between Neogenin and RGMa induces a chemorepulsive response. Evidence is now accumulating that Neogenin is a multi-functional receptor regulating many diverse developmental processes, including neural tube and mammary gland formation, myogenesis and angiogenesis. Little is known of the function of Neogenin in the adult, however, a novel role in the regulation of iron homeostasis is now emerging. While the signal transduction pathways activated by Neogenin are poorly understood, it is clear that the functional outcome of Neogenin activation, at least in the embryo, depends on both the developmental context as well as the nature of the ligand. (c) 2006 Elsevier Ltd. All rights reserved.

Developmental anomalies of the eye: the genetic link

As in other areas of the body, developmental anomalies of the eye arise as a result of the disturbance of events during embryology and in a proportion of cases these anomalies are genetically inherited. Developmental anomalies that occur early in embryonic life may be so severe that the embryo may not survive but others result in the birth of healthy babies but with developmental eye defects of varying severity. The most dramatic developmental defects of the eye include anophthalmos (complete absence of an eye), microphthalmos (a general failure of the eye to develop resulting in a small, undeveloped eye), coloboma (caused by failure of the optic vesicle to invaginate), and aniridia (complete or partial loss of the iris). The present article does not provide an exhaustive review of the topic but considers the major types of developmental anomaly to affect the eye and will discuss how recent progress in genetics has increased our understanding of these disorders. The major genes linked to the developmental anomalies are discussed as well as how defects in these genes might lead to specific problems.

The neural correlates of reading impairment in adults with developmental dyslexia:evidence from fMRI between group analyses and an fMRI multiple-case study

The goal of this project was to investigate the neural correlates of reading impairment in dyslexia as hypothesised by the main theories – the phonological deficit, visual magnocellular deficit and cerebellar deficit theories, with emphasis on individual differences. This research took a novel approach by: 1) contrasting the predictions in one sample of participants with dyslexia (DPs); 2) using a multiple-case study (and between-group comparisons) to investigate differences in BOLD between each DP and the controls (CPs); 3) demonstrating a possible relationship between reading impairment and its hypothesised neural correlates by using fMRI and a reading task. The multiple-case study revealed that the neural correlates of reading in dyslexia in all cases are not in agreement with the predictions of a single theory. The results show striking individual differences - even, where the neural correlates of reading in two DPs are consistent with the same theory, the areas can differ. A DP can exhibit under-engagement in an area in word, but not in pseudoword reading and vice versa, demonstrating that underactivation in that area cannot be interpreted as a ‘developmental lesion’. Additional analyses revealed complex results. Within-group analyses between behavioural measures and BOLD showed correlations in the predicted regions, areas outside ROI, and lack of correlations in some predicted areas. Comparisons of subgroups which differed on Orthography Composite supported the MDT, but only for Words. The results suggest that phonological scores are not a sufficient predictor of the under-engagement of phonological areas during reading. DPs and CPs exhibited correlations between Purdue Pegboard Composite and BOLD in cerebellar areas only for Pseudowords. Future research into reading in dyslexia should use a more holistic approach, involving genetic and environmental factors, gene by environment interaction, and comorbidity with other disorders. It is argued that multidisciplinary research, within the multiple-deficit model holds significant promise here.

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.

Child parent dyadic treatment for anxiety disorders in youths

There is evidence for the efficacy of treatments for childhood anxiety disorders; however, less is known about whether including parents in the child's treatment enhances child treatment response. There also are few studies that have examined predictors of treatment completion/non-completion and success/failure. In this dissertation, a child focused individual treatment was compared to a dyadic child-parent treatment. In dyadic, parent anxiety symptoms and child-parent relationships were targeted. Based on the Transfer of Control Model proposed by Silverman and Kurtines (1996a, b, 2005), it was hypothesized that treatment changes in parent anxiety symptoms and child-parent relationships would be related to positive child treatment response. ^ Participants were 119 youths (ages 6 to 16 years, M = 9.93 SD = 2.75; 68 girls) and their parents. All youth were born in the U.S. but had various backgrounds; 40 were European American, 73 were Latinos/as, 6 were of other ethnic backgrounds or did not report their ethnicity. Participants signed informed consent (assent for youths) and completed a pretreatment assessment. Participants were randomized to a child individual treatment or dyadic treatment, were assessed immediately after treatment and one year post treatment. Findings showed that treated youths improved across all measures over time. Comparison of treatment conditions across all measures showed no statistically significant differences between the child individual and dyadic treatment. Reductions in parent anxiety symptoms and improvements in child-parent relationships were significantly related to child treatment change at posttreatment and at one year follow-up across treatments. No factors differentiated completers from non-completers and only parent reported child internalizing behavior problems were significantly negatively related to child treatment response. ^ The study findings support a premise of the Transfer of Control Model that changes in parent anxiety symptoms and child-parent relationships are related to child treatment response. The study findings show that children can be successfully treated when parents are included as co-clients in dyadic treatment, thereby supporting the utility of this approach in practice. ^

Evaluating the external validity of comorbid disorders in youth using rating scales and behavior observations

To evaluate the theoretical underpinnings of current categorical approaches to classify childhood psychopathological conditions, this dissertation examined whether children with a single diagnosis of an anxiety disorder (ANX only) and children with an anxiety diagnosis comorbid with other diagnoses (i.e., anxiety + anxiety disorder [ANX + ANX], anxiety + depressive disorder [ANX + DEP], and anxiety + disruptive disorder [ANX + EXT]) could be differentiated using external validation criteria of clinical phenomenology (i.e., levels of anxiety, depression, and internalizing, externalizing and total behavior problems). This study further examined whether the four groups could be differentiated in terms of their interaction patterns with their parents and peers, respectively. The sample consisted of 129 youth and their parents who presented to the Child Anxiety and Phobia Program (CAPP) housed within the Child and Family Psychosocial Research Center at Florida International University, Miami. Youth were between the ages of 8 and 14 years old. A battery of questionnaires was used to assess participants' clinical presentation in terms of levels of anxiety, depression, and internalizing and externalizing symptoms. Family and peer interaction were evaluated through rating scales and through behavior observation tasks. Statistics based on the parameter estimates of the structured equation models indicated that all the comorbid groups were significantly different from the pure anxiety disorder group when it came to depression indices of clinical phenomenology. Further, significant differences appeared mainly in terms of the ANX + DEP comorbid group relative to the other comorbid groups. In terms of Parent-child interaction the ANX + EXT and the ANX + DEP comorbid groups were differentiated from the pure anxiety disorder and ANX + ANX comorbid group when it came to the appraisal of the parent/child relationship by the parent, and the acceptance subscale according to the mother report. In terms of peer-child interaction the ANX + EXT and the ANX + DEP comorbid groups were statistically significantly different from the pure anxiety disorder only when it came to the positive interactions and the social skills as rated by mother. Limitations and future research recommendations are discussed.

An evaluation of functional impairment among children with anxiety disorders

Despite a considerable progress in developing and testing psychosocial treatments to reduce youth anxiety disorders, much remains to learn about the relation between anxiety symptom reduction and change in youth functional impairment. The specific aims of this dissertation thus were to examine: (1) the relation between different levels of anxiety and youth functional impairment ratings; (2) incremental validity of the Children Global Assessment Scale (CGAS); (3) the mediating role of anxiety symptom reduction on youth functional impairment ratings; (4) the directionality of change between anxiety symptom reduction and youth functional impairment; (5) the moderating effects of youth age, sex, and ethnicity on the mediated relation between youth anxiety symptom reduction and change in functional impairment; and (6) an agreement (or lack thereof) between youths and their parents in their views of change in youth functional impairment vis-à-vis anxiety symptom reduction. ^ The results were analyzed using archival data set acquired from 183 youths and their mothers. Research questions were tested using SPSS and structural equation modeling techniques in Mplus. ^ The results supported the efficacy of psychosocial treatments to reduce the severity of youth anxiety symptoms and its associated functional impairment. Moreover, the results revealed that at posttreatment, youths who scored either low or medium on anxiety levels scored significantly lower on impairment, than youths who scored high on anxiety levels. Incremental validity of the CGAS was also revealed across all assessment points and informants in my sample. In addition, the results indicated the mediating role of anxiety symptom reduction with respect to change in youth functional impairment at posttest, regardless of the youth’s age, sex, and ethnicity. No significant findings were observed with regard to the bidirectionality and an informant disagreement vis-à-vis the relation between anxiety symptom reduction and change in functional impairment. ^ The study’s main contributions and potential implications on theoretical, empirical, and clinical levels are further discussed. The emphasis is on the need to enhance existing evidence-based treatments and develop innovative treatment models that will not only reduce youth’s symptoms (such anxiety) but also evoke genuine and palpable improvements in lives of youths and their families.^

Group cognitive -behavioral therapy for heterogeneous anxiety disorders in children and adolescents: A multiple baseline study

This study investigated the efficacy of Group Cognitive-Behavioral Therapy (GCBT) in the treatment of heterogeneous anxiety disorders in children. A partially nonconcurrent multiple baseline across groups design was used to assess the effects of the treatment on 12 clinically referred children and adolescents between 6 and 16 years of age who met DSM-IV criteria for an anxiety disorder. Targeted diagnoses included Obsessive Compulsive Disorder, Simple Phobia, Separation Anxiety Disorder, Social Phobia, and Generalized Anxiety Disorder, with three of the children also presenting with school refusal behavior. Duration of baseline for each of the three groups varied and ran for one, two, or three weeks. Dependent measures included diagnostic status, child and parent-completed reports, and daily child and parent ratings of child anxiety severity. Results indicated that GCBT was efficacious in reducing anxious symptoms in children and adolescents treated in diagnostically heterogeneous groups, and that gains were generally maintained at 6 and 12 month follow-ups. Findings are discussed in terms of their theoretical and practical implications for the efficient treatment of children and adolescents with anxiety disorders. ^

Evaluating the Effectiveness of Discrete Trial Procedures for Teaching Receptive Discrimination to Children with Autism Spectrum Disorders

Research has found that children with autism spectrum disorders (ASD) show significant deficits in receptive language skills (Wiesmer, Lord, & Esler, 2010). One of the primary goals of applied behavior analytic intervention is to improve the communication skills of children with autism by teaching receptive discriminations. Both receptive discriminations and receptive language entail matching spoken words with corresponding objects, symbols (e.g., pictures or words), actions, people, and so on (Green, 2001). In order to develop receptive language skills, children with autism often undergo discrimination training within the context of discrete trial training. This training entails teaching the learner how to respond differentially to different stimuli (Green, 2001). It is through discrimination training that individuals with autism learn and develop language (Lovaas, 2003). The present study compares three procedures for teaching receptive discriminations: (1) simple/conditional (Procedure A), (2) conditional only (Procedure B), and (3) conditional discrimination of two target cards (Procedure C). Six children, ranging in age from 2-years-old to 5-years-old, with an autism diagnosis were taught how to receptively discriminate nine sets of stimuli. Results suggest that the extra training steps included in the simple/conditional and conditional only procedures may not be necessary to teach children with autism how to receptively discriminate. For all participants, Procedure C appeared to be the most efficient and effective procedure for teaching young children with autism receptive discriminations. Response maintenance and generalization probes conducted one-month following the end of training indicate that even though Procedure C resulted in less training sessions overall, no one procedure resulted in better maintenance and generalization than the others. In other words, more training sessions, as evident with the simple/conditional and conditional only procedures, did not facilitate participants’ ability to accurately respond or generalize one-month following training. The present study contributes to the literature on what is the most efficient and effective way to teach receptive discrimination during discrete trial training to children with ASD. These findings are critical as research shows that receptive language skills are predictive of better outcomes and adaptive behaviors in the future.

Investigating the developmental and behavioral consequences of maternal immune activation on affected offspring

Maternal infection during pregnancy increases the risk of several neuropsychiatric disorders later in life, many of which have a component of dopaminergic (DA) dysfunction, including schizophrenia, autism spectrum disorders (ASD), and attention deficit hyperactivity disorder (ADHD). The majority of DA neurons are found in the adult midbrain; as such the midbrain is a key region of interest regarding these disorders. The literature is conflicting regarding the behavioral alterations following maternal immune activation (MIA) exposure, and the cellular and molecular consequences of MIA on the developing midbrain remain to be fully elucidated. Thus, this thesis aimed to establish the consequences of acute and mild MIA on offspring dopamine-related behaviors, as well as the associated cellular and molecular disturbances of MIA on offspring midbrains. We utilized a rat model of MIA using low dose (50μg/kg, I.P.) of LPS administered at different gestational ages. Our first study indicated that MIA at later gestational ages significantly increased pro-inflammatory IL-1β expression, and reduced HSD11B2 expression in the placenta, which is an important regulator of fetal development. In utero LPS exposure at later gestational ages also impaired the growth of neurons from affected offspring. This study identified key gestational stages during which MIA resulted in differential effects. We utilized these time points in subsequent studies, the next of which investigated neurobehavioral outcomes following MIA. Our results from that study showed that motor differences occurred in juvenile offspring following MIA at E16 only, and these differences were compensated for in adolescence. Then, there was a decline in motor behavior capabilities in adulthood, again only for animals exposed to MIA on E16 (and not E12). Furthermore, our results also demonstrated adolescent and adult offspring that were exposed to MIA at E12 had diminished responses to amphetamine in reward seeking behaviors. In our final study, we aimed to investigate the molecular and cellular changes following MIA which might explain these behavioral alterations. This final study showed a differential inflammatory response in fetal midbrains depending on gestational age of exposure as well as differential developmental alterations. For example, LPS exposure at E16 resulted in decreased VM neurosphere size after 7DIV and this was associated with an increased susceptibility to neurotoxic effects of pro-inflammatory cytokines for VM neurospheres and VM DA neurons treated in culture. In utero LPS exposure at E16 also reduced DA neuron count of fetal VM, measured by TH staining. However, there were no differences in DA neuron number in juvenile, adolescent, or adult offspring. Similarly, LPS exposure did not alter cell number or morphology of glial cells in the midbrains of affected offspring. In conclusion, this thesis indicated later rat pregnancy (E16) as vulnerable time for MIA to affect the development of the nigrostriatal pathway and subsequent behavioral outcomes, possibly implicating a role for MIA in increased risk for disorders associated with motor behavior, like PD. These effects may be mediated through alterations in the placenta and altered inflammatory mediators in the offspring brain. This thesis has also shown that MIA in earlier rat pregnancy (E12) results in altered mesocorticolimbic function, and in particular MIA on E12 resulted in a differential response to amphetamine in affected offspring, which may implicate a role for MIA in increasing the risk for disorders associated with this pathway, including drug tolerance and addiction.

Cognitive behavior therapy for anxiety disorders in youth: Treatment specificity and mediation effects

The present study investigated the efficacies of Individual CBT (ICBT), Parent Relationship Skill Training (RLST, which targets increasing parental acceptance of youth and increasing autonomy granting) and Parent Reinforcement Skills Training (RLST, which targets increasing parental positive reinforcement and decreasing negative reinforcement). The specific aims were to examine treatment specificity and mediation effects of parenting variables. ICBT was used as a baseline comparison condition. The sample consisted of 253 youth (ages 5-16 years; M = 9.38; SD = 2.42) and their parents. To examine treatment outcome and specificity, the data were analyzed using analysis of variance within a structural equation modeling framework. Mediation was analyzed via structural equation modeling using MPlus. Results indicated that ICBT, RLST, and RFST 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). RLST was associated with incremental reduction in youth anxiety symptoms beyond ICBT, as per youth report. Treatment specificity effects were found for participants in RFST in terms of parental reinforcement, as per parent report only. Treatment mediation was not found for any of the hypothesized parenting variables (i.e., parental acceptance, parental autonomy granting, parental reinforcement). The results support the use of CBT involving only the youth and the parent and youth together for treating youth 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 youth anxiety treatment.

Perception of Filtered Speech by Children with Developmental Dyslexia and Children with Specific Language Impairments

Here we use two filtered speech tasks to investigate children’s processing of slow (<4 Hz) versus faster (∼33 Hz) temporal modulations in speech. We compare groups of children with either developmental dyslexia (Experiment 1) or speech and language impairments (SLIs, Experiment 2) to groups of typically-developing (TD) children age-matched to each disorder group. Ten nursery rhymes were filtered so that their modulation frequencies were either low-pass filtered (<4 Hz) or band-pass filtered (22 – 40 Hz). Recognition of the filtered nursery rhymes was tested in a picture recognition multiple choice paradigm. Children with dyslexia aged 10 years showed equivalent recognition overall to TD controls for both the low-pass and band-pass filtered stimuli, but showed significantly impaired acoustic learning during the experiment from low-pass filtered targets. Children with oral SLIs aged 9 years showed significantly poorer recognition of band pass filtered targets compared to their TD controls, and showed comparable acoustic learning effects to TD children during the experiment. The SLI samples were also divided into children with and without phonological difficulties. The children with both SLI and phonological difficulties were impaired in recognizing both kinds of filtered speech. These data are suggestive of impaired temporal sampling of the speech signal at different modulation rates by children with different kinds of developmental language disorder. Both SLI and dyslexic samples showed impaired discrimination of amplitude rise times. Implications of these findings for a temporal sampling framework for understanding developmental language disorders are discussed.

Evaluating the effectiveness of discrete trial procedures for teaching receptive discrimination to children with autism spectrum disorders

Research has found that children with autism spectrum disorders (ASD) show significant deficits in receptive language skills (Wiesmer, Lord, & Esler, 2010). One of the primary goals of applied behavior analytic intervention is to improve the communication skills of children with autism by teaching receptive discriminations. Both receptive discriminations and receptive language entail matching spoken words with corresponding objects, symbols (e.g., pictures or words), actions, people, and so on (Green, 2001). In order to develop receptive language skills, children with autism often undergo discrimination training within the context of discrete trial training. This training entails teaching the learner how to respond differentially to different stimuli (Green, 2001). It is through discrimination training that individuals with autism learn and develop language (Lovaas, 2003). The present study compares three procedures for teaching receptive discriminations: (1) simple/conditional (Procedure A), (2) conditional only (Procedure B), and (3) conditional discrimination of two target cards (Procedure C). Six children, ranging in age from 2-years-old to 5-years-old, with an autism diagnosis were taught how to receptively discriminate nine sets of stimuli. Results suggest that the extra training steps included in the simple/conditional and conditional only procedures may not be necessary to teach children with autism how to receptively discriminate. For all participants, Procedure C appeared to be the most efficient and effective procedure for teaching young children with autism receptive discriminations. Response maintenance and generalization probes conducted one-month following the end of training indicate that even though Procedure C resulted in less training sessions overall, no one procedure resulted in better maintenance and generalization than the others. In other words, more training sessions, as evident with the simple/conditional and conditional only procedures, did not facilitate participants’ ability to accurately respond or generalize one-month following training. The present study contributes to the literature on what is the most efficient and effective way to teach receptive discrimination during discrete trial training to children with ASD. These findings are critical as research shows that receptive language skills are predictive of better outcomes and adaptive behaviors in the future. ^