Prenatal environmental exposure and neurodevelopmentally important gene expression in malformed brain tissue from pediatric intractable epilepsy patients

The primary objective of this proposal was to determine whether mitochondrial oxidative stress and variation in a particular mtDNA lineage contribute to the risk of developing cortical dysplasia and are potential contributing factors in epileptogenesis in children. The occurrence of epilepsy in children is highly associated with malformations of cortical development (MCD). It appears that MCD might arise from developmental errors due to environmental exposures in combination with inherited variation in response to environmental exposures and mitochondrial function. Therefore, it is postulated that variation in a particular mtDNA lineage of children contributes to the effects of mitochondrial DNA damage on MCD phenotype. Quantitative PCR and dot blot were used to examine mitochondrial oxidative damage and single nucleotide polymorphism (SNP) in the mitochondrial genome in brain tissue from 48 pediatric intractable epilepsy patients from Miami Children’s Hospital and 11 control samples from NICHD Brain and Tissue Bank for Developmental Disorders. Epilepsy patients showed higher mtDNA copy number compared to normal health subjects (controls). Oxidative mtDNA damage was lower in non-neoplastic but higher in neoplastic epilepsy patients compared to controls. There was a trend of lower mtDNA oxidative damage in the non-neoplastic (MCD) patients compared to controls, yet, the reverse was observed in neoplastic (MCD and Non-MCD) epilepsy patients. The presence of mtDNA SNP and haplogroups did not show any statistically significant relationships with epilepsy phenotypes. However, SNPs G9804A and G9952A were found in higher frequencies in epilepsy samples. Logistic regression analysis showed no relationship between mtDNA oxidative stress, mtDNA copy number, mitochondrial haplogroups and SNP variations with epilepsy in pediatric patients. The levels of mtDNA copy number and oxidative mtDNA damage and the SNPs G9952A and T10010C predicted neoplastic epilepsy, however, this was not significant due to a small sample size of pediatric subjects. Findings of this study indicate that an increase in mtDNA content may be compensatory mechanisms for defective mitochondria in intractable epilepsy and brain tumor. Further validation of these findings related to mitochondrial genotypes and mitochondrial dysfunction in pediatric epilepsy and MCD may lay the ground for the development of new therapies and prevention strategies during embryogenesis.

Anxiety disorders and depression and risk for drug use disorders across the life course: Sex and ethnic contrasts

The present study examined the linkage between mental (i.e., anxiety disorders and depression) and drug use disorders in a multi-ethnic (i.e., 25% Euro-American, 38% Hispanic/Latino, 33% African American, 4% other) sample of adults (N = 1638, age 18–93 years old). Risk for drug use disorders was examined, while attending to methodological issues of prior research including (1) psychiatric comorbidity, (2) variations in risk associated with sex, ethnicity, and age, and (3) temporal order between mental and drug use disorders. ^ Participants were assessed using the Composite International Diagnostic Interview (CIDI; World Health Organization, 1990). A life history calendar (Freedman et al., 1988) was used to aid the ordering of onsets of all disorders assessed. ^ Preliminary analysis indicated anxiety disorders and depression were significant predictors of drug use disorders, but after controlling for comorbidity and temporal order, anxiety disorders and depression were no longer predictive of drug use disorders. Findings are discussed in terms of their usefulness for prevention and treatment of drug use disorders. ^

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 investigation of multiple pathways of developmental intervention change

Convergence among treatment, prevention, and developmental intervention approaches has led to the recognition of the need for evaluation models and research designs that employ a full range of evaluation information to provide an empirical basis for enhancing the efficiency, efficacy, and effectiveness of prevention and positive development interventions. This study reports an investigation of a positive youth development program using an Outcome Mediation Cascade (OMC) evaluation model, an integrated model for evaluating the empirical intersection between intervention and developmental processes. The Changing Lives Program (CLP) is a community supported positive youth development intervention implemented in a practice setting as a selective/indicated program for multi-ethnic, multi-problem at risk youth in urban alternative high schools. This study used a Relational Data Analysis integration of quantitative and qualitative data analysis strategies, including the use of both fixed and free response measures and a structural equation modeling approach, to construct and evaluate the hypothesized OMC model. Findings indicated that the hypothesized model fit the data (χ2 (7) = 6.991, p = .43; RMSEA = .00; CFI = 1.00; WRMR = .459). Findings also provided preliminary evidence consistent with the hypothesis that in addition to having effects on targeted positive outcomes, PYD interventions are likely to have progressive cascading effects on untargeted problem outcomes that operate through effects on positive outcomes. Furthermore, the general pattern of findings suggested the need to use methods capable of capturing both quantitative and qualitative change in order to increase the likelihood of identifying more complete theory informed empirically supported models of developmental intervention change processes.

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.

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.

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. ^

Individual Child Cognitive Behavioral Treatment versus Child-Parent Cognitive Behavioral Treatments for Anxiety Disorders in Children and Adolescents: Comparative Outcomes

Anxiety disorders; such as separation anxiety disorder, generalized anxiety disorder, social phobia and specific phobia, are widespread in children and adolescents. Cognitive behavioral therapy (CBT) has been shown to be effective in reducing excessive fears and anxieties in children and adolescents. Research has produced equivocal findings that involving parents in treatment of child anxiety enhances effects over individual CBT (ICBT). The present dissertation study examined whether parental involvement can enhance individual treatment effect if the parent conditions are streamlined by targeting specific parental variables. The first parent condition, Parent Reinforcement Skills Training (RFST), involved increasing mothers’ use of positive reinforcement and decreasing use of negative reinforcement. The second parent condition, Parent Relationship Skill Training (RLST), involved increasing maternal child acceptance and decreasing maternal control (or increasing autonomy granting). Results of the present dissertation findings support the use of all three treatment conditions (ICBT, RLST, RFST) for child anxiety; that is, significant reductions in anxiety were found in each of the three treatment conditions. No significant differences were found between treatment conditions with respect to diagnostic recovery rate, clinician rating, and parent rating of child anxiety. Significant differences between conditions were found on child self rating of anxiety, with some evidence to support the superiority of RLST and RFST to ICBT. These findings support the efficacy of individual, as well as parent involved CBT, and provide mixed evidence with respect to the superiority of parent involved CBT over ICBT. The conceptual, empirical, and clinical implications of the findings are discussed.