Rochelle Caplan, MD - US grants

This is a proposal to study formal thought disorder in mid- and late-childhood psychoses. The proposed research portion project will incorporate cognitive and linguistic elements into the Childhood Psychoses Formal Thought Disorder Rating Scale (CPFTD-RS), developed by the PI for an evaluation in children of the DSM-III's formal thought disorder symptoms. Age-related changes in the measurement of formal thought disorder will be assessed in normal and psychotic children, aged 5-12 years; as well as an assessment of the relationship between formal thought disorder and language and cognitive deficits in psychotic children. The occurrence of formal thought disorder will be determined in three subgroups of childhood psychoses: Schizophrenia, schizotypal personality disorder, and childhood onset pervasive developmental disorder. Each of these groups will be equally represented in a sample of 108 boys, and will be compared to 72 normal boys on the CPFTD-RS, the Curtiss-Yamada Comprehensive Language Evaluation (CYCLE), and on cognitive measures of memory, metamemory, attention, metaattention, conservation, and IQ. The purpose of the supervised research and development portion of the proposal is to train the PI in those skills necessary to rigorously conduct the research project. Although the PI has clinical and research expertise in child psychiatry, she needs supplemental training in language development, cognitive development, and psychometrics. This training will contribute to the inclusion of developmental considerations into the CPFTD-RS. The value of the psychometric training is that the methodological and statistical basis of the CPFTD-RS can then be perfected. This proposed research is particularly important for future research on childhood psychoses. It will provide a reliable method for the evaluation of formal thought disorder in children, and will allow the discipline of child psychiatry to overcome a major obstacle to reliable diagnosis of the childhood psychoses.

The proposed study extends the PI's preliminary work and examines hypotheses on the developmental impact of complex partial seizure disorder (CPSD) on children's thought processes. It will identify the complex relationships between impaired thought processes (i.e., formal thought disorder and discourse deficits) and biological, cognitive, linguistic, and behavioral variables in pediatric CPSD. This research will examine if impaired thought processes in children with CPSD are associated with focal fronto-temporal involvement by comparing measures of formal thought disorder and discourse in these children to those of children with primary generalized epilepsy with absences (PGE) and to normal children. Within each seizure disorder group, this study will assess the developmental impact of early age of onset, frequent seizures, and elevated blood levels of multiple antiepileptic drugs on the severity of impaired thought processes. Due to the complex effects of the biological properties of epilepsy on the child's functioning, this study will also examine if the impaired thought processes of children with CPSD reflect attention/cognitive, language, and behavioral dysfunction. Finally, it will also determine if frontal lobe dysfunction is associated with the impaired thought processes of children with CPSD. If the study's hypotheses are confirmed, the findings of the proposed research will make three important contributions. First, they will identify impaired thought processes as a developmental disability that reflects the impact of the biological properties of CPSD on the maturation of children's thinking. Second, they will pave the way for educational detection and remedial intervention by replicating the PI's preliminary finding that CPSD subjects with IQ scores below and above average have respectively. Third, they will determine if children with CPSD have interictal language dysfunction and its relationship to impaired thought processes and cognitive dysfunction.

The proposed study will examine the social communication and neuroanatomical correlates of autistic disorder (i.e., qualitative impairment in social interaction, qualitative impairment in communication. restricted repetitive stereotyped patterns of behavior. interests. and activities) in a cohort of surgically treated children with infantile spasms. We will also examine the degree of tuberous sclerosis (TSC)-like changes and cortical dysplasias in the resected brain tissue of these children. and determine its correlation with the diagnosis of autism. Specific Aims 1. We will examine the hypothesis that surgically treated children with infantile spasms who meet criteria for autistic disorder have specific social communication deficits (i.e., underutilization of joint attention and social interaction, impaired distribution of positive affect during nonverbal communication) at the 2 year follow-up after surgery compared to those who do not meet criteria for autistic disorder. 2. We will examine the hypothesis that the resected hemisphere of the surgically treated infantile spasms patients who meet criteria for autistic disorder has more severe cortical dysplasia with TSC-like lesions than the patients who do not meet criteria for autistic disorder. 3. We will test the hypothesis that, compared to the children who do not meet criteria for autistic disorder, the nonresected hemisphere of the children who meet criteria for autistic disorder will have: a) presurgical FDG hypometabolism of the temporal, parietal, and/or frontal lobes b) postsurgical MRI evidence for increased volume of the nonresected hemisphere and reduced area of cerebellar lobules VI and VII. 4. We will examine hypotheses that an intact remaining hemisphere can support social communication by determining if the postoperative change in specific social communication behaviors are associated with presurgical FDG metabolic patterns.

Specific Aims 1. To use MR technology to study neurodevelopmental abnormalities in schizophrenia, as revealed through gyrification patterns and the presence of abnormalities in midline structures such as the thalamus 2. To extend our work defining and quantifying surface anatomy to the development of "flat maps" that will provide additional measures of surface complexity 3. To examine hypothesized anatomic substrates of cognitive dysmetria by measuring specific nodes on the CCTCC (e.g.. areas of prefrontal cortex, cerebellum. and thalamus) 4. To develop methods to parcellate and measure structural characteristics of the prefrontal cortex, using indices of sulca/gyral anatomy thus far developed 5. To develop methods to measure structural characteristics of the cerebellum (including both deep nuclei and surface anatomy) using MR 6. To apply the technique of neural networks to develop reliable and automated measures of neural structures relevant to schizophrenia 7. To examine the relationship between CCTCC abnormalities, symptom patterns, and cognitive performance

This prospective study will determine if uncontrolled seizures over time impair development by comparing measures of morphometry, cognition, thought disorder, and psychopathology in 6 - 18 year old children with complex partial seizure disorder (CPS), primary generalized epilepsy with absences (PGE), and normal children at baseline and 2 years later. By including nonepileptic siblings of the CPS, PGE, and normal subjects, the project will ascertain if the hypothesized developmental abnormalities in the patients are epilepsy-related rather than familial. Specific Aims: The study will test 3 main hypotheses: (a) CPS and PGE patients with an increase in seizure frequency from baseline through the 2 year follow-up will have a drop in IQ and an associated increase in thought disorder and psychopathology compared to patients with a decrease in seizure frequency and the normal subjects. (b) The patients with an increase in seizure frequency will have a smaller age-related increase in mesial temporal lobe (i.e., hippocampus, amygdala) and frontal lobe white matter volumes than the patients with a decrease in seizure frequency and the normal subjects. (c) The smaller age-related increase in mesial temporal lobe and frontal lobe white matter volumes will be associated with the predicted drop in IQ, and increase in thought disorder and psychopathology in the patients with uncontrolled seizures. Significance: By addressing the on-going debate "Do seizures impair development?" the study's findings will delineate neurobiologic mechanisms of impaired cognition, thought disorder, and psychopathology in middle childhood epilepsy. They will underscore the importance of medical control of seizures to promote optimal development of cognition, communication, and behavior in these children. They will highlight the potential use of MRI for identifying children at risk for thought disorder and pave the way for future studies on treatment and prevention of thought disorder and psychopathology in pediatric CPS and PGE. Research Design and Methods: The study mill recruit 40 CPS, 40 PGE, and 40 normal children matched on age, gender, ethnicity, and socioeconomic status. Twenty-five siblings of the CPS, PGE, and normal subjects will also participate in the study. Each subject will undergo an MRI, as well as cognitive, thought disorder, behavioral, and linguistic testing at baseline and 2 years later. Weekly seizure frequency data will be obtained on a monthly basis from the parent during the 2 years.

0-11 years old; 21+ years old; Adult; Area; Area, Broca; Brain; Broca's area; CRISP; Child; Child Youth; Childhood; Children (0-21); Clinical; Code; Coding System; Collection; Communication; Complex Partial Epilepsy; Complex Partial Seizure Disorder; Computer Retrieval of Information on Scientific Projects Database; Development; Disease; Disorder; Dysfunction; Encephalon; Encephalons; Epilepsy, Complex Partial; Epilepsy, Psychic Equivalent; Epilepsy, Psychomotor; Functional Magnetic Resonance Imaging; Functional disorder; Funding; Future; Gender; GeneHomolog; Grant; Handedness; Homolog; Homologous Gene; Homologue; Human, Adult; Human, Child; Impairment; Inferior Frontal Convolution; Inferior frontal gyrus; Institution; Intervention Studies; Investigators; Knowledge; Language; Laterality; Left; Linguistic; Linguistics; MR Imaging; MR Tomography; MRI; MRI, Functional; Magnetic Resonance Imaging; Magnetic Resonance Imaging Scan; Magnetic Resonance Imaging, Functional; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; Memory; Mental Health; Mental Hygiene; Morbidity; Morbidity - disease rate; NIH; NMR Imaging; NMR Tomography; National Institutes of Health; National Institutes of Health (U.S.); Nervous System, Brain; Neural Pathways; Neurologist; Nuclear Magnetic Resonance Imaging; Onset of illness; Pathway interactions; Pattern; Physiopathology; Prefrontal Cortex; Procedures; Process; Psychological Health; Research; Research Personnel; Research Resources; Researchers; Resources; Sampling; Schizophrenia; Schizophrenic Disorders; Semantic; Semantics; Societies; Source; Speech; Structure; Structure of Broca's area; Superior temporal gyrus; Symptoms; Testing; Thinking; Thinking, function; United States National Institutes of Health; Zeugmatography; adult human (21+); aged; children; cohesion; cost; dementia praecox; disease onset; disease/disorder; disorder onset; executive control; executive function; fMRI; improved; insight; network models; neuroimaging; normal aging; pathophysiology; pathway; pediatric; prevent; preventing; repair; repaired; schizophrenic; skills; social; syntactic; syntax; youngster

0-11 years old; 18 year old; Active Follow-up; Address; Age; Ammon Horn; Amygdala; Amygdaloid Body; Amygdaloid Nucleus; Amygdaloid structure; Behavior Disorders; CRISP; Child; Child Development Disorders; Child Youth; Childhood; Children (0-21); Cognition; Cognitive; Cognitive Disturbance; Cognitive Impairment; Cognitive decline; Cognitive function abnormal; Complex Partial Epilepsy; Complex Partial Seizure Disorder; Computer Retrieval of Information on Scientific Projects Database; Cornu Ammonis; Data; Development; Developmental Disabilities; Disease; Disorder; Disturbance in cognition; Drops; Epilepsy; Epilepsy, Complex Partial; Epilepsy, Generalized; Epilepsy, Psychic Equivalent; Epilepsy, Psychomotor; Epileptic Seizures; Epileptics; Ethnic Origin; Ethnicity; Ethnicity aspects; Frequencies (time pattern); Frequency; Funding; Future; Gender; Generalized Epilepsy; Grant; Hippocampus; Hippocampus (Brain); Human, Child; Impaired cognition; Institution; Investigators; Linguistic; Linguistics; MR Imaging; MR Tomography; MRI; Magnetic Resonance Imaging; Magnetic Resonance Imaging Scan; Measures; Medical; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; Methods; NIH; NMR Imaging; NMR Tomography; National Institutes of Health; National Institutes of Health (U.S.); Nuclear Magnetic Resonance Imaging; Parents; Patients; Prevention; Prospective Studies; Psychopath; Psychopathology; Recruitment Activity; Research; Research Design; Research Personnel; Research Resources; Researchers; Resources; Risk; Seizure Disorder; Seizure Disorder, Generalized; Seizures; Siblings; Socio-economic status; Socioeconomic Status; Source; Status, Socioeconomic; Study Type; Temporal Lobe; Testing; Thinking; Thinking, function; Time; United States National Institutes of Health; Zeugmatography; abnormal psychology; age dependent; age related; amygdaloid nuclear complex; base; behavioral disorder; children; cognitive dysfunction; cognitive loss; cognitively impaired; communication behavior; disease/disorder; eighteen year old; epilepsia; epileptiform; epileptogenic; follow-up; frontal cortex; frontal lobe; hippocampal; morphometry; pediatric; recruit; study design; substantia alba; temporal cortex; temporal lobe/cortex; white matter; youngster