Executive Dysfunction is Predictive of Clinical Symptomatology in 22q11.2 Deletion Syndrome

Transcription

1 Loma Linda University Digital Archive of Research, Scholarship & Creative Works Loma Linda University Electronic Theses, Dissertations & Projects Executive Dysfunction is Predictive of Clinical Symptomatology in 22q11.2 Deletion Syndrome Chinonyere Kemdirim Bello Follow this and additional works at: Part of the Clinical Psychology Commons Recommended Citation Bello, Chinonyere Kemdirim, "Executive Dysfunction is Predictive of Clinical Symptomatology in 22q11.2 Deletion Syndrome" (2015). Loma Linda University Electronic Theses, Dissertations & Projects This Dissertation is brought to you for free and open access by Digital Archive of Research, Scholarship & Creative Works. It has been accepted for inclusion in Loma Linda University Electronic Theses, Dissertations & Projects by an authorized administrator of Digital Archive of Research, Scholarship & Creative Works. For more information, please contact

2 LOMA LINDA UNIVERSITY School of Behavioral Health in conjunction with the Faculty of Graduate Studies Executive Dysfunction is Predictive of Clinical Symptomatology in 22q11.2 Deletion Syndrome by Chinonyere Kemdirim Bello A Dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Clinical Psychology December 2015

3 2015 Chinonyere Kemdirim Bello All Rights Reserved

4 Each person whose signature appears below certifies that this dissertation in his/her opinion is adequate, in scope and quality, as a dissertation for the degree Doctor of Philosophy. Richard E. Hartman, Associate Professor of Psychology, Chairperson Carrie E Bearden, Associate Professor, Semel Institute, University of California, Los Angeles Louis E. Jenkins, Professor Emeritus of Psychology David A. Vermeersch, Professor of Psychology iii

5 ACKNOWLEDGEMENTS I would like to thank Dr. Carrie Bearden for allowing me to take part in her research study and for helping me every step of the way to accomplish this project. I hope I made you proud! I would also like to thank my committee for all of the support and helpful suggestions they provided. Last, but not least, I would like to thank my husband, family, and friends for their tireless encouragement. Without your love and support I would not have made it this far in my academic journey. iv

6 CONTENT Approval Page... iii Acknowledgements... iv List of Figures... viii List of Tables...x List of Abbreviations... xi Abstract... xiii Chapter 1. Introduction...1 Schizophrenia q11.2 deletion syndrome q11.2 deletion syndrome...4 Behavioral phenotype of 22qDS...4 Psychiatric phenotype of 22qDS...5 Cognitive phenotype of 22qDS Psychoses/Schizophrenia and neurocognition...13 Research studies...13 Deficits in cognition Materials and Methods...18 Objective...18 Hypotheses...19 Study Design...19 Trail-making Test Part B...20 University of Maryland Letter Number Span...20 D-KEFS Verbal Fluency...21 Rey Osterrieth Complex Figure Test...21 The Structured Interview for Prodromal Syndromes (SIPS)...22 Research Site and Procedures...23 Cognitive Testing...23 v

7 Interviews/Questionnaires...26 Statistical Analyses...25 T-tests...25 Pearson s correlations...25 Regression...25 Power Analyses Results...27 Independent Samples t-test...27 Pearson s correlations...29 Regression...30 Discussion...34 Limitations...36 Future directions...36 References...38 Appendices A. The del22q11.2 region on chromosome B. Facial dysmorphia...49 C. Organization of the SIPS and the SOPS and listing of associated acronyms...50 vi

8 FIGURES Figures Page 1. Group Differences Variance Explained by Regression with Rey Osterrieth Complex Figure Test Copy Portion and Executive Measures Predicting Total Positive Symptoms Variance Explained by Regression with Rey Osterrieth Complex Figure Test Copy Portion and Executive Measures Predicting Total Negative Symptoms...33 vii

9 TABLES Tables Page 1. Subject Demographics Mean Scores of Cognitive Measures for 22qDS and Controls Summary of Correlational Analyses Results of Regression with Rey Osterrieth Complex Figure Test Copy Portion and Executive Measures Predicting Total Positive Symptoms Results of Regression with Rey Osterrieth Complex Figure Test Copy Portion and Executive Measures Predicting Total Negative Symptoms...33 viii

10 ABBREVIATIONS 22qDS SIPS LNS ROCFT D-KEFS Comp Matrix TMT-B VCFS FISH ADHD DSM-IV fmri NVLD SSRS BRIEF NEPSY CBCL WISC WIAT MATRICS ADOS 22q11.2 Deletion Syndrome Structured Interview for Prodromal Syndromes Letter-Number Sequencing Rey Osterrieth Complex Figure Test copy portion Delis Kaplan Executive Function System Verbal Fluency Composite Score Matrix Reasoning Trail-making Test Part B Velo-cardio-facial syndrome Fluorescence In Situ Hybridization Attention deficit hyperactivity disorder Diagnostic and statistical manual of mental disorders fourth edition Functional magnetic resonance imaging Non-verbal learning disability Social skills rating system Behavior inventory of executive function A developmental neuropsychological assessment Child behavior checklist Wechsler intelligence scale for children Wechsler individual achievement test Measurement and treatment research to improve cognition in schizophrenia Autism diagnostic observation schedule ix

11 ADI-R DISC Autism diagnostic interview revised Diagnostic interview schedule for children x

12 ABSTRACT OF THE DISSERTATION Executive Dysfunction is Predictive of Clinical Symptomatology in 22q11.2 Deletion Syndrome by Chinonyere Kemdirim Bello Doctor of Philosophy, Graduate Program in Clinical Psychology Loma Linda University, December 2015 Dr. Carrie Bearden, Dr. Richard Hartman, Chairpersons By adulthood, 25%- 30% of individuals with 22q11.2 deletion syndrome (22qDS) develop a psychotic disorder, often schizophrenia, and it is not understood why. Given the known genetic etiology of this disorder and the greatly elevated risk for development of schizophrenia, this group offers the possibility of defining a seemingly homogenous maturational pathway to psychosis. Neurocognitive deficits have been increasingly recognized as an important dimension of schizophrenia, particularly in the executive domain. Thus, we assessed multiple aspects of executive cognition in 22qDS, in order to: 1) characterize performance across this domain as compared to age-matched healthy controls; and 2) determine whether executive function performance is significantly predictive of positive and negative psychotic symptoms in 22qDS above and beyond nonverbal functioning. We assessed psychomotor speed and mental flexibility (Trails-B), working memory (Letter-Number Sequencing: LNS) and D-KEFS verbal fluency. Psychotic symptomatology was measured using scores obtained from the Structured Interview for Prodromal Syndromes (SIPS). 22qDS patients (N= 48, mean age: 15.23) showed impairment relative to healthy controls (N= 37, mean age: 14.97) on all measures of executive functioning. Regression analysis revealed that executive deficits are xi

13 predictive of positive psychological symptomatology above and beyond non-verbal deficits. Specifically, D-KEFS verbal fluency added meaningfully to the prediction of positive psychiatric symptoms. Given this significant prediction it is suggested that executive function may be an important domain for providing information about the development of psychosis. xii

14 CHAPTER ONE INTRODUCTION Schizophrenia Schizophrenia is a debilitating disorder that places a burden on the individual, family unit, and society (Harrison, & Weinberger, 2005). The cost to the individual involves personal suffering, while the detriment to the family unit involves the burden of care giving. Society is disrupted by the individual s hospitalizations, need for long-term care, and loss of productivity (Davis & Drummond, 1994; Guest & Cookson, 1999). A review by Knapp et al. (2004) examined the cost-of-illness estimate internationally. They suggested that the expense includes national total, direct, and indirect costs; direct, indirect, and total costs per patient each year; inpatient services, medication, lost productivity, mortality, family impact, and criminal justice system costs. Given the expenditure involved with schizophrenia, it is widely studied specifically for its genetic basis. However, despite intensive search for the schizophrenia susceptibility gene, the genetic basis of this disorder remains elusive (Baron, 2001). 22q11.2 deletion syndrome (22qDS) may provide a means of advancing our understanding of the pathophysiology underlying the development of schizophrenia. By adulthood, approximately 25% to 30% of individuals with 22qDS develop a psychotic disorder, often schizophrenia (Bassett & Chow 1999; Murphy 2002; Murphy, Jones, & Owen, 1999; Murphy & Owen, 1996) and it is not understood why. Due to the high frequency of schizophrenia in 22qDS patients, the 22q11.2 region is now thought to be one of the main schizophrenia susceptibility loci in humans (Bassett and Chow 2008; Insel 2010). Cognitive deficits, particularly executive dysfunction are core features of 1

15 schizophrenia. These deficits are relatively stable across clinical state changes and are present before the onset of clinical/psychotic symptoms (Levin et al. 1989; Crawford et al. 1993; Evans et al. 1997). Executive deficits are also prominent in 22qDS. Therefore given these relationships, we evaluated whether executive deficits are associated with clinical symptomatology. 22q11.2 deletion syndrome 22q11.2 deletion syndrome, velo-cardio-facial syndrome (VCFS), DiGeorge syndrome, and Shprintzen syndrome are all different names for a chromosomal deletion of one segment of the chromosome pair at band q11.2. These syndromes were all originally thought to be different genetic conditions but it is now known that they all refer to individuals who have a 1.5 to 3 megabase (unit of length for DNA fragments) microdeletion on the long (q) arm of chromosome 22 (Shprintzen, 2008) (See Appendix A). The 1.5 to 3 megabase microdeletion covers a region containing 35 to 60 genes (Drew et al., 2011; Edelmann et al., 1999). The deletion can be detected by a diagnostic procedure called Fluorescence In Situ Hybridization (FISH). This procedure is used to detect and localize the presence or absence of specific DNA sequences on chromosomes FISH uses fluorescent probes that bind to the missing segment of DNA on one chromosome if it is missing (Amann & Fuchs, 2008). With this procedure, 22q11.2DS is now often detected in infancy via genetic testing. We will refer to this condition as 22qDS. 22qDS is one of the most common multiple anomaly syndromes in human beings. Its prevalence is estimated at 1/4000 live births (Basset et al, 1998). Up to 93% of cases occur de novo, whereas 7% of deletions are inherited from a parent (Phillip and Basset, 2011). 22qDS is characterized by 2

16 multiple developmental anomalies; over 180 have been identified (Shprintzen, 2000). These include cleft palate and velopharyngeal insufficiency which is a condition characterized by hypernasal speech, nasal emission and turbulence, and in some cases nasal regurgitation of fluids (Saunders, Hartley, Sell & Somerlad, 2004). Furthermore, the anomalies include hypernasality, cardiac defects, endrocrinological and neurological problems (Robin & Shprintzen, 2005). Craniofacial anomalies (cleft-palate, velopharyngeal insufficiency) occur in % of children born with this syndrome. Thymic and parathyroid defects including hypocalcemia (low serum calcium blood levels) occur in 17-60% of children born with this condition. Cardiovascular problems occur in 70% of children with 22qDS, as the first presenting symptom is usually a congenital heart defect (Robin and Shprintzen, 2005; Kobrynski and Sullivan, 2007). The multiple anomalies of 22qDS are associated with behavioral, psychiatric, and cognitive phenotypes. 3

17 CHAPTER TWO 22Q11.2 DELETION SYNDROME Behavioral Phenotype of 22qDS The behavioral phenotype of 22qDS was first described by Golding- Kushner et al. (1985). They suggested that there is a distinctive temperament that severely hinders successful social contact. Golding-Kushner and colleagues explained a profile of withdrawn, socially isolated individuals that displayed extremes of behavior including disinhibition, impulsiveness, and shyness. Papolos, Faedda, Veit, Goldberg, Morrow and Kucherlapati (1996) described a profile comparable to Golding-Kushner of 22qDS during childhood as they suggested this phenotype to include disinhibition, inattention, impulsivity, anxiety, schizoid features, social withdrawal, and flat affect. Similarly, Antshel et al. (2007) found that children with 22qDS were rated by their parents as being: less regular in their daily habits; less able to focus/sustain attention; less cheerful/pleasant; less likely to stay with an activity for a long time; and less able to respond flexibly to changes in the environment. Aneja et al., (2007) found that manic symptoms in 22qDS predicted significantly elevated scores on four Child Behavior Checklist (CBCL) subscales, namely anxiety, somatization, thought, and conduct problems. There are other behavioral features indicated in 22qDS, but they are not well captured by standard assessment scales. These include difficulties socializing, dependency on a caregiver, impulsivity, temper outbursts, perseverative speech and repetitive behaviors (Bassett et al., 2003; Swillen et al., 2000). There is also an associated psychiatric phenotype with this syndrome, as described below. 4

18 Psychiatric Phenotype of 22qDS There are several psychiatric disorders related to 22qDS, with Attention deficit hyperactivity disorder (ADHD) being the most prevalent. ADHD occurs in approximately one-third to half of all children with 22qDS (Gothelf, Presburger, Namani et al., 2004; Antshel et al., 2006; Zagursky et al., 2006). High rates of affective disorders, anxiety disorders, phobic disorders, and obsessive- compulsive disorders in children and adults with 22qDS have been reported as well (Murphy, Jones, and Owen, 1999; Feinstein et al., 2002; Gothelf et al., 2004; Antshel et al., 2006). Several studies have assessed and characterized psychiatric features in this population. In particular, using structured diagnostic interviews Papalos et al., 1996 found that 64% (N = 16 of 25) of patients met DSM-III-R criteria for a spectrum of bipolar disorders with full syndromal onset in late childhood or early adolescence (mean age at onset = 12 years, SD = 3). In addition, 20% (N = 5) met DSM-III-R criteria for attention deficit hyperactivity disorder (ADHD), and 16% (N = 4) met criteria for attention deficit disorder without hyperactivity. Similarly, using the Children's Interview for Psychiatric Symptoms, Child (ChIPS) and Parent (P-ChIPS) Forms (Weller et al., 2000), Jolin et al., 1998) found that participants had a mean of two DSM-IV psychiatric disorders. 79% of these participants met criteria for at least one DSM-IV psychiatric disorder and over one third had three or more diagnoses. 12.5% met criteria for major depression, 54% for anxiety disorders, 38% for attention-deficit/hyperactivity disorder, and 38% for oppositional defiant disorder. Notably, in adulthood many of these children develop psychoses, specifically schizophrenia. By adulthood, estimates of approximately 25%- 30% have been reported of individuals with 22qDS developing a severe psychiatric disorder, often schizophrenia 5

19 (Bassett & Chow 1999; Murphy 2002; Murphy, Jones, & Owen, 1999; Murphy & Owen, 1996) and it is not understood why. However, due to the high frequency of schizophrenia in 22qDS patients, the 22q11.2 region is now thought to be one of the main schizophrenia susceptibility loci in humans (Bassett and Chow 2008; Insel 2010). Conversely, about 1% of individuals with schizophrenia in the general population have 22q11.2 deletions (Bassett et al. 2010). In a sample of 100 patients with 22qDS Shprintzen et al. (1997) and Chow et al. (1999) found that by adulthood, 10-30% met criteria for chronic paranoid schizophrenia. This finding was congruent with what Shprintzen and colleagues discovered in They reported psychotic symptoms, which they described as resembling chronic paranoid schizophrenia in 12 of 90 children and adults with 22qDS (Shprintzen et al., 1992). Participants with 22qDS, an age and IQ matched control group, and the parents/caregivers for participants under age 16 completed a semi-structured interview. The Child and Adolescent Psychiatric Assessment (CAPA; Angold et al, 1995) was used to obtain a descriptive record of each participant s current and previous (3 months) mental-state. Psychiatric disorders were more prevalent among those with the syndrome and included attention deficit, depression, and anxiety symptoms. Additionally, nearly half of the participants with 22qDS reported transient psychotic experiences (Baker and Skuse, 2005). Gothelf and colleagues conducted baseline psychiatric, psychological, and adaptive functioning evaluations of children with 22qDS and comparison subjects with idiopathic developmental disability matched for age and IQ. Five years later the participants were evaluated again. Although the two groups had similar baseline 6

20 neuropsychiatric profiles, at follow up 32% of the 22qDS group met DSM-IV criteria for psychotic depression, schizoaffective disorder, schizophrenia or schizophreniform disorder (Gothelf et al., 2007). Furthermore, Murphy et al. (1999) evaluated adults with 22qDS using either the Schedules for Clinical Assessment in Neuropsychiatry or Psychiatric Assessment Schedule for Adults With Developmental Disability if their IQ was lower than 50. Results revealed that 30% of the adults with 22qDS had a psychotic disorder, and 24% met DSM-IV criteria for schizophrenia. In addition to high rates of psychopathology and particularly psychosis, a characteristic cognitive profile has also been observed. However, the specific cognitive risk factors for the development of psychosis have not yet been identified. Cognitive Phenotype of 22qDS 22qDS is associated with general cognitive functioning in the low borderline range to mentally retarded range (Antshel et al, 2008; Eliez et al., 2000). De Smedt, Devriendt, Fryns, Vogels, Gewillig, and Swillen (2007) found that 60% of the children showed borderline to normal intelligence (FSIQ > 70), whereas an intellectual disability (FSIQ < 70) was noted in 40% of the children. The 22qDS cognitive profile includes impairment in speech and language. Speech onset is mildly delayed and receptive language tends to develop more rapidly than expressive language. These children often have a hypernasal speech pattern (75%) and articulation impairment (Golding-Kushner, 2000). Neuropsychological testing in this population suggests a relative strength in verbal abilities relative to non-verbal abilities (Bearden, Woodin, Wang, Moss, McDonald-McGinn, Zackai, Emanuel, & Cannon, 2001; Wang et al., 1998). In early 7

21 childhood, many individuals with the syndrome present with a cognitive profile that is similar to that profile identified in children with non-verbal learning disabilities (NVLD), i.e., performance IQ significantly lower than verbal IQ (Goldberg et al., 1992; De Smedt et al., 2009; Jacobson et al., 2010; Swillen et al., 1999; Moss et al., 1999; Swillen et al, 2000). Goldberg, Motzkin, Marion, Scambler, and Shprintzen (1992) suggests that this discrepancy is related to a combination of impairments in visuospatial ability, planning ability, non-verbal reasoning, and deficits in novel reasoning and concept formation. Henry, Van Amelsvoort, Morris, Owen, Murphy, and Murphy (2002) found that in comparison to demographically matched controls, 22qDS participants demonstrated significant impairments in visuoperceptual ability, problem solving and planning, and abstract and social thinking. These demonstrated deficits are similar to the ones suggested by Goldberg and colleagues (1992). Bearden et al. (2001) assessed 22qDS children with a comprehensive neuropsychological battery to evaluate the nonverbal learning deficit that has been previously identified in this population. A significant discrepancy was found between visual-spatial and verbal abilities within the domain of memory. This was taken to suggest that a differential impairment in visual-spatial information-processing exists, consistent with the previously found non-verbal deficits. Swillen et al. (1999) also found a Verbal IQ-Performance IQ discrepancy, in favor of VIQ, with significantly better scores for reading (decoding) and spelling. Weaknesses were seen in arithmetic, tactileperceptual skills, visual-perceptual abilities, visual-spatial skills, (extremely poor) psychomotor skills, processing of new and complex material, and visual attention. Eliez et al. (2001) conducted a fmri study of math reasoning in eight children with 22qDS. 8

22 Their results indicate that children with 22qDS showed less activation than controls in the angular gyrus, a posterior parietal brain region typically activated during such tasks. In addition, increased activation was observed in the left supramarginal gyrus as a function of task difficulty. Eliez et al. (2001) concluded that children with 22qDS may utilize an atypical and less effective circuit for completing math problems, which may lead to impairment. Furthermore, visual attention impairment was also noted in a study by Sobin et al. (2005). Deficits in executive function and planning are also a prominent part of the 22qDS cognitive phenotype. Goldman-Rakic has defined executive function as a set of various interrelated cognitive abilities that operate metaphorically as a company executive and are thought to be largely mediated by prefrontal-parietal and prefrontal-subcortical circuits (Goldman-Rakic, 1995). Executive function includes planning, cognitive flexibility, abstract thinking, rule acquisition, initiating appropriate actions and inhibiting inappropriate actions, and selecting relevant sensory information (Stuss and Knight, 2002). The executive functions that are most often evaluated in the 22qDS literature are cognitive flexibility, response inhibition, and working memory both verbal and nonverbal. Previous research has demonstrated an executive deficit in 22qDS behaviorally, anatomically, and in the performance of neuropsychological tasks. In a study by Kiley-Brabeck and Sobin parents rated their child with 22qDS and the unaffected sibling with the Social Skills Rating System (SSRS) and Behavior Inventory of Executive Function (BRIEF). Children with 22qDS had significantly lower SSRS ratings for cooperation, assertion, responsibility, and self-control. On the BRIEF the 22qDS children had significantly higher ratings for initiation, planning, working 9

23 memory, and monitoring. These results indicate that the children with 22qDS display poor executive functioning in that they have lower initiation, planning, working memory, and monitoring skills as compared to their unaffected siblings (Kiley- Brabeck and Sobin, 2006). Sobin and colleagues also demonstrated a deficit in executive function in 22qDS as compared to their unaffected sibling. Participants were administered a developmental neuropsychological assessment (NEPSY) and the Stanford Binet Intelligence Scale. Although, no differences were found between the groups on tests of verbal or quantitative ability, children with 22qDS had impaired performance in the executive domain (Sobin et al., 2005). An earlier study by Sobin et al suggested an executive attention deficit in 22qDS as compared to unaffected siblings. Performances on specific tasks have been indicative of executive dysfunction in 22qDS. Woodin et al. (2001) used the Trail-making Test to examine cognitive function in 22qDS. Their results suggested that children and adolescents with 22qDS struggle more on the Trail-making test Part B, a test of cognitive flexibility and set-shifting. This result was suggestive of poorly developed working memory (Woodin et al., 2000). Lajiness- O Neill and colleagues examined the cognitive profile of children with 22qDS. Visualspatial working memory was found to be less well developed than simple object memory (Lajiness- O Neill et al., 2005). On the Wisconsin Card Sorting Test, Lewandowski et al. (2007) reported that children with 22qDS made more perseverative errors than control participants. Working memory deficits were demonstrated in a 22qDS group as compared to controls on a serial order task (Majerus et al., 2007). Furthermore, Wang et al. (2000) assessed verbal working memory using a digit span task. Children with 22qDS 10

24 performed less well than control participants. Anatomical studies have also indicated an executive deficit involved in 22qDS. In 2007, Kates and colleagues used functional magnetic resonance imaging (fmri) to examine neural activation during non-spatial working memory tasks in children with 22qDS, their unaffected siblings, and controls with the same proportion of learning disabilities as the 22qDS participants. Intelligence and academic achievement were assessed with the Wechsler Intelligence Scale for Children, 3rd Edition and the Wechsler Individual Achievement Test, 2nd edition (WIAT-II). A two back, non-spatial working memory task was administered while the participants were in the scanner. The task required participants to respond using a button box when they saw the same letter as two letters back for the experimental condition and during the control block, participants were asked to respond only to the letter X. Results revealed that during the experimental condition (relative to the control condition) individuals with 22qDS exhibited significant activation in the left and right inferior frontal gyri and the left and right inferior parietal lobule. However, in analyses where subjects were matched for performance, relative to performance-matched youth with 22qDS, both the control and the sibling samples recruited significantly more voxels in the frontal cortex, including the cingulate, the precentral gyrus, and the operculum. These findings suggest that frontal lobe function is disrupted in youth with 22qDS (Kates et al., 2007). Another study by Kates and colleagues examined the morphology of the frontal lobe and the caudate nucleus in children with 22qDS. Volumes of the caudate nucleus and frontal lobe were compared between 10 children with 22qDS and 10 matched controls. Frontal deep white matter was reduced significantly (by about 23%) in 11

25 participants with 22qDS relative to controls. Frontal and prefrontal volumes were also reduced as compared to controls. These findings suggest frontostriatal dysfunction in children with 22qDS (Kates et al. 2004). Cognitive impairment is also seen in psychoses/schizophrenia, with executive dysfunction being a prominent feature. 12

26 CHAPTER THREE PSYCHOSES/SCHIZOPHRENIA AND NEUROCOGNITION Research studies Neurocognitive deficits have been increasingly recognized as an important dimension of schizophrenia (Bilder et al., 2000; Green et al., 2000). Wide ranges of cognitive impairments have been reported in people with schizophrenia, particularly problems in attention, verbal and working memory, and executive function (Rushe et al., 1999; Morris et al., 1995; Kravariti et al., 2003). Kravariti and colleagues investigated cognitive function in adolescents with recent onset schizophrenia as compared to healthy controls. A comprehensive battery was used including measures of intelligence, memory, and executive function paradigms. Specifically, the executive paradigms evaluated were planning and problem solving, spatial working memory, sequencing and mental flexibility, and dual-task performance. Significant deficits were seen in the schizophrenia participants as compared to the controls. Deficits were seen in full scale IQ, performance IQ, verbal memory, visual memory, general memory, delayed recall, perceptual-motor processing time, betweensearch errors/spatial working memory, and spatial strategy. Problem solving ability was examined in participants with schizophrenia (DSM- III-R diagnosis) as compared to controls. The 3-D computerized Tower of London task was used. Participants with schizophrenia showed impairments in motor initiation and execution. They were also impaired on accuracy of problem solving which includes number of moves above the minimum and number of problems solved using the minimum number of moves. Results indicated that the schizophrenia group demonstrated 13

27 a pattern of performance that is similar to performances by participants with frontal lobe lesions (Morris, Rushe, Woodruffe, and Murray, 1995). Holmen and colleagues examined whether a battery of tests, the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS), would be useful in detecting differences between a schizophrenia group and healthy controls. Speed of processing, attention/vigilance, working memory, verbal learning, visual learning, reasoning and problem solving, social cognition, and intelligence were assessed. There were significant differences in the performances between the schizophrenia group and the controls on every domain except for social cognition. There was a generalized neurocognitive deficit of SD s compared with controls, with verbal learning, working memory, and visual learning being the most affected areas (Holmen et al., 2010). Bressi et al. (1996) evaluated the hypothesis that patients with schizophrenia have an impaired central executive component of working memory. Participants with schizophrenia (DSM-IV criteria) and age-education matched controls were asked to combine the performance on a computerized tracking task with articulatory suppression, simple reaction time (RT) to a tone, or auditory digit span concurrently. The schizophrenia group s performance deteriorated when tracking was combined with reaction time. The authors concluded that these results are reflective of a dysfunction of central executive working memory in schizophrenia (Bressi et al., 1996). Bilder and colleagues aimed to provide a comprehensive neuropsychological characterization of participants with schizophrenia after the first episode of illness as compared to healthy controls. Participants met diagnostic criteria for paranoid, 14

28 disorganized, catatonic, and undifferentiated schizophrenia or schizoaffective disorder. Neuropsychological testing was conducted to assess the language, memory, attention, executive, motor, and visuospatial domains. Results revealed that the schizophrenia group was more impaired than the comparison group on every neuropsychological dimension measured. The overall profile mean for the patients was 1.53, indicating a generalized deficit of approximately 1.5 standard deviations. The schizophrenia group showed greater impairment on certain domains. Specifically, this group demonstrated significantly more impairment on memory and executive areas (Bilder et al., 2000). Toulopoulou, Morris, Rabe-Hesketh, and Murray (2003) evaluated memory and executive processing in a group of schizophrenic patients, their healthy relatives, and normal controls. Verbal and visual memory was assessed as well as various aspects of executive function (problem solving, planning ability, spatial working memory, working memory, strategy formation, mental flexibility). Neuropsychological function in the patients was lower than that of their relatives, which in turn was lower than that of controls on most measures. Verbal memory/learning and visual memory/learning were impaired as well as aspects of executive function including planning and spatial working memory (Toulopoulou et al., 2003). Deficits in cognition Cognitive impairment is considered a core feature of schizophrenia that includes problems in speed of processing, attention/vigilance, verbal learning, visual learning, social cognition and executive aspects including working memory, cognitive flexibility, planning, and reasoning and problem solving (Green 2006, Goldman-Rakic 1986; Goldberg et al. 1990; Morris et al. 1995). As a core feature, these cognitive deficits are 15

29 not attributed to the symptoms of schizophrenia or of the treatment of the illness with antipsychotic medication. Instead, cognitive deficits are relatively stable across clinical state changes, present before the onset of clinical/psychotic symptoms, and may be seen in attenuated form in unaffected first-degree relatives of people with schizophrenia (Finklestein et al., 1997; Gold 2004; Crow, Done, and Sacker, 1995). Given this, it is important to assess cognitive function in 22qDS, considering its relationship with schizophrenia. Deficits in cognition, specifically executive deficits given their consistency and prominence in schizophrenia, may be associated with conversion to this disorder in 22qDS. Therefore, assessing whether these deficits are associated with psychological symptoms in 22qDS is valuable. It is important to understand the predictors of schizophrenia in 22qDS given that schizophrenia is considered to be the most expensive and difficult psychiatric disorder to treat (Capri 1994; Torrey 2002; Knapp 1997). One of the factors that greatly contributes to the cost and difficulty in treating the illness is functional impairment (Kenny and Meltzer, 1991). In 1996 Green suggested that these core cognitive deficits are an enduring feature of the illness and that these deficits are more important than positive and negative symptoms in predicting functional outcome. 16

30 CHAPTER FOUR MATERIALS AND METHODS Objective Given that people with 22qDS have high rates of psychosis in adulthood and it is not understood why, we are attempting to identify factors that might be associated with who is likely to develop psychosis. Executive functioning is a prominent feature in schizophrenia, thus we believe that executive deficits will be associated with psychotic symptoms. In fact in a study of four patients with 22qDS who developed schizophrenia, they were retrospectively discovered to have displayed delayed motor development, language deficits, learning disabilities, mental retardation, early age of onset, chronic and disabling course of illness and poor response to classical neuroleptic drugs and electroconvulsive therapy before adulthood (Gothelf et al., 1999). Premorbid assessment may have been able to identify these differences. Thus, we intend to evaluate child to early adulthood participants with 22qDS in terms of executive functioning to characterize performance across this domain as compared to age-matched healthy controls and to determine if executive deficits are associated with psychotic symptoms. Given that psychoses do not fully manifest until adulthood, efforts to recognize the more mild, subthreshold psychotic symptoms that occur in 30 50% of youth with 22qDS (Feinstein et al., 2002; Baker & Skuse, 2005), will be valuable. Increased methods to identify these premorbid symptoms are needed. It is possible that 22qDS patients who eventually develop psychosis exhibited subthreshold psychotic symptoms early on that differentiated them from those that did not go on to develop a psychotic disorder (Gothelf et al., 2004). We will examine if these subthreshold symptoms can be indicated by executive 17

31 dysfunction. Using executive deficits as an indication of psychopathology in 22qDS participants is novel. Although non-verbal learning deficits are characteristic in 22qDS, we speculate that executive function deficits will provide greater association with psychotic symptoms. Therefore, we will examine if executive deficits are associated with psychopathology above and beyond non-verbal deficits. We will evaluate the following hypotheses: Hypotheses 1. 22qDS patients will show the greatest impairment relative to healthy controls on measures of psychomotor speed and mental flexibility (Trail-making test part B), working memory (Letter-Number Sequencing), and the D-KEFS verbal fluency composite. 2. Executive deficits in working memory (Letter-Number Sequencing), and the D- KEFS verbal fluency composite will be significantly predictive of total positive and total negative symptomatology above and beyond non-verbal visuospatial deficits (copy portion of the Rey Osterrieth Complex Figure Test) in 22qDS patients. Study Design A cross-sectional design was used for this project. This project focused upon the Trail-making Test Part B, University of Maryland Letter-Number Span, and DKEFS Verbal Fluency as measures of executive function. To examine non-verbal function, the Rey Osterrieth Complex Figure Test was evaluated (ROCFT). The Structured Interview for Prodromal Syndromes (SIPS) was used to measure psychiatric symptoms. Psychotic 18

32 symptom severity is defined as a quantitative trait, according to SIPS criteria (i.e., ratings range from 0 [not present] to 6 [ severe and psychotic ]). Dimensional ratings of 3 or higher on SIPS positive symptoms ( prodromal or sub-psychotic range) are associated with high rates of subsequent conversion to overt psychosis and are also associated with substantial functional impairment. Total positive and total negative symptoms were obtained by adding together the ratings of individual questions. Trail-making Test Part B The Trail Making Test (Reitan and Wolfson, 1985) is a measure of attention, speed, and mental flexibility. It requires the participant to connect encircled numbers randomly arranged on a page in proper order and then encircled numbers and letters in alternating order. Test re-test reliability in young adults retested after an interval of three weeks on the TMT B was.75 (Bornstein et al., 1987). Inter-rater reliability for the TMT has been reported as.94 for part A and.90 for part B (Fals-Stewart, 1991). The validity of the TMT shows that Parts A and B correlate moderately well with each other (r=.31 to.60) suggesting that they measure similar although somewhat different functions (Heilbronner et al., 1991; Pineda and Merchan, 2003; Royan et al., 2004). Royan et al. (2004) reported that the TMT-B correlated moderately well with scores on other measures of speeded processing (i.e., Symbol Digit Modality Test and a variant of the PASAT). University of Maryland Letter-Number Span The University of Maryland Letter-Number Span task is a measure of verbal working memory. This task requires mental reordering of orally presented lists with 19

33 letters and numbers and repeating them back (Holmen at al., 2010). D-KEFS Verbal Fluency The Delis-Kaplan Executive Function System (D-KEFS) (Delis, et al., 2001) was designed to detect even the mildest forms of executive dysfunction (Delis, et al., 2004). The D-KEFS Verbal Fluency Test requires the participant to say words that begin with a specified letter, say words that belong to a designated semantic category, and alternate between saying words from two different semantic categories. The internal consistency for the verbal fluency test is reported to be marginal ( ), however the test re-test reliability is adequate ( ). In terms of validity, it ranges from.44 to.83 when comparing semantic category switching and letter fluency (Delis et al., 2004). This study utilized various aspects of verbal fluency including phonemic fluency, semantic fluency, category switching and switching accuracy. These aspects were averaged to create an overall verbal fluency composite score. Rey Osterrieth Complex Figure Test The Rey-Osterrieth Complex Figure Test (ROCFT) was designed to assess visualspatial constructional ability and visual memory. Examinees are asked to reproduce a complicated line drawing, first by copying and then from memory. It was developed by Rey (1941) and then was elaborated by Osterrieth (1944). Internal consistency was calculated by computing split-half and alpha coefficients (Berry et al., 1991; Fasteneau et al., 1996). Both split-half and coefficient alpha reliabilities were greater than.60 for the copy condition and.80 for recall conditions. Meyers and Meyers (1995) correlated scores of normal individual s performances on the ROCF and found the largest 20

34 correlations to be between immediate recall and delayed recall (r=.88). Immediate recall and delayed recall demonstrated low, but significant correlations with Recognition Total Correct (r=.15). The Structured Interview for Prodromal Syndromes (SIPS) The SIPS is a structured diagnostic interview used to identify the three prodromal syndromes. These syndromes are thought to be (1) frankly psychotic positive symptoms that appeared too brief and too intermittent to constitute a fully psychotic syndrome, (2) attenuated positive symptoms, and (3) functional decline in the presence of genetic risk (Yung et al. 1996, 1998). The SIPS includes the SOPS, the Schizotypal Personality Disorder Checklist (APA 1994), a family history questionnaire (Andreasen et al. 1977), and a version of the Global Assessment of Functioning scale (GAF; Hall 1995). The SIPS is used to operationally define the three prodromal syndromes using the Criteria of Prodromal Syndromes (COPS) and psychosis onset by evaluating the Presence of Psychotic Syndrome (POPS). Information from the COPS and the POPS are evaluated in terms of the positive symptoms of the schizotypal personality disorder checklist and the family history questionnaire in order to determine if a diagnosis of a prodromal syndrome or the presence of psychosis should be given. This diagnostic interview addresses positive, negative, disorganized, and general symptoms (see Appendix C). For the purposes of this study, we will only be focusing on total positive and total negative symptoms. Research Site and Procedures Participants between the ages of 10 and 25 with previously confirmed 22q11.2DS 21

35 were recruited through distribution of fliers to research sites and genetic clinics as well as word-of-mouth. Interested families contacted the research coordinator at UCLA and underwent an initial phone screening to determine eligibility. On the day of the visit, the child undergoes cognitive testing, magnetic resonance imaging (MRI), a blood draw, and the Autism Diagnostic Observation Schedule (ADOS). Depending on the age and cognitive ability, he or she is also asked to complete a short packet of questionnaires. The parent completes the Autism Diagnostic Interview-Revised (ADI-R), the Diagnostic Interview Schedule for Children (DISC), and a packet of questionnaires. Cognitive testing was conducted by advanced graduate students in clinical psychology and took place in a quiet room. The MRI was conducted at the Abrahamson-Lovelace Brain Mapping Center and autism diagnostic measures were administered by trained staff at the UCLA Autism Evaluation Clinic. All families received a summary report that included the results of cognitive testing as well as diagnostic impressions. Cognitive Testing The testing battery included measures of visuospatial ability such as the Rey Osterrieth Complex Figure Test (ROCFT) and the Children s Memory Scale (CMS) Faces and Dot Locations. The ROCFT is designed to assess visual-spatial constructional ability and visual memory (Rey, 1941; Osterrieth, 1944). Examinees are asked to reproduce a complicated line drawing, first by copying and then from memory. CMS Faces and Dot Locations assess recall for spatial location and recognition of human faces (Cohen, 1997). Social cognition was measured with the Animations task, Penn Emotion Identification/Discrimination Tasks, and Awareness of Social Inference Task (TASIT). The Animations task requires the examinee to observe shapes on a screen performing 22

36 human-like actions and describe what the shapes are doing. The Penn Emotion Identification/Discrimination Tasks is a computer-based test that includes 96 color photographs of facial expression of evoked or felt emotions: happy, sad, angry, fearful, disgusted, and non-emotional or neutral. Participants are asked to rate the emotional valence of each expression (Kohler, Turner, Bilker, Brensinger et al. 2003). The TASIT is an audiovisual tool designed for the clinical assessment of social perception. The task assesses emotion recognition, the ability to interpret conversational remarks meant literally (i.e., sincere remarks and lies) or non-literally (i.e., sarcasm) as well as the ability to make judgments about the thoughts, intentions and feelings of speakers (McDonald, Bornhofen, Shum, Long, et al., 2007). Memory was assessed with the California Verbal Learning Test for children (CVLT-C). The CVLT-C requires the examinee to recall two word lists over immediate and delayed memory trials (Delis et al., 1994). Speed of processing was measured with the Brief Assessment of Cognition in Schizophrenia Symbol Coding (BACS). The BASC is a timed task where the examinee is asked to use a key to write numbers that correspond to nonsense symbols (Keefe et al., 2004). Attention, psychomotor speed and mental flexibility was measured with the Trail-making Test Part A & B. It requires the subject to connect by making pencil lines, encircled numbers randomly arranged on a page in proper order (Part A) or for Part B encircled numbers and letters in alternating order (Reitan, 1955). General cognitive function/assessment of premorbid intelligence was assessed using the WASI Matrix Reasoning & Vocabulary. Matrix reasoning requires the respondent to look at a picture with a section missing and identify the missing part by pointing or by the number of one of five choices and the vocabulary task requires the respondent to provide oral definitions 23

37 to words (The Psychological Corporation, 1999). The University of Maryland Letternumber Span task was used to measure working memory. This task requires mental reordering of orally presented lists with letters and numbers and repeating them back (Holmen at al., 2010). Executive function was measured with the Delis-Kaplan Executive Function System Verbal Fluency (D-KEFS). The D-KEFS Verbal Fluency Test requires the participant to say words that begin with a specified letter, say words that belong to a designated semantic category, and alternate between saying words from two different semantic categories (Delis, et al., 2004). Attention was measured by Simple Reaction Time, the Continuous Performance Test (CPT-II), and Time Reproduction. Simple reaction time is a computerized task that requires the subject to press a button whenever they see the target stimulus appear on the screen. The CPT-II is a computeradministered measure of sustained attention in which the respondent presses a response button whenever they see consecutive matching numbers. Risk taking behavior was assessed with the Balloon Analog Risk Task (BART). In the BART the participant is presented with a balloon and offered the chance to win a prize by pumping the balloon up by clicking a button. Each click causes the balloon to incrementally inflate and earn the participant points to be added to a counter up until some threshold, at which point the balloon is over inflated and explodes (Lejuez et al., 2002). Interviews/Questionnaires The Structured Interview for Prodromal Syndromes (SIPS) (McGlashan et al. 2001; Miller et al. 2002; Rosen et al. 2002) and Autism Diagnostic Observation Schedule (ADOS) are conducted. The parent completes the Autism Diagnostic Interview-Revised 24

38 (ADI-R), the Diagnostic Interview Schedule for Children (DISC), and a packet of questionnaires. Statistical Analyses T-tests In order to evaluate the hypothesis 22qDS patients will show the greatest impairment relative to healthy controls on measures of psychomotor speed and mental flexibility (Trail-making test part B), working memory (Letter-Number Sequencing), and the D-KEFS verbal fluency composite, T-tests were run. T-tests were also run with comparison measures outside of the executive domain namely, Vocabulary, Matrix Reasoning, and the Rey Osterrieth Complex Figure test (copy portion). Effect sizes were also calculated for all of these measures to assess the magnitude of the difference between the patient and control groups. Pearson s Correlations To determine the convergent and discriminant validity between and amongst the executive measures, visuospatial ability, and total positive and total negative psychotic symptoms and to determine which predictor variables (dependent variables) to include in the regression analyses, Pearson s correlations were calculated. Regression In order to evaluate the hypothesis executive deficits in working memory (Letter- Number Sequencing), and the D-KEFS verbal fluency composite will be significantly predictive of total positive and total negative symptomatology above and beyond non- 25

39 verbal visuospatial deficits (copy portion of the Rey Osterrieth Complex Figure Test) in 22qDS patients, multiple regression analyses were conducted. For the regression analysis predicting total positive symptoms, in order to control for age, age was entered into the first block. Visuospatial ability was included in the second block and working memory and the verbal fluency composite score were entered into the third block. For the regression analysis predicting total negative symptoms, age was also controlled for. Visuospatial ability was entered into the second block. Only working memory was entered into the third block because the verbal fluency composite score was not significantly correlated with total negative symptoms. Power Analyses A post hoc power analysis was conducted using the software package, G*Power (Faul and Erdfelder, 1992) to determine the power for our t-tests. Our sample size of 48 for our patient group and sample size of 37 for our control group was utilized. The alpha level used for this analysis was p <.05. The post hoc analysis revealed that with the statistical power for our t-test we had a 98% chance to detect a large effect (i.e., Cohen s d of.80), a 73% chance to detect a medium effect (i.e., Cohen s d of.50) and a 23% chance to detect a small effect (i.e., Cohen s d of.20) given our sample size. A post hoc power analysis was also conducted for our regression analyses. The post hoc analysis revealed that the statistical power for our regressions produced a 92% chance to detect a large effect (i.e., f 2 =.35), 56% chance to detect a medium effect (i.e., f 2 =.15) and an 11% chance (i.e., f 2 =.02) to detect a small effect given our sample size. Thus, for both the t-test and regressions there was more than sufficient power at the large effect size but less than adequate power at the small effect size. 26

40 CHAPTER FIVE RESULTS Independent Samples T-tests T-tests were run to analyze significant differences between 22qDS patients and controls on executive measures and other comparison tests including Vocabulary, Matrix Reasoning, and the Rey Osterrieth Complex Figure test (copy portion). Effect sizes were also calculated and these results are depicted in Figure 1. 22qDS patients (N= 48, mean age: 15.23) showed impairment relative to healthy controls (N= 37, mean age: 14.97) on all measures of cognition. See table 1 for subject demographics and table 2 for results of t-tests. Figure 1. Group Differences. Note. Cognitive measure effect sizes. ROCFT= Rey Osterrieth Complex Figure test copy portion; Matrix= Matrix Reasoning; TMT-B= Trail-making test part B; LNS= Letter Number-Sequencing; DKEFS Comp= Delis-Kaplan Executive Function System composite score. Composite score calculated as the average of phonemic fluency, semantic fluency, category switching and switching accuracy. 27

41 Table 1 Subject Demographics 22qDS (N=48) Controls (N=37) Age Gender (N, % female) 26 (54.2%) 17 (45.9%) N, % race Caucasian 42 (87.5%) 22 (59.5%) Black/African American 1 (2.1%) 5 (13.5) Asian 0 (0.0%) 3 (8.1%) Multiple 5 (10.4%) 7 (18.9%) Table 2 Mean Scores of Cognitive Measures for 22qDS and Controls Groups 22qDS Controls t df Working Memory ( ) ( ) * 83 Verbal Fluency Composite ( ) ( ) * 83 Psychomotor Speed/Mental Flexibility ( ) ( ) 4.657* 81 Visuospatial Ability ( ) Vocabulary ( ) ( ) ( ) * * 83 Matrix Reasoning ( ) ( ) * 83 Note. *p<.01. Standard Deviations appear in parentheses below means. 28

42 Pearson s Correlations To determine the convergent and discriminant validity between and amongst the executive measures, visuospatial ability, and total positive and total negative psychotic symptoms and to determine which predictor variables to include in the regression analyses, Pearson s correlations were calculated. Results are listed in Table 3. The executive measures that significantly correlated (p <.05) with total positive and total negative psychiatric symptoms were included in the regression analyses. Working memory (Letter-Number Sequencing) and the Verbal Fluency Composite Score (Average of D-KEFS verbal letter fluency, category fluency, category switching, and switching accuracy) were significantly correlated with total positive symptoms, p <.05. Only working memory was significantly correlated with total negative symptoms. Psychomotor speed and mental flexibility (Trail-making test part B) was not significantly correlated with total positive and total negative symptoms. Therefore, it was not included in the regression analyses. 29

43 Table 3 Summary of Correlational Analyses for Executive Measures and SIPS Symptoms Working Memory Verbal Fluency Working Memory Verbal Fluency Psychomotor speed Visuospatial Ability Positive Total Negative Total _.545** -.559**.334* -.431** -.369*.545** _ -.369*.587** -.481** Psychomotor speed Visuospatial Ability Positive Total Negative Total -.559** _ *.587** _ ** -.481** _.528** -.369* ** - Note. * p<.05; ** p<.01. Verbal Fluency= Verbal Fluency Composite Score, Psychomotor speed= Psychomotor speed/mental flexibility. Regression To address the hypothesis that deficits on D-KEFS verbal fluency composite, and working memory (Letter-Number Sequencing) will be significant predictors of SIPS total positive and total negative symptoms, and will be significantly predictive of positive and negative symptomatology above and beyond non-verbal visuospatial deficits (copy portion of the Rey Osterrieth Complex Figure Test) in 22qDS patients, multiple regression analyses were conducted. Overall, this analysis was used to determine if the addition of executive measures would improve prediction of psychotic symptoms beyond that afforded by visuospatial ability. 30

44 Results revealed that the optimal linear combination of age, the copy portion of the Rey-Osterrieth Complex Figure Test, Letter-Number Sequencing, and the D-KEFS verbal fluency composite score accounted for 32% of the variance in total positive psychiatric symptoms (R 2 =.32). On average for every one-point increase in the D-KEFS verbal fluency composite score, total positive symptoms decreased by.224 points (b = -.224, 95% CI [-.407, -.041], p <.05). The copy portion of the Rey Osterrieth Complex Figure test (b =.144, 95% CI [-.268,.555], p >.05 and Letter-Number Sequencing (b = -.358, 95% CI [-1.088,.371], p >.05; were not significant individual predictors. Therefore, the model was driven by the D-KEFS verbal fluency composite score. See figure 2 and table 4. Figure 2. Variance Explained by Regression with Rey Osterrieth Complex Figure Test Copy Portion and Executive Measures Predicting Total Positive Symptoms 31

45 Table 4 Results of Hierarchical Regression Analysis with Visuospatial Ability and Executive Measures Predicting Total Positive Symptoms b β t Sig. 95% CI (b) ΔR 2 Step (Constant) [-2.513, ] Age [-.602,.606] Step (Constant) [-.811, ] Age [-.527,.723] Visuospatial ability [-.609,.179] Step 3.279* (Constant) [4.051, ] Age [-.162, 1.010] Visuospatial ability Working memory Verbal Fluency Composite [-.268,.555] [-1.088,.371] [-.407, -.041] There were no linear combinations that resulted in significance regarding total negative symptoms. Additionally, the copy portion of the Rey-Osterrieth Complex Figure Test (b =.226, 95% CI [-.663,.211], p <.05), and Letter Number Sequencing (b = -.657, 95% CI [-1.439,.125], p <.05) were not found to be significant individual predictors of negative symptoms. See figure 3 and table 5. 32

46 Figure 3. Variance Explained by Regression with Rey Osterrieth Complex Figure Test Copy Portion and Executive Measures Predicting Total Negative Symptoms Table 5 Results of Hierarchical Regression Analysis with Visuospatial Ability and Executive Measures Predicting Total Negative Symptoms b β t Sig. 95% CI (b) ΔR 2 Step (Constant) [-4.375, ] Age [-.464,.849] Step (Constant) [.338, ] Age [-.294, 1.014] Visuospatial Ability [-.791,.026] Step (Constant) [1.443, ] Age [-.185, 1.104] Visuospatial Ability Working Memory [-.663,.211] [-1.439,.125] 33

47 Discussion We hypothesized that 22qDS patients will show the greatest impairment relative to healthy controls on measures of executive functioning and non-executive comparison measures. This investigation partially confirmed our hypothesis as 22qDS patients showed impairment relative to healthy controls on psychomotor speed and mental flexibility (Trail-making Test Part B), working memory (Letter-Number Sequencing), verbal fluency (Composite score: D-KEFS phonemic fluency, semantic fluency, category switching and switching accuracy), non-verbal abstract problem solving (Matrix Reasoning), Vocabulary, and visuospatial ability (Rey Osterrieth Complex Figure test copy portion). However, we also calculated effect sizes to assess the magnitude of the difference between the two groups on cognitive measures. As depicted in figure 1, large effect sizes were demonstrated for Vocabulary (Cohen s d= 1.51), Matrix Reasoning (Cohen s d= 1.36), and the Rey Osterrieth Complex Figure test copy portion (Cohen s d= 1.24). Although the 22qDS group appears to show deficits in multiple domains, we believe executive function deficits are more relevant to psychotic symptom development. This makes sense given that the Rey Osterrieth Complex Figure test copy portion was not significantly correlated with positive or negative symptoms while the executive measures were. Our second hypothesis purported that deficits on the verbal fluency composite, psychomotor speed and mental flexibility (Trail-making Test Part B), and working memory (Letter- Number Sequencing) will be significant predictors of total positive and total negative symptoms, above and beyond non-verbal visuospatial deficits (copy portion of the Rey Osterrieth Complex Figure Test) in 22qDS patients. This hypothesis was partially supported. For the regression analysis predicting total positive symptoms, 34

48 executive measures accounted for 32% of the variance. The D-KEFS verbal fluency composite scores drove this finding; executive measures did add meaningfully to the prediction of total positive symptoms. This finding is inline with our hypothesis. In the regression analysis predicting total negative psychological symptoms, however, the model was not significant and there were no significant individual predictors p>.05. This lack of significance may be due to the limited power. We had an 11% chance to detect a small effect with our regressions given our sample size. Overall, these results can be interpreted to mean executive deficits are predictive of total positive symptoms above and beyond non-verbal visuospatial abilities. This information is very useful because cognitive deficits within the executive domain are a prominent impairment also seen in schizophrenia. Being that cognitive deficits are relatively stable across clinical state changes and present before the onset of clinical/psychotic symptoms (Finklestein et al., 1997; Gold 2004; Crow, Done, and Sacker, 1995), it is important to assess executive function in 22qDS, considering its relationship with schizophrenia. The consistency and prominence of executive deficits in schizophrenia may be associated with conversion to this disorder in 22qDS. Assessing whether these deficits are associated with positive and negative psychological symptoms in 22qDS is a novel and valuable pursuit. Along with Green (2006) we are in favor of evaluating cognitive deficits as they relate to schizophrenia. Green suggests evaluating and treating cognitive deficits in patients that are currently suffering from schizophrenia. He argues that cognitive deficits can serve as endophenotypes for the genetic basis of schizophrenia because they show characteristics that are associated with genetic vulnerability to the illness (Finkelstein, 35

49 Cannon, Gur et al., 1997). We also believe that cognitive deficits, specifically executive deficits can serve as an endophenotype for the genetic basis of schizophrenia in 22qDS. Evaluating persons with 22qDS in terms of executive function over various time points will provide a different means to study and understand schizophrenia. This information may lead to identifying executive dysfunction in 22qDS as a potential risk factor for the later development of psychoses/schizophrenia, which may aid in early detection. Data has suggested that early intervention with medication in first-break patients with schizophrenia increases the likelihood of an improved long-term course (Wyatt, 1991). Using executive function as an endophenotypic marker for positive and negative psychological symptoms is a novel concept, can ultimately lead to early detection and earlier treatment, and some relief of the burden schizophrenia poses to the individual, the caregiver, and society. Limitations The limitation of our study was the issue of power. A post hoc power analysis revealed that given our sample size of 48 in the 22qDS group we had an 11% chance to detect a small effect with our regressions. We did not have any significant findings for our regression analysis with visuospatial ability and executive function predicting total negative symptoms. Perhaps with more power to detect a small effect significant findings may have resulted with this regression. Future Directions Our results suggest that executive function may be an important domain for providing information about the development of psychosis. This study utilized a cross 36

50 sectional design. Future directions include employing a longitudinal design in order to detect progression of positive and negative psychotic symptoms over various time points. Furthermore, this research leads to questions regarding the neurobiological basis of executive function deficits in 22qDS. Investigations of these questions are already underway. Future directions also include replicating this study with a larger sample to insure greater power for detecting effects. Replication of this study with a larger sample size may also lead to the creation of a questionnaire or battery of tests specifically used in the detection of increased psychiatric symptoms coupled with a decrease in executive function for patients with 22qDS. 37

51 REFERENCES Amann, R., & Fuchs, B. M. (2008). Single-cell identification in microbial communities by improved fluorescence in situ hybridization techniques. Nature Reviews Microbiology 6(5), American Psychiatric Association (1994). Diagnostic and Statistical Manual of Mental Disorders 94 th (edition) (DSM-IV). Washington, DC: APA. Andreasen, N. C., Endicott, J., & Winokur, G. (1977). The family history method using diagnostic criteria: reliability and validity. Arch Gen Psychiatry 34, Aneja, A., Fremont, W. P., Antshel, K. M., Faraone, S. V., AbdulSabur, N., Higgins, A. M., Shprintzen, R., & Kates, W. R. (2007). Manic symptoms and behavioral dysregulation in youth with velocardiofacial syndrome (22q11.2 deletion syndrome). Journal of Child and Adolescent Psychopharmacology, 17, Angold, A., Prendergast, M., Cox, A., Harrington, R., Simonoff, E., & Rutter, M. (1995). The child and adolescent psychiatric assessment (CAPA). Psychological Medicine 25, Antshel, K. M., Stallone, K., AbdulSabur, N., Shprintzen, R., Roizen, N., Higgins, A. M., & Kates, W. R. (2007). Temperament in velocardiofacial syndrome. Journal of Intellectual Disability Research, 51, Baker, K. D., & Skuse, D. H. (2005). Adolescents and young adults with 22q11 deletion syndrome: psychopathology in an at-risk group. The British Journal of Psychiatry 186, Bassett, A. S. & Chow, E. W. C. (1999). 22q11 deletion syndrome: a genetic subtype of schizophrenia. Biology Psychiatry, 46, Bassett, A. S. & Chow, E. W. C. (2008). Schizophrenia and 22q11.2 deletion syndrome. Curr Psychiatry Rep, 10, Bassett, A. S., Chow, E. W., AbdelMalik, P., Gheorghiu, M., Husted, J., & Weksberg, R. (2003). The schizophrenia phenotype in 22q11.2 deletion syndrome. Am J Psychiatry 160, Bassett, A. S., Costain, G., Fung, W. L. A., Russell, K. J., Pierce, L., Kapadia, R., Carter, R. F., Chow, E. W., & Forsythe, P. J. (2010). Clinically detectable copy number variations in a Canadian catchment population of schizophrenia. J Psychiatr Res 44,

52 Basset, A. S., Hodgkinson, K., Chow, E. W., Cerreia, S., Scutt, L. E., Weksberg, R. (1998). 22q11 deletion syndrome in adults with schizoprhrenia. American Journal Medical Genetics 81, Bearden, C. E., Jawad, A. F., Lynch, D. R., Monterossso, J. R., Sokol, S., McDonald- McGinn, D. M., Saitta, S. C., Harris, S. E., Moss, E., Wang, P. P., Zackai, E., Emanuel, B. S., & Simon, T. J. (2005). Effects of comt genotype on behavioral symptomatology in the 22q11.2 deletion syndrome. Child Neuropsychol, 11(1), Bilder, R. M., Goldman, R. S., Robinson, D., Reiter, G., Bell, L., Bates, J. A., Pappadopulos, E., Wilson, D. F., Alvir, J. M. J., Woerner, M. G., Geisler, S., Kane, J. M., & Lieberman, J. A. (2000). Neuropsychology of the first-episode schizophrenia: initial characterization and clinical correlates. Am. J. Psychiatry 157, Bornstein, R. A., Baker, G. B., & Douglas, A. B. (1987). Short-term retest reliability of the Halstead-Reitan Battery in a normal sample. Journal of Nervous and Mental Disease 175, Bressi, S., Miele, L., Bressi, C., Astori, S., et al. (1996). Deficit of central executive component of working memory in schizophrenia. New Trends Exp Clin Psychiatry 12, Capri, S. (1994). Methods for evaluation of the direct and indirect costs of long-term schizophrenia. Acta Psychiatr Scand 382, Cohen, M. J. (1997). Children s Memory Scale. San Antonio, Texas: The Psychological Corporation. Cornblatt, B. A., Risch, N. J., Faris, G., Friedman. D., & Erlenmeyer-Kimling, L. (1988). The continuous performance test, identical pairs version (CPT-IP): I. new findings about sustained attention in normal families. Psychiatry Research, 26(2), Crawford, J. R., Obonswain, M., & Bremner, M. (1993). Frontal lobe impairment in schizophrenia: relationship to intellectual functioning. Psychological Medicine 23, Crow, T. J., Done, D. J., & Sacker, A. (1995). Childhood precursors of psychosis as clues to its evolutional origins. Eur Arch Psychiatry Clin Neurosci 245, Davis, L. M., & Drummond, M. F. (1994). Economics and schizophrenia: the real cost. Br J Psychiatry 165,

53 Delis, D. C., Kaplan, E., & Kramer, J. H. (2001). Delis-Kaplan Executive Function System. San Antonio, TX: The Psychological Corporation. Delis, D. C., Kramer, J. H., Kaplan, E. & Holdnack, J. (2004). Reliability and validity of the Delis-Kaplan Executive Function System: an update. Journal of the International Neuropsychological Society 10, Delis, D. C., Kramer, J. H., Kaplan, E., & Ober, B. A. (1994). California Verbal Learning Test-Children s Memory Scale. San Antonio Texas: The Psychological Corporation. De Smedt, B., Devriendt, K., Fryns, J. P., Vogels, A., Gewillig, M., & Swillen, A. (2007). Intellectual abilities in a large sample of children with Velo-Cardio-Facial Syndrome: an update. Journal of Intellectual Disability Research 51, De Smedt, B., Swillen, A., Verschaffel, L., & Ghesquiere, P. (2009). Mathematical learning disabilities in children with 22q11.2 deletion syndrome: a review. Dev Disabil Res Rev 15, Drew, L. J., Crabtree, G. W., Markx, S., Stark, K. L., Chaverneff, F., Xu, B., Mukai, J., Fenelon, K., Hsu, P. K., Gogos, J. A., Karaviorgou, M. (2011). The 22q11.2 micro-deletion: fifteen years of insights into the genetic and neural complexity of psychiatric disorders. Int. J. Dev. Neurosci., 29, Edelmann, L., Pandita, R. K., Morrow, B. E. (1999). Low-copy repeats mediate the common 3-Mb deletion in patients with velo-cardio-facial syndrome. Am. J. Hum. Genet., 64(4), Eliez, S., Blasey, C. M., Menon, V., White, C. D., Schmitt, J. E., & Reiss, A. L. (2001). Functional brain imaging study of mathematical reasoning abilities in velocardiofacial syndrome (del22q11.2). Genet Med, 3, Eliez, S., Palacio-Espasa, F., Spira, A., Lacroix, M., Pont, C., Luthi, F., Robert-Tissot, C., Feinstein, C., Schorderet, D. F., Antonarakis, S. E., Cramer, B. (2000). Young children with velocardiofacial syndrome (CATCH-22). Psychological language and phenotypes. Eur Child Adolesc Psychiatry, 9, Evans, J. J., Chua, S., McKenna, P., & Wilson, B. (1997). Assessment of the dysexecutive syndrome in schizophrenia. Psychological Medicine 27, Fals-Stewart, W. (1991). An interrater reliability study of the Trail Making Test (Part A and B). Unpublished Manuscript. Feinstein, C., Eliez, S., Blasey, C. & Reiss, A. L. (2001). Psychiatric disorders and behavioral problems in children with velocardiofacial syndrome: usefulness as a phenotypic indicators of schizophrenia risk. Biology Psychiatry, 15,

54 Finkelstein, J. R., Cannon, T. D., Gur, R. E., & Moberg, P. (1997). Attentional dysfunctions in neuroleptic-naïve and neuroleptic-withdrawn schizophrenic patients and their siblings. J Abnorm Psychol 106, Gerdes, M., Solot, C., Wang, P. P., McDonald-McGinn, D. M., & Zackai, E. H. (2001). Taking advantage of early diagnosis: preschool children with the 22q11.2 deletion. Genet Med, 3, Gold, J. M. (2004). Cognitive deficits as treatment targets in schizophrenia. Schizophr Res 72, Goldberg, R., Motzkin, B., Marion, R., Scambler, P. J., & Shprintzen, R. J. (1992). Velocardio-facial syndrome: a review of 120 patients. American Journal of Medical Genetics 45, Goldberg, T. E., Saint-Cyr, J. A., & Weinberger, D. R. (1990). Assessment of procedural learning and problem solving in schizophrenia patients by tower of Hanoi type tasks. Journal of Neuropsychiatry and Clinical Neuroscience 2, Golding-Kushner, K., Weller, G., & Shprintzen, R. J. (1985). Velo-cardio-facial syndrome: language and psychological profiles. J Craniofac Genet Dev Biol 5, Goldman-Rakic, P. S. (1986). Circuitry of Primate Prefrontal Cortex and Regulation of Behavior by Representional Memory: Handbook of Physiology. Vol. 4. Philadelphia, PA: American Physiological Society, Goldman-Rakic, P. S. (1995). Architecture of the prefrontal cortex and the central executive. Ann NY Acad Sci, 769, Gothelf, D., Feinstein, C., Thompson, D., Gu, E., Penniman, L., Van Stone, E., Kwon, H., Eliez, S., & Reiss, A. L. (2007). Risk factors for the emergence of psychotic disorders in adolescents with 22q11.2 deletion syndrome. Am. J. Psychiatry 164, Gothelf, D., Frisch, A., Munitz, H., Rockah, R., Laufer, N., Mozes, T., Hermesh, H., Weizman, A. & Frydman, M. (1999). Clinical characteristics of schizophrenia associated with velo-cardio-facial syndrome. Schizophrenia Research 35, Gothelf, D., Gruber, R., Presburger, G., Dotan, I., Brand-Gothelf, A., Burg, M., Inbar, D., Steinberg, T., Frisch, A., Apter, A. & Weizman, A. (2003). Methylphenidate treatment for attention-deficit/hyperactivity disorder in children and adolescents with velocardiofacial syndrome: an open-label study. Journal of Clinical Psychiatry, 64,

55 Gothelf, D., Presburger, D. L., Nahmani, A., Burg, M., Berant, M., Blieden, L. C., Finklestein, Y., Frisch, A., Apter, A. & Weizman, A. (2004). Genetic, developmental, and physical factors associated with attention deficit hyperactivity disorder in patients with velocardiofacial syndrome. American Journal of Medical Genetics, 126B, Green, M. F. (1996). What are the functional consequences of neurocognitive deficits in schizophrenia? Am J Psychiatry 153, Green, M. F., Kern, R. S., Braff, D. L., & Mintz, J. (2000). Neurocognitive deficits and functional outcome in schizophrenia: are we measuring the right stuff? Schizophr. Bull. 26, Guest, J. F., & Cookson, R. F. (1999). Cost of schizophrenia to U.K. society: an incidence-based cost of illness model for the first 5 years following diagnosis. Pharmacoeconomics 6, Harrison, P. J., & Weinberger, D. R. (2005). Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Molecular Psychiatry 10, Heilbronner, R. L., Henry, G. K., Buck. P., Adams, R. L., & Fogle, T. (1991). Lateralized brain damage and performance on Trail Making A and B, Digit Span Forward and Backward, and TPT memory and location. Archives of Clinical Neuropsychology 6, Henry, J. C., van Amelsvoort, T., Morris, R. G., Owen, M. J., Murphy, D. G. M., & Murphy, K. C. (2002). An investigation of the neuropsychological profile in adults with velo-cardio-facial syndrome (VCFS). Neuropsychologia 40, Holmen, A., Juuhl-Langseth, M., Thormodsen, R., Melle, I., & Rund, B. R. (2010). Neuropsychological profile in early-onset schizophrenia spectrum disorders: measured with the MATRICS battery. Schizophrenia Bulletin 36, Horan, H. P., Kring, A. M., & Blanchard, J. J. (2006). Schizophrenia: a review of assessment strategies. Schizophr Bull 32, Insel, T. R. (2010). Rethinking schizophrenia. Nature 468, Jacobson, C., Shearer, J., Habel, A, Kane, F., Tsakanikos, E., & Kravariti, E. (2010). Core neuropsychological characteristics of children and adolescents with 22q11.2 deletion. J Intellect Disabil Res 54, Jolin, E. M., Weller, R. A., Jessani, N. R., Zackai, E. H., McDonald-McGinn, D. M., & Weller, E. B. (2009). Affective disorders and other psychiatric diagnoses in children and adolescents with 22q11.2 deletion syndrome. Journal of Affective Disorders 119,

56 Karayiorgou, M., Antonarakis, S. E., Housman, D., & Kucherlapati, R. (1994). Psychotic illness in patients diagnosed with velo-cardio-facial syndrome and their relatives. J Nerv Ment Dis, 182, Kates, W. R., Burnette, C. P., Bessette, B. A., Folley, B. S., Strunge, L., Jabs, E. W., & Pearlson, G. D. (2004). Frontal and caudate alterations in velocardiofacial syndrome (deletion at chromosome 22q11.2). J Child Neurol 19, Keefe, R. S. E., Goldberg, T. E., Harvey, P. D., Gold, J. M., Poe, M., & Coughenour, L. (2004). The brief assessment of cognition in schizophrenia: reliability, sensitivity, and comparison with a standard neurocognitive battery. Schizophrenia Research 68(2-3), Kenny, J. T., & Meltzer, H. Y. (1991). Attention and higher cortical functions in schizophrenia. J Neuropsychiatry Clin Neurosci 3, Kiley-Brabeck, K., & Sobin, C. (2006). Social skills and executive function deficits in children with the 22q11.2 deletion syndrome. Appl Neuropsychol, 13, Knapp, M. (1997). Cost of schizophrenia. Br J Psychiatry 171, Kobrynski, L. J., & Sullivan, K. E. (2007). Velocardiofacial syndrome, DiGeorge syndrome: the chromosome 22q11.2 deletion syndromes. Lancet, 370, Kohler, C. G., Turner, T. H., Bilker, W. B., Brensinger, C. M., Siegel, S. J., Kanes, S. J., Gur, R. E., & Gur, R. C. (2003). Facial emotion recognition in schizophrenia: intensity effects and error pattern. Am J Psychiatry 160, Kravariti, E., Morris, R. G., Rabe-Hesketh, S., Murray, R. M., & Frangou, S. (2003). The Maudsley early onset schizophrenia study: cognitive function in adolescents with recent onset schizophrenia. Schizophr. Res. 61, Lajiness-O Neill, R. R., Beaulieu, I., Titus, J. B., Asamoah, A., Bigler, E. D., Bawle, E. V., & Pollack, R. (2005). Memory and learning in children with 22q11.2 deletion syndrome: evidence for ventral and dorsal stream disruption? Child Neuropsychol, 11, Lejuez, C. W., Read, J. P., Kahler, C. W., Richards, J. B., Ramsey, S. E., Stuart, G. L., Strong, D. R., Brown, R. A. (2002). Evaluation of a behavioral measure of risk taking: the Balloon Analogue Risk Task (BART). Journal of Experimental Psychology: Applied 8, Levin, S., Yurgelun-Todd, D., & Craft, S. (1989). Contributions of clinical neuropsychology to the study of schizophrenia. Journal of Abnormal Psychology 98,

57 Lewandowski, K. E., Shashi, V., Berry, P. M., Kwapil, T. R. (2007). Schizophrenia-like neurocognitive deficits in children and adolescents with 22q11 deletion syndrome. Am J Med Genet B Neuropsychiatr Genet, 144, Majerus, S., Van der Linden, M., Braissand, V., Eliez, S. (2007). Verbal short-term memory in individuals with chromosome 22q11.2 deletion: specific deficit in serial order retention capacities? Am J Ment Retard 112, McDonald, S., Bornhofen, C., Shum, D., Long, E., Saunders, C., & Neulinger, K. (2007). Reliability and validity of the Awareness of Social Inference Test (TASIT): a clinical test of social perception. Disability and Rehabilitation 28(24), Miller, T. J., McGlashan, T. H., Rosen, J. L., Somjee, L., Markovich, P. J., Stein, K., & Woods, S. W. (2002). Prospective diagnosis of the initial prodrome for schizophrenia based on the structured interview for prodromal syndromes: preliminary evidence of interrater reliability and predictive validity. Am J Psychiatry 159, Miller, T., Mednick, S. A., McGlashan, T. H., Libiger, J., & Johannessen, J. O. (2001). Early Intervention in Psychotic Disorders. Kluwer Academic Publishers: Dordrecht, The Netherlands, Morris, R. G., Rushe, T., Woodruffe, P. W. R., & Murray, R. M. (1995). Problem solving in schizophrenia: a specific deficit in planning ability. Schizophrenia Research 14, Moss, E. M., Wang, P. P., Solot, C. B., Gerdes, M., McDonald-McGinn, D. M., Driscoll, D. A., Emanuel, B. S., Zackai, E. H., & Batshaw, M. L. (1999). Psychoeducational profile of the 22q11.2 microdeletion: a complex pattern. The Journal of Pediatrics 134, Murphy, K. C. (2002). Schizophrenia and velo-cardio-facial syndrome. Lancet 359, Murphy, K. C., Jones, L. A., & Owen, M. J. (1999). High rates of schizophrenia in adults with velo-cardio-facial syndrome. Archives of General Psychiatry, 56, Papolos, D. F., Faedda, G. L., Veit, S., Goldberg, R., Morrow, B., & Kucherlapati, R. (1996). Bipolar spectrum disorders in patients diagnosed with velo-cardio-facial syndrome: does a hemizygous deletion of chromosome 22q11 result in bipolar affective disorder? American Journal of Psychiatry 153, Phillip, N., & Basset, A. (2011). Cognitive, Behavioural and Psychiatric Phenotype in 22q11.2 deletion syndrome. Behav Genet 41, Pineda, D. A., & Merchan, V. (2003). Executive function in young Colombian adults. International Journal of Neuroscience 113,

58 Pulver, A. E., Nestadt, G., Goldberg, R., Shprintzen, R. J., Lamacz, M., Wolyniec, P. S., Morrow, B., Karayiorgou, M., Antonarakis, S. E., Housman, D., et al. (1994). J Nerv Ment Dis 182, Reitan, R. M. (1955). The relation of the Trail Making Test to organic brain damage. Journal of Consulting Psychology 19, Reitan, R. M., & Wolfson, D. (1985). The Halstead-Reitan Neuropsychological Test Battery. Tucson, Ariz.: Neuropsychology Press. Robin, N. H. & Shprintzen, R. J. (2005). Defining the clinical spectrum of deletion 22q11.2. The Journal of Pediatrics 147, Roizen, N. J., Antshel, K. M., Fremont, W., AbdulSabur, N., Higgins, A. M., Shprintzen, R. J. & Kates, W. R. (2007). 22q11.2 DS deletion syndrome: developmental milestones in infants and toddlers. J Dev Behav Pediatr 28, Royan, J., Tombaugh, T. N., Rees, L., & Francis, M. (2004). The Adjusting-Paced Serial Addition Test (Adjusting PASAT): Thresholds for speed of information processing as a function of stimulus modality and problem complexity. Archives of Clinical Neuropsychology 19, Rushe, T. M., Morris, R. G., Miotto, E. C., Feigenbaum, J. D., Woodruff, P. W. R., & Murray, R. M. (1999). Problem-solving and spatial working memory in patients with schizophrenia and with focal frontal and temporal lobe lesions. Schizophr. Res. 37, Saunders, N. C., Hartley, B. E. J., Sell, D. G. & Sommerlad, B. (2004). Velopharyngeal insufficiency following adenoidectomy. Clin. Otolaryngol 29, Scherer, N. J., D Antonio, L. L., & Kalbfleisch, J. H. (1999). Early speech and language development in children with velocardiofacial syndrome. Am J Med Genet 88, Shprintzen, R. J. (1997). Genetics, Syndromes, and Communication Disorders. San Diego: Singular Publishing. Shprintzen, R. J. (2000). Velo-cardio-facial syndrome: a distinct behavioral phenotype. Mental Retardation and Developmental Disabilities 6, Shprintzen, R. J. (2008). Velo-cardio-facial syndrome: 30 years of study. Dev Disabil Res Rev. 14, Shprintzen, R. J., Goldberg, R., Golding-Kushner, K. J., Marion, R. W. (1992). Lateonset psychosis in the velo-cardio-facial syndrome. Am J Med Genet 42,

59 Shprintzen, R. J., Morrow, B., Kucherlapati, R. (1997). Vascular anomalies may explain many of the features of the velo-cardio-facial syndrome. Am J Hum Genet 61: A5. Sobin, C., Daniels, S., Kiley-Brabeck, K., Blundell, M., Anyane-Yeboa, K. & Karayiorgou, M. (2005). Neuropsychological characteristics of children with 22q11 deletion syndrome: A descriptive analysis. Child Neuropsychology, 11, Sobin, C., Kiley-Brabeck, K., Daniels, S., Khuri, J., Taylor, L., Blundell, M., Anyane- Yeboa, K., & Karayiorgou (2004). Networks of attention in children with the 22q11 deletion syndrome. Developmental Neuropsychology 26, Stuss, D. & Knight, R. T. (Editors) (2002). The Frontal Lobes. New York: Oxford University Press. Swillen, A., Deveriendt, K., Legius, E., Eyskens, B., Gewillig, M., & Fryns, J. P. (1997). Intelligence and psychosocial adjustment in velocardiofacial syndrome: a study of 37 children and adolescents with VCFS. Journal of Medical Genetics 34, Swillen, A., Devriendt, K., Legius, E., Prinzie, P., Vogels, A., Ghesquiere, P., & Fryns, J. P. (1999). The behavioural phenotype in velo-cardio-facial syndrome (VCFS): from infancy to adolescence. Genet Couns 10, Swillen, A., Vandeputte, L., Cracco, J., Maes, B., Ghesquiere, P., Devriendt, K., & Fryns, J. P. (2000). Neuropsychological, learning, and psychosocial profile of primary school aged children with velocardiofacial syndrome (22q11 deletion): evidence for a nonverbal learning disability? Child Neuropsychology 6, Swillen, A., Vogels, A., Devriendt, K., & Fryns, J. P. (2000). Chromosome 22q11 deletion syndrome: update and review of the clinical features, cognitivebehavioural spectrum, and psychiatric complications. Am J Med Genet 97, The Psychological Corporation (1999). Wechsler Abbreviated Scale of Intelligence (WASI) manual. San Antonio, Texas: Author. Torrey, E. F. (2002). Surviving schizophrenia: a manual for families, consumers and providers. New York: Harper Collins. Toulopoulou, T., Morris, R. G., Rabe-Hesketh, S., & Murray, R. M. (2003). Selectivity of verbal memory deficit in schizophrenic relatives. Am. J. Med. Genet. (Neuropsych. Genetics) 116B, 1-7. US Department of Health & Human Services. Mental Heath: A report of the Surgeon General. Maryland: National Institute of Mental Health, Office of the Surgeon General,

60 Van Amelsvoort, T., Henry, J., Morris, R., Owen, M., Linszen, D., Murphy, K., & Murphy, D. (2004). Cognitive deficits associated with schizophrenia in velocardio-facial syndrome. Schizophr Res 70, Wang, P. P., Solot, C., Moss, E. M., Gerdes, M., McDonald-McGinn, D. M., Driscoll, D. A., Emanuel, B. S., & Zackai, E. H. (1998). Developmental presentation of 22q11.2 deletion (DiGeorge/velo-cardiofacial syndrome). Journal of Developmental Behavioral Pediatrics 19, Wang, P. P., Woodin, M. F., Kreps-Falk, R., & Moss, E. M. (2000). Research on behavioral phenotypes: velocardiofacial syndrome (deletion 22q11.2). Dev Med Child Neurol 42, Weller, E. B., Weller, R. A., Fristad, M. A., Rooney, M. T., & Schecter, J. (2000). Children s interview for psychiatric symptoms (ChIPS). J. Am. Acad. Child Adolesc, Psych. 39, Woodin, M., Wang, P. P., Aleman, D., McDonald-McGinn, D., Zackai, E., & Moss, E. (2001). Neuropsychological profile of children and adolescents with the 22q11.2 microdeletion. Genet Med 3, Woodin, M., Wang, P. P., Bearden, C., McDonald-McGinn, D., Zackai, E, Emanuel, B., & Moss, E. (2000). Attention, working memory, and executive functions in children and adolescents with velocardiofacial syndrome: patterns, profiles, and presentation. Journal of the International Neuropsychological Society 6, 160. Wyatt, R. J. (1991). Neuroleptics and the natural course of schizophrenia. Schizophrenia Bulletin 17(2), Yung, A. R., McGorry, P. D., McFarlane, C. A., Jackson, H. J., Patton, G. C., & Rakkar, A. (1996). Monitoring and care of young people at incipient risk of psychosis. Schizophrenia Bulletin 22,

61 APPENDIX A THE DEL22Q11.2 REGION ON CHROMOSOME 22 48

62 APPENDIX B FACIAL DYSMORPHIA Figure 2. Facial dysmorphia, characteristic facial feature in chromosome 22q11.2 deletion syndrome. A slightly bulbous nose tip and hooded eyes are the primary features. 49