Psychiatric disturbances in children with intellectual disability : Prevalence, risk factors and assessment

Children with intellectual disability are at increased risk for emotional and behavioural problems, but many of these disturbances fail to be diagnosed. Structured checklists have been used to supplement the psychiatric assessment of children without intellectual disability, but for children with intellectual disability, only a few checklists are available. The aim of the study was to investigate psychiatric disturbances among children with intellectual disability: the prevalence, types and risk factors of psychiatric disturbances as well as the applicability of the Finnish translations of the Developmental Behaviour Checklist (DBC-P) and the Child Behavior Checklist (CBCL) in the assessment of psychopathology. The subjects comprised 155 children with intellectual disability, and data were obtained from case records and five questionnaires completed by the parents or other carers of the child. According to case records, a psychiatric disorder had previously been diagnosed in 11% of the children. Upon careful re-examination of case records, the total proportion of children with a psychiatric disorder increased to 33%. According to checklists, the frequency of probable psychiatric disorder was 34% by the DBC-P, and 43% by the CBCL. The most common diagnoses were pervasive developmental disorders and hyperkinetic disorders. The results support previous findings that compared with children without intellectual disability, the risk of psychiatric disturbances is 2-3-fold in children with intellectual disability. The risk of psychopathology was most significantly increased by moderate intellectual disability and low socio-economic status, and decreased by adaptive behaviour, language development, and socialisation as well as living with both biological parents. The results of the study suggest that both the DBC-P and the CBCL can be used to discriminate between children with intellectual disability with and without emotional or psychiatric disturbance. The DBC-P is suitable for children with any degree of intellectual disability, and the CBCL is suitable at least for children with mild intellectual disability. Because the problems of children with intellectual disability differ somewhat from those of children without intellectual disability, checklists designed specifically for children with intellectual disability are needed.

Suicidal ideation and attempts among psychiatric patients with major depressive disorder

This study is part of an ongoing collaborative research and development project, the Vantaa Depression Study (VDS), between the National Public Health Institute, Helsinki and the Department of Psychiatry of Helsinki University Hospital (HUCH), Peijas hospital, Vantaa. The VDS is a prospective, naturalistic cohort study of 269 secondary-level care psychiatric out- and inpatients with a new episode of DSM-IV major depressive disorder (MDD). 269 patients (Nmales=72, Nfemales=197) with a current DSM-IV MDD were interviewed with semistructured interviews to assess all other psychiatric diagnoses. At 6- and 18-month follow-up the interviews were repeated. Suicidal behaviour was investigated both at intake and follow-up by using a psychometric scale (Scale for Suicidal Ideation) and interviewer's questions as well as the patient's psychiatric records. Patients, who reported suicidal ideation while entering the study were followed up weekly, and their level of suicidal ideation, hopelessness, anxiety and depression was measured. In this study suicidal ideation was common among psychiatric patients with MDD. Almost 60% of the depressed patients reported suicidal ideation and 15% of patients attempted suicide at the baseline. Patients with suicidal ideation or attempts had a clearly higher level of overall psychopathology than non-suicidal patients. During the 18-month follow-up period 8% of patients attempted suicide. The risk of an attempt was markedly higher (RR=7.54) during an episode of major depression compared with a period of remission. Suicide attempt during the follow-up period was predicted by lack of partner, a history of previous suicide attempts and time spent in depression. Suicidal ideation resolved for most of the suicidal patients during the first 2 to 3 months. The duration of suicidal ideation was longer for patients with an initially higher level of psychopathology. Declines both in depression and hopelessness independently predicted the subsequent decline in suicidal ideation. They both could have a causal role in reversing the suicidal process. Thus effective treatment of depression is a credible measure in suicide prevention. Patients with suicidal behaviour often received more antidepressants and had more frequent appointments with mental health professionals than non-suicidal patients. Suicidal patients had also more favourable attitudes towards antidepressant treatment and comparable adherence to treatment than those not suicidal. This study does not support the conception that patient attitudes or adherence to treatments would be a factor differentiating suicidal patients from non-suicidal. Instead, problems with adherence or attitudes seem to be generic to all psychiatric care.

Developmental origins of physiological stress reactivity

The model of developmental origins of health and disease proposes that organisms during fetal period utilize cues that enable their adaptation in the postnatal environment they are likely to live, having short-term advantages when trying to survive in environment but simultaneously in the long run have costs for health. A large body of epidemiological research has found that low birth weight, a marker of intrauterine conditions, is associated with cardiovascular (CV) disease. Since the reported associations of birth weight with normal variation in the resting blood pressure (BP), a major predictor of CV disease risk, have been modest, a key candidate mediating the link has been CV and hypothalamus-pituitary-adrenal axes (HPAA) reactivity to stress. In addition, not only weight at birth but also gestational age and early postnatal growth may have independent associations to stress reactivity. The aim of this thesis was to investigate whether pre- and postnatal growth and gestational age are associated with CV and HPAA activity before, during and after stress in childhood and in late adulthood. Altogether 287 men and women aged 60-70 and 299 boys and girls aged 7-9 underwent Trier Social Stress Test. Several indices of HPAA and CV were measured and birth size and gestational age were obtained from birth records. Results showed that low birth weight was associated with low HPAA activity during psychosocial stress, and rapid gain in BMI during years 7-11 was related to heightened stress reactivity to psychosocial stress. Size at birth in children and gestational age and early postnatal (0-2 years) gain in height in adults were associated with CV stress responses; however, in a sex-specific manner. Given that CV stress responses and HPAA activity are markers of CV disease vulnerability, our results may partly explain the associations between early environment and later CV disease.

Genetic Mechanisms Underlying Autism Spectrum Disorders

Autism is a childhood-onset developmental disorder characterized by deficits in reciprocal social interaction, verbal and non-verbal communication, and dependence on routines and rituals. It belongs to a spectrum of disorders (autism spectrum disorders, ASDs) which share core symptoms but show considerable variation in severity. The whole spectrum affects 0.6-0.7% of children worldwide, inducing a substantial public health burden and causing suffering to the affected families. Despite having a very high heritability, ASDs have shown exceptional genetic heterogeneity, which has complicated the identification of risk variants and left the etiology largely unknown. However, recent studies suggest that rare, family-specific factors contribute significantly to the genetic basis of ASDs. In this study, we investigated the role of DISC1 (Disrupted-in-schizophrenia-1) in ASDs, and identified association with markers and haplotypes previously associated with psychiatric phenotypes. We identified four polymorphic micro-RNA target sites in the 3 UTR of DISC1, and showed that hsa-miR-559 regulates DISC1 expression in vitro in an allele-specific manner. We also analyzed an extended autism pedigree with genealogical roots in Central Finland reaching back to the 17th century. To take advantage of the beneficial characteristics of population isolates to gene mapping and reduced genetic heterogeneity observed in distantly related individuals, we performed a microsatellite-based genome-wide screen for linkage and linkage disequilibrium in this pedigree. We identified a putative autism susceptibility locus on chromosome 19p13.3 and obtained further support for previously reported loci at 1q23 and 15q11-q13. To follow-up these findings, we extended our study sample from the same sub-isolate and initiated a genome-wide analysis of homozygosity and allelic sharing using high-density SNP markers. We identified a small number of haplotypes shared by different subsets of the genealogically connected cases, along with convergent biological pathways from SNP and gene expression data, which highlighted axon guidance molecules in the pathogenesis of ASDs. In conclusion, the results obtained in this thesis show that multiple distinct genetic variants are responsible for the ASD phenotype even within single pedigrees from an isolated population. We suggest that targeted resequencing of the shared haplotypes, linkage regions, and other susceptibility loci is essential to identify the causal variants. We also report a possible micro-RNA mediated regulatory mechanism, which might partially explain the wide-range neurobiological effects of the DISC1 gene.

Brain oscillatory responses, working memory and cognitive developmental stages in 11- and 14-year-old children: an ERD/ERS study

Aim: So far, most of the cognitive neuroscience studies investigating the development of brain activity in childhood have made comparisons between different age groups and ignored the individual stage of cognitive development. Given the wide variation in the rate of cognitive development, this study argues that chronological age alone cannot explain the developmental changes in brain activity. This study demonstrates how Piaget s theory and information on child s individual stage of development can complement the age-related evaluations of brain oscillatory activity. In addition, the relationship between cognitive development and working memory is investigated. Method: A total of 33 children (17 11-year-olds, 16 14-year-olds) participated in this study. The study consisted of behavioural tests and an EEG experiment. Behavioral tests included two Piagetian tasks (the Volume and Density task, the Pendulum task) and Raven s Standard Progressive Matrices task. During EEG experiment, subjects performed a modified version of the Sternberg s memory search paradigm which consisted of an auditorily presented memory set of 4 words and a probe word following these. The EEG data was analyzed using the event-related desynchronization / synchronization (ERD/ERS) method. The Pendulum task was used to assess the cognitive developmental stage of each subject and to form four groups based on age (11- or 14-year-olds) and cognitive developmental stage (concrete or formal operational stage). Group comparisons between these four groups were performed for the EEG data. Results and conclusions: Both age- and cognitive stage-related differences in brain oscillatory activity were found between the four groups. Importantly, age-related changes similar to those reported by previous studies were found also in this study, but these changes were modified by developmental stage. In addition, the results support a strong link between working memory and cognitive development by demonstrating differences in memory task related brain activity and cognitive developmental stages. Based on these findings it is suggested that in the future, comparisons of development of brain activity should not be based only on age but also on the individual cognitive developmental stage.

Developmental-like responses in injured mature central neurons

Traumatic insults to the central nervous system are frequently followed by profound and irreversible neuronal loss as well as the inability of the damaged neurons to regenerate. One of the major therapeutic challenges is to increase the amount of surviving neurons after trauma. Thus it is crucial to understand how injury affects neuronal responses and which conditions are optimal for survival to prevent neuronal loss. During development neuronal survival is thought to be dependent on the competition for the availability of survival-promoting molecules called neurotrophic factors. Much less is known on the survival mechanisms of mature neurons under traumatic conditions. Increasing amount of evidence points towards the possibility that after injury neuronal responses might aquire some developmental characteristics. One of the important examples is the change in the responses to the neurotransmitter GABA: it is inhibitory in the intact mature neurons, but can induce excitation during development and after trauma. An important step in the maturation of GABAergic transmission in the CNS is the developmental shift in the action of GABAA receptor from depolarization in immature neurons to hyperpolarization in mature neurons. GABAA-mediated responses are tightly linked to the homeostasis of the chloride anion (Cl-), which in neurons is mainly regulated by Na+-K+-2Cl- cotransporter NKCC1 and K+-Cl- cotransporter KCC2. Trauma-induced functional downregulation of KCC2 promotes a shift from hyperpolarizing GABAA-mediated responses to depolarizing. Other important consequences of neuronal trauma are the emergence of dependency of central neurons on brain-derived neuro¬trophic factor (BDNF) for survival, as well as the upregulation of neurotrophin receptor p75NTR. Our aim was to answer the question whether these post-traumatic events are interrelated, and whether the regulation of BDNF and KCC2 expression is different under traumatic conditions and in intact neurons. To study responses of injured mature central neurons, we used an in vitro and in vivo axotomy models. For in vitro studies, we lesioned organotypic hippocampal slices between CA3 and CA1 regions, which resulted in selective axotomy of the CA3 neurons and denervation of the CA1 neurons. Some experiments were repeated in vivo by lesioning the neurons of the corticospinal tract at the internal capsule level, or by lesioning spinal motoneurons at the ventral root. We show that intact mature neurons do not require BDNF for survival, whereas in axotomized neurons apoptosis is induced upon BDNF deprivation. We further show that post-traumatic dependency on BDNF is mediated by injury-induced upregulation of p75NTR. Post-traumatic increase in p75NTR is induced by GABAA-mediated depolarization, consequent opening of voltage-gated Ca2+ channels, and the activation of Rho kinase ROCK. Thus, post-traumatic KCC2 downregulation leads to the dependency on BDNF through the induction of p75NTR upregulation. Neurons that survive after axotomy over longer period of time lose BDNF dependency and regain normal KCC2 levels. This phenomenon is promoted by BDNF itself, since after axotomy contrary to normal conditions KCC2 is upregulated by BDNF. The developmentally important thyroid hormone thyroxin regulates BDNF expression during development. We show that in mature intact neurons thyroxin downregulates BDNF, whereas after axotomy thyroxin upregulates BDNF. The elevation of BDNF expression by thyroxin promoted survival of injured neurons. In addition, thyroxin also enhanced axonal regeneration and promoted the regaining of normal levels of KCC2. Thus we show that this hormone acts at several levels on the axotomy-initiated chain of events described in the present work, and could be a potential therapeutic agent for the injured neurons. We have also characterized a previously unknown downregulatory interaction between thyroxin and KCC2 in intact neurons. In conclusion, we identified several important interactions at the neurotrophin-protein and hormone-neurotrophin level that acquire immature-like characteristics after axotomy and elucidated an important part of the mechanism by which axotomy leads to the requirement of BDNF trophic support. Based on these findings, we propose a new potential therapeutic strategy where developmentally crucial agents could be used to enhance survival and regeneration of axotomized mature central neurons.

Cognitive functioning and its heritability in bipolar I disorder

Bipolar I disorder is a severe psychiatric disorder characterized by episodic mood alterations that can be manic, depressive or mixed. Bipolar disorder seems to be highly genetic, but the etiology of this complex disorder has remained elusive. In recent years, studies have found that euthymic patients with bipolar disorder may have impairments particularly in executive functioning, verbal learning and memory. These impairments may be present also among some of the relatives of these patients, who may be vulnerable to the disorder. Using neuropsychological variables as endophenotypes, i.e. intermediate phenotypes between genes and the phenotypes, has been suggested to aid search for the etiological background of the disorder, but evidence is sparse on whether these variables fulfill the criteria for endophenotypes. The present thesis is part of the Genetic Epidemiology and Molecular Genetics of Severe Mental Disorders in Finland project. The specific aim was to investigate whether neuropsychological test variables would indicate genetic liability to the disorder and could therefore be regarded as endophenotypes. Thus, cognitive functions and their heritability were studied in bipolar I disorder patients and in their unaffected first-degree relatives from a population-based sample of families, comparing them to a population-based control group. In order to add homogeneity to the subgroups of bipolar disorder patients and their relatives, cognitive functions and their heritability were further studied in a group of families affected by bipolar I disorder only (bipolar families) and another group of families affected by both bipolar I disorder and schizophrenia or schizoaffective disorders (mixed families). Finally, the effect of processing speed on other cognitive functions was investigated. The study showed that especially executive functioning and processing speed fulfilled the endophenotype criteria. Impairments in these functions were found in bipolar patients and in their relatives irrespective of other severe psychopathology in the family. These functions were highly heritable in these families. Study also showed that generalized impairment in verbal memory may associate more with bipolar disorder than to vulnerability to other psychotic disorders, and be more related to fully developed disease; impairments in verbal learning and memory were found only in patients, and they were not found to be highly heritable. Finally, the most potential endophenotype, i.e. processing speed, seemed to contribute to a range of other cognitive dysfunctions seen in bipolar disorder patients. Processing speed, in particular, has also been shown to be a valid endophenotype in subsequent association analyses in psychiatric genetics in Finland and internationally. Information concerning cognitive impairments and their association with the psychosocial consequences of bipolar disorder is important in planning treatment. It is also important to understand and acknowledge that patients may have cognitive impairments that affect their everyday life. Psychosocial interventions and neuropsychological rehabilitation may supplement other conventional treatments for bipolar patients.

Eteva Järvenpään perhepalvelukeskuksen lyhytaikaishoidon suunnittelun kehittäminen

Objectives. The thesis objective was to analyze how person-centred planning is applied to develop short term care in interaction between the disabled children, their families and the workers of the family service centre of Eteva Järvenpää. The thesis contributes to developing the methods of person-centred planning. I applied theoretical frameworks of activity theory and developmental work research, family-based work framework and disability phenomenon. The research questions were: What development needs did the families of disabled children have for the services? How were viewpoints of disabled children, their families and Eteva workers noticed in person-centred planning in the interaction between the disabled children, their families and Eteva workers? What disturbances and development challenges emerged during the person-centred planning? Methods. I first analysed the local history of the disability sector and the short term care to analyse challenges arising from the local history. The actural research material consisted of interviews with four families, two person-centred planning discussions and two discussions where the person-centred planning was reflected by the families.I used interaction voice analysis as defined by the activity theory and developmental work research. From the recorded interviews and discussions I analysed scripts, disturbances, innovation attempts and innovations. From the discussions I analysed also the interaction types (cooperation, coordination and communication). Results and conclusions. As problems, the families considered the scarce resources and the inflexibility of services. The challenges of developing the short term care were how to transfer information from short term care to home, how to develop activities for the children and how to take into account the individual needs of the children in the short term care. Both from the local history analysis and from the family interviews arised the conflict between caring and fulfilling the individual needs. In person-centred planning, the voice of the child was either interpreted by other family members or guided by family members or workers. I modelled the progress of person-centred planning in a two-dimensional coordination. Person-centred planning should be deepened in cooperation between the child, the family and the workers in everyday situations at home and during the short term care. The challenge is to expand person-centred planning to become cross-organizational cooperation connecting the actors of the child s service network in everyday life. Avainsanat Nyckelord - Keywords short term care, activity theory and developmental work research, person-centred planning, disability

Kielellinen erityisvaikeus : oirekuva ja familiaalisuus potilasasiakirjojen perusteella

Goals. Specific language impairment (SLI) has a negative impact on child s speech and language development and interaction. Disorder may be associated with a wide range of comorbid problems. In clinical speech therapy it is important to see the child as a whole so that the rehabilitation can be targeted properly. The aim of this study was to describe the linguistic-cognitive and comorbid symptoms of children with SLI at the age of five, as well as to provide an overwiew of the developmental disorders in the families. The study is part of a larger research project, which will examine paths of development and quality of life of children with SLI as young adults. Methods. The data consisted of patient documents of 100 5-year old children, who were examined in Lastenlinna mainly at 1998. Majority of the subjects were boys, and children s primary diagnosis was either F80.1 or F80.2, which was most common, or both. The diagnosis and the information about the linguistic-cognitive status and comorbid symptoms were collected from reports of medical doctors and experts of other fields, as well as mentions related to familiality. Linguistic-cognitive symptoms were divided into subclasses of speech motor functions, prosessing of language, comprehension of language and use of language. Comorbid symptoms were divided into subclasses of interaction, activity and attention, emotional and behavior problems and neurologic problems. Statistical analyses were based mainly on Pearson s Chi Square test. Results and conclusions. Problems in language processing and speech motor functions were most common of the linguistic-cognitive symptoms. Most of the children had symptoms from two or three symptom classes, and it seemed that girls had more symptoms than boys. Usually children did not have any comorbid symptoms, or had them from one or three symptom classes. Of the comorbid symptoms the most prevalent ones were problems in activity and attention and neurological symptoms, which consisted mostly of motoric and visuomotoric symptoms. The most common of the comorbid diagnoses was F82, specific developmental disorder of motor function. According to literature children with SLI may have problems in mental health, but the results of this study did not confirm that. Children with diagnosis F80.2 had more linguistic-cognitive and comorbid symptoms than children with diagnosis F80.1. The cluster analyses based on all the symtoms revealed four subgroups of the subjects. Of the subjects 85 percent had a positive family history of developmental disorders, and the most prevalent problem in the families was delayed speech development. This study outlined the symptom profile of children with SLI and laid a foundation for the future longitudinal study. The results suggested that there are differences between linguistic-cognitive symptoms of boys and girls, which is important to notice especially when assessing and diagnosing children with SLI.

Molecular diagnosis of developmental disorders

ABSTRACT Idiopathic developmental disorders (DDs) affect ~1% of the population worldwide. This being a considerable amount, efforts are being made to elucidate the disease mechanisms. One or several genetic factors cause 30-40% of DDs, and only 10% are caused by environmental factors. The remaining 50% of DD patients go undiagnosed, mostly due to a lack of diagnostic techniques. The cause in most undiagnosed cases is though to be a genetic factor or a combination of genetic and environmental factors. Despite the surge of new technologies entering the market, their implementation into diagnostic laboratories is hampered by costs, lack of information about the expected diagnostic yield, and the wide range of selection. This study evaluates new microarray methods in diagnosing idiopathic DDs, providing information about their added diagnostic value. Study I analysed 150 patients by array comparative genomic hybridization (array CGH, 44K and 244K), with a subsequent 18% diagnostic yield. These results are supported by other studies, indicating an enourmous added diagnostic value of array CGH, compared with conventional cytogenetic analysis. Nevertheless, 80% of the patients remained undiagnosed in Study I. In an effort to diagnose more patients, in Study IV the resolution was increased from 8.9 Kb of the 244K CGH array to 0.7 Kb, by using a single-nucleotide polymorphism (SNP) array. However, no additional pathogenic changes were detected in the 35 patients assessed, and thus, for diagnostic purposes, an array platform with ca 9 Kb resolution appears adequate. The recent vast increase in reports of detected aberrations and associated phenotypes has enabled characterization of several new syndromes first based on a common aberration and thereafter by delineation of common clinical characteristics. In Study II, a familial deletion at 9q22.2q22.32 with variable penetrance was described. Despite several reports of aberrations in the adjacent area at 9q associated with Gorlin syndrome, the patients in this family had a unique phenotype and did not present with the syndrome. In Study III, a familial duplication of chromosome 6p22.2 was described. The duplication caused increased expression of an important enzyme of the γ-aminobutyric acid (GABA) degradation pathway, causing oxidative stress of the brain, and thus, very likely, the mild mental retardation of these patients. These two case studies attempted to pinpoint candidate genes and to resolve the pathogenic mechanism causing the clinical characteristics of the patients. Presenting rare genetic and clinical findings to the international science and medical community enables interpretation of similar findings in other patients. The added value of molecular karyotyping in patients with idiopathic DD is evident. As a first line of testing, arrays with a median resolution of at least 9 Kb should be considered and further characterization of detected aberrations undertaken when possible. Diagnostic whole-exome sequencing may be the best option for patients who remain undiagnosed after high-resolution array analysis.