Childhood neuromotor dysfunction in schizophrenia patients and their unaffected siblings: a prospective cohort study

Neuromotor dysfunction is a consistent finding in high-risk and archival studies of schizophrenia, but the sources of this dysfunction and its role in the developmental course of the disorder remain poorly understood. This study examined childhood motor predictors of adult psychiatric outcome in a birth cohort sample (72 patients with schizophrenia or schizoaffective disorder, 63 unaffected siblings, and 7,941 nonpsychiatric controls), evaluated prospectively with neurologic examinations at 8 months, 4 years, and 7 years of age. Deviance on motor coordination measures at 7 years was associated with both adult schizophrenia and unaffected sibling status, suggesting that a cofamilial (and perhaps genetic) factor underlies motor coordination deficits in schizophrenia. Unusual movements at ages 4 and 7 predicted adult schizophrenia but not unaffected sibling status, indicating that these deficits may be specific to those who will develop the clinical phenotype. None of the motor precursors were confined to patients with an early age at first treatment contact. Fetal hypoxia predicted unusual movements at 4 but not 7 years among the preschizophrenia subjects, suggesting neurodevelopmental dependence of its functional effects. Neither prenatal complications nor birth weight were associated with motor dysfunction in preschizophrenia subjects or their unaffected siblings at any age. Finally, preschizophrenia children did not show the expected developmental decline in unusual movements, perhaps reflecting aberrant functional maturation of cortical-subcortical pathways.     

Childhood cognitive functioning in schizophrenia patients and their unaffected siblings: a prospective cohort study

While it is known that children of schizophrenia parents perform more poorly on tests of cognitive functioning than children of normal parents, less certain is the degree to which such deficits predict schizophrenia outcome, whether cognitive functioning deteriorates during childhood in preschizophrenia individuals, and whether nongenetic etiologic factors (such as obstetric complications) contribute to these deficits. In the present study, 72 patients with schizophrenia or schizoaffective disorder, 63 of their siblings not diagnosed with schizophrenia, and 7,941 controls with no diagnosis were ascertained from a birth cohort whose members had been evaluated with standardized tests of cognitive functioning at 4 and 7 years of age. Adult psychiatric morbidity was ascertained via a longitudinal treatment data base indexing regional public health service utilization, and diagnoses were made by review of all pertinent medical records according to DSM-IV criteria. Both the patients with schizophrenia and their unaffected siblings performed significantly worse than the nonpsychiatric controls (but did not differ from each other) on verbal and nonverbal cognitive tests at 4 and 7 years of age. Preschizophrenia cases and their siblings were increasingly overrepresented across decreasing quartiles of the performance distributions. There was not significant intra-individual decline, and there were no significant relationships between obstetric complications and test performance among the preschizophrenia subjects. These results suggest that during the period from age 4 to age 7 years, premorbid cognitive dysfunction in schizophrenia represents a relatively stable indicator of vulnerability deriving from primarily genetic (and/or shared environmental) etiologic influences.     

Neural anomalies during visual search in schizophrenia patients and unaffected siblings of schizophrenia patients

Schizophrenia patients and their unaffected first-degree relatives exhibit performance deficits on attention tasks, perhaps indicating genetic influence over attentional abnormalities in schizophrenia. To identify anomalous brain function associated with attention in individuals who likely have unexpressed genetic liability for schizophrenia, we studied electrophysiological characteristics of unaffected siblings of schizophrenia patients during a visual serial search task. We gathered behavioral and electrophysiological data from 19 schizophrenia patients, 18 unaffected biological siblings of schizophrenia patients, and 19 nonpsychiatric control participants during performance of the Span of Apprehension (Span) task and a control task. Schizophrenia patients had lower Span task accuracy than the other two groups. Schizophrenia and sibling groups exhibited diminished late positive potentials (P300) over parietal brain regions during Span trials. Compared to control task stimuli, attentional demands of Span stimuli elicited augmented early negative potentials (N1, P2) over posterior brain regions. The degree of augmentation was reduced in schizophrenia patients but not in siblings compared to control subjects. Unaffected siblings of schizophrenia patients appear to modulate early attentional functions of posterior brain regions more effectively than schizophrenia patients but show later electrophysiological anomalies suggestive of abnormal updating of task-relevant information. While the latter may reflect neural mechanisms predisposing performance deficits on attentional tasks, the former may reflect compensatory processes present in unaffected relatives of schizophrenia patients.     

Abnormal fMRI response of the dorsolateral prefrontal cortex in cognitively intact siblings of patients with schizophrenia

OBJECTIVE: The identification of neurobiological intermediate phenotypes may hasten the search for susceptibility genes in complex psychiatric disorders such as schizophrenia. Earlier family studies have suggested that deficits in executive cognition and working memory may be related to genetic susceptibility for schizophrenia, but the biological basis for this behavioral phenotype has not been identified. METHOD: The authors used functional magnetic resonance imaging (fMRI) during performance of the N-back working memory task to assess working memory-related cortical physiology in nonschizophrenic, cognitively intact siblings of patients with schizophrenia. They compared 23 unaffected siblings of schizophrenic patients to 18 matched comparison subjects. As a planned replication, they studied another 25 unaffected siblings and 15 comparison subjects. RESULTS: In both cohorts, there were no group differences in working memory performance. Nevertheless, both groups of siblings showed an exaggerated physiological response in the right dorsolateral prefrontal cortex that was qualitatively similar to results of earlier fMRI studies of patients with schizophrenia. CONCLUSIONS: These fMRI data provide direct evidence of a primary physiological abnormality in dorsolateral prefrontal cortex function in individuals at greater genetic risk for schizophrenia, even in the absence of a manifest cognitive abnormality. This exaggerated fMRI response implicates inefficient processing of memory information at the level of intrinsic prefrontal circuitry, similar to earlier findings in patients with schizophrenia. These data predict that inheritance of alleles that contribute to inefficient prefrontal information processing will increase risk for schizophrenia.     

Paternal age of schizophrenia probands and endophenotypic differences from unaffected siblings

We evaluated the discrepancy of endophenotypic performance between probands with schizophrenia and unaffected siblings by paternal age at proband birth, a possible marker for de novo mutations. Pairs of schizophrenia probands and unaffected siblings (N=220 pairs) were evaluated on 11 neuropsychological or neurophysiological endophenotypes previously identified as heritable. For each endophenotype, the sibling-minus-proband differences were transformed to standardized scores. Then for each pair, the average discrepancy was calculated from its standardized scores. We tested the hypothesis that the discrepancy is associated with paternal age, controlling for the number of endophenotypes shared between proband and his or her sibling, and proband age, which were both associated with paternal age. The non-significant association between the discrepancy and paternal age was in the opposite direction from the hypothesis. Of the 11 endophenotypes only sensori-motor dexterity was significant, but in the opposite direction. Eight other endophenotypes were also in the opposite direction, but not significant. The results did not support the hypothesized association of increased differences between sibling/proband pairs with greater paternal age. A possible explanation is that the identification of heritable endophenotypes was based on samples for which schizophrenia was attributable to inherited rather than de novo/non-inherited causes.     

Lack of evidence for elevated obstetric complications in childhood onset schizophrenia.

BACKGROUND: Pre-, peri-, and postnatal obstetric complications (OC) are reported to be more frequent in adult patients with schizophrenia and have been linked to both greater severity and to "earlier" age of onset (before either age 18 or 22) in studies of adult patients. We hypothesized that by extrapolation, patients with childhood-onset schizophrenia (COS), with very early onset and very severe illness, would have had more numerous or more salient OC compared with their healthy siblings. METHODS: We compared the obstetric records of 60 COS children and 48 healthy siblings using the Columbia Obstetrics Complication Scale, a comprehensive measurement scale consisting of 37 variables having included a separate scale for fetal hypoxia. RESULTS: Patients with COS did not have a higher incidence of OC than the healthy sibling control group with the exception of increased incidence of maternal vomiting. CONCLUSIONS: Obstetric complications, with the possible exception of maternal vomiting, are unlikely to play a major role in the etiopathogenesis of childhood-onset schizophrenia.     

A prospective study of childhood neurocognitive functioning in schizophrenic patients and their siblings

OBJECTIVE: This study evaluated childhood cognitive functioning in individuals who later developed schizophrenia and in their unaffected siblings. METHOD: Through the National Collaborative Perinatal Project, seven subtests of the Wechsler Intelligence Scale for Children were administered at age 7 to 32 individuals who developed schizophrenia in adulthood, 25 of their nonschizophrenic siblings, and 201 demographically similar nonpsychiatric comparison subjects. Mixed model analysis was used to examine between-group differences in standardized scores on the subtests. RESULTS: The probands and unaffected siblings had lower scores for picture arrangement, vocabulary, and coding than the comparison subjects but differed from each other only on the coding subtest. CONCLUSIONS: Children who later developed schizophrenia and their siblings showed similar patterns of deficits involving spatial reasoning, verbal knowledge, perceptual-motor speed, and speeded processes of working memory. However, the probands exhibited more severe deficits in perceptual-motor speed and speeded processes of working memory than their unaffected siblings.     

Decreased resting-state interhemispheric functional connectivity in unaffected siblings of schizophrenia patients

BackgroundNeuroimaging studies in unaffected siblings of schizophrenia patients can provide clues to the pathophysiology for the development of schizophrenia. However, little is known about the alterations of the interhemispheric resting-state functional connectivity (FC) in siblings, although the dysconnectivity hypothesis is prevailing in schizophrenia for years. In the present study, we used a newly validated voxel-mirrored homotopic connectivity (VMHC) method to identify whether aberrant interhemispheric FC was present in unaffected siblings at increased risk of developing schizophrenia at rest.MethodsForty-six unaffected siblings of schizophrenia patients and 50 age-, sex-, and education-matched healthy controls underwent a resting-state functional magnetic resonance imaging (fMRI). Automated VMHC was used to analyze the data.ResultsThe sibling group had lower VMHC than the control group in the angular gyrus (AG) and the lingual gyrus/cerebellum lobule VI. No region exhibited higher VMHC in the sibling group than in the control group. There was no significant sex difference of the VMHC values between male siblings and female siblings or between male controls and female controls, although evidence has been accumulated that size and shape of the corpus callosum, and functional homotopy differ between men and women.ConclusionsOur results first suggest that interhemispheric resting-state FC of VMHC is disrupted in unaffected siblings of schizophrenia patients, and add a new clue of abnormal interhemispheric resting-state FC to the pathophysiology for the development of schizophrenia.     

Adult siblings of individuals with Down syndrome versus with autism: findings from a large-scale US survey

Background As adults with Down syndrome live increasingly longer lives, their adult siblings will most likely assume caregiving responsibilities. Yet little is known about either the sibling relationship or the general functioning of these adult siblings. Using a national, web‐based survey, this study compared adult siblings of individuals with Down syndrome to siblings of individuals with autism in terms of a potential ‘Down syndrome advantage’ and changes across age of the brother/sister with disabilities. Methods Two groups were examined, siblings of persons with Down syndrome (n = 284) and with autism (n = 176). The Adult Sibling Questionnaire measured the number and length of contacts between siblings and their brothers/sisters with disabilities; the warmth, closeness and positiveness of the sibling relationship; and the sibling's overall levels of perceived health, depression and rewards of being a sibling. Results Compared with siblings of brothers/sisters with autism, siblings of brothers/sisters with Down syndrome showed closer, warmer sibling relationships, along with slightly better health, lower levels of depressive symptoms and more contacts. Across age groups of the brother/sister with disabilities, both groups showed lessened contacts, with less close sibling relationships occurring when brothers/sisters with disabilities were aged 30–44 years and 45 years and older (in Down syndrome) and 45 years and older (in autism). Within both groups, closer sibling relationships were associated with more frequent and lengthy contacts, brothers/sisters with disabilities who were better at maintaining friendships and had lower levels of behavioural/emotional problems, and siblings who felt themselves more rewarded by being a sibling to a brother/sister with disabilities. Conclusions In line with earlier work on families of children with disabilities, this study shows an advantage for siblings of adults with Down syndrome, in terms of both sibling relationships and of slightly better health and lessened depressive symptoms. Both joint contacts and close sibling relationships do, however, differ when the brother/sister with disabilities is older. As the first generation of probable caregivers, siblings of persons with Down syndrome who are in their forties, fifties and sixties require increased research attention.     

Childhood sibling relationships as a predictor of major depression in adulthood: a 30-year prospective study

OBJECTIVE: The authors examined the quality of sibling relationships in childhood as a predictor of major depression in adulthood. METHOD: Study subjects were 229 men selected for mental and physical health and followed from ages 20 through 50 and beyond as part of a study of adult psychosocial development. Data were obtained from interviews with participants and their parents at intake and from follow-up interviews and self-report questionnaires completed by participants at regular intervals. These data were used to rate the quality of relationships with siblings, the quality of parenting received in childhood, and family history of depression as well as the occurrence, by age 50, of major depression, alcoholism, and use of mood-altering drugs (tranquilizers, sleeping pills, and stimulants). RESULTS: Poorer relationships with siblings prior to age 20 and a family history of depression independently predicted both the occurrence of major depression and the frequency of use of mood-altering drugs by age 50, even after adjustment for the quality of childhood relationships with parents. Poor relationships with parents in childhood did not predict the occurrence of depression by age 50 when family history of depression and the quality of relationships with siblings were taken into account. Quality of sibling relationships and family history of depression did not predict later alcohol abuse or dependence. CONCLUSIONS: Poor sibling relationships in childhood may be an important and specific predictor of major depression in adulthood. Further study of links between childhood sibling relationships and adult depression is warranted.     

Childhood videotaped social and neuromotor precursors of schizophrenia: a prospective investigation

OBJECTIVE: The authors examined videotaped behaviors of children who developed schizophrenia as adults and of comparison subjects to disclose possible social and neuromotor deficits foreshadowing later development of schizophrenia. METHOD: In 1972, a sample of 265 11-13-year-old Danish children were filmed under standardized conditions while they were eating lunch. The examination was part of a larger study investigating early signs of schizophrenia spectrum disorders. Many of the subjects had a parent with schizophrenia, leaving them at high risk for developing a schizophrenia spectrum disorder. In 1991, adult psychiatric outcome data were obtained for 91.3% (N=242). This study systematically analyzed the videotapes to determine whether the children who developed schizophrenia as adults evidenced greater social and/or neuromotor deficits than children who did not develop a psychiatric disorder and children who developed other psychiatric disorders. RESULTS: The findings from this study suggest that the brief videotaped footage of children eating lunch was able to discriminate between the individuals who later developed schizophrenia and those who did not. Specifically, the preschizophrenia children evidenced differences on measures of sociability and general neuromotor functioning (among boys) from the children who developed other psychiatric disorders and the children who did not develop a psychiatric disorder. CONCLUSIONS: Social and neuromotor deficits specific to children who develop schizophrenia in adulthood provide further support for a neurodevelopmental hypothesis of schizophrenia.     

Variability of ecological executive function in children and adolescents genetically at high risk for schizophrenia: a latent class analysis

Executive impairments have been observed both in patients with schizophrenia and in their unaffected first-degree relatives. Very few studies have investigated neurocognitive subgroups in unaffected first-degree relatives and in healthy participants using data-driven methods. The study included a high-risk group consisting of 100 unaffected young offspring and siblings of patients with schizophrenia and 198 healthy controls, all aged between 9 and 23 years. Executive function, victimization, and emotional and behavioral problems of participants were assessed by a series of self-report scales. Neurocognitive subgroups were investigated using latent class analysis of executive function measures. Four neurocognitive clusters were identified: a good performance cluster, a good self-control cluster, a low self-control cluster, and a severe impairment cluster. Participants in severe impaired executive function cluster reported a significantly higher level of victimization and had more prominent emotional and behavioral problems than the good performance cluster. Neurocognitive differences between high-risk young people and healthy controls were driven by individuals who have severe and global, rather than selective, executive deficits. Our results may provide clues to an explanation of the mechanisms behind executive impairments in young individuals at genetic risk and help to identify new targets for early interventions.

     

Physical violence experienced and witnessed by siblings of persons with schizophrenia in Japan

Violence committed by patients with mental illness is mostly perpetuated against family members, not strangers. The present study aimed to clarify the rate of violence that is experienced and/or witnessed by siblings of patients with schizophrenia and factors related to sibling’s experiencing and/or witnessing violence committed by patients. A self-administered survey was completed by family members of patients with schizophrenia, including siblings. The final sample consisted of 113 siblings. Of the 113 siblings, 52 (46.0%) had experienced and 56 (49.6%) had witnessed physical violence at some point. A logistic regression revealed that siblings tended to experience physical violence by patients with younger age of onset of the disorder. Witnessing physical violence was significantly related to being a female sibling, a male patient, younger age of patient, and younger age of onset of schizophrenia. Crisis intervention and respite services for female siblings in particular need to be developed in Japan.     

Familial liability to schizophrenia: a sibling study of negative symptoms

Negative symptoms are important features in schizophrenia, so in milder form they might also serve as indicators of "unexpressed" liability to schizophrenia among patients' adult relatives without schizophrenia. To address this question, we assessed negative symptoms in 39 stable schizophrenia or schizoaffective outpatients, 39 of their siblings, 38 well control probands, and 38 of their siblings. Negative symptom measures included standard behavior ratings of the core negative symptoms of affective flattening and alogia, as well as a self-report measure of social anhedonia. As expected, even stable outpatients with schizophrenia exhibited significantly more negative symptoms than control probands and control siblings. However, negative behavioral symptoms of affective flattening, alogia, and anhedonia did not significantly differentiate the siblings of the schizophrenia patients from the control probands or their siblings, although there were some trends for anhedonia. The findings suggest that core negative symptoms of observed affective flattening and poverty of speech are not likely to be useful as strong indicators of "unexpressed" liability to schizophrenia.     

Qualifying language disorders of schizophrenia through the speech therapists' assessment

This study investigates a comprehensive assessment of language disorders in order to identify impaired and unaffected language abilities of individuals with schizophrenia. Furthermore, the purpose of this study was to demonstrate the importance of the role of speech therapists in the treatment of schizophrenia. Speech therapy is especially thought to treat language disorders. However, to date, speech therapists have not been solicited in the treatment of schizophrenia, despite growing evidence supporting that schizophrenia is characterized by cognitive disorders such as impairments in memory, attention, executive functioning and language. In this article, we discuss the fact that elements of language and cognition are interactively affected and that cognition influences language. We then demonstrate that language impairments can be treated in the same way as neurological language impairments (cerebrovascular disease, brain injury), in order to reduce their functional outcome. Schizophrenia affects the pragmatic component of language with a major negative outcome in daily living skills [Champagne M, Stip E, Joanette Y. Social cognition deficit in schizophrenia: accounting for pragmatic deficits in communication abilities? Curr Psychiatry Rev:2006;(2):309-315]. The results of our comprehensive assessment also provide a basis for the design of a care plan. For this, subjects with schizophrenia were examined for language comprehension and language production with a focus on pragmatic abilities. In neurology, standardized tests are available that have been designed specifically to assess language functions. However, no such tests are available in psychiatry, so we gathered assessments widely used in neurology and examined the more relevant skills. In this article, each test we chose is described and particular attention is paid to the information they provided on impaired language abilities in schizophrenia. In this manner, we provide an accurate characterization of schizophrenia-associated language impairments and offer a solid foundation for rehabilitation. Current research makes connections between schizophrenia and other neurological disorders concerning language. Nevertheless, further studies are needed to explore these connections to complete our investigations. The strategies we designed are aimed at enabling a subject with schizophrenia to improve his/her language skills. We support the idea that such improvement could be reached by speech therapy. We conclude that speech therapists can play an important role in the non pharmacological treatment of schizophrenia, by selecting appropriate interventions that capitalize on spared abilities to compensate for impaired abilities.     

The persistence of developmental markers in childhood and adolescence and risk for schizophrenic psychoses in adult life. A 34-year follow-up of the Northern Finland 1966 birth cohort

Childhood precursors of schizophrenia include multiple abnormalities of development. Continuities between early and subsequent deviance are poorly characterised. We studied associations among premorbid developmental deviance using data at ages 1 year (learning to stand, walk, and speak, attainment of bladder and bowel control) and 16 years (success at school). Generalised linear modelling was used to examine differential linear associations and trends across adult psychiatric diagnoses. In babies who, as adults, suffered schizophrenia or any psychosis, those who learned to stand latest were also more likely to perform poorly at school in both motor and theoretical domains at age 16 when compared with earlier learners. The effect was independent of genetic and perinatal factors. We conclude that the early developmental deviation in the first year of life is associated with lower school performance at age 16. Developmental continuity among children who develop psychoses was stronger than among normal controls and those hospitalized for nonpsychotic psychiatric disorder. These findings are in line with the hypothesis that a neural diathesis is present during postnatal brain development before schizophrenia. This supports the longitudinal dimension and life span models of schizophrenia.     

Reduction in temporal lobe size in siblings with schizophrenia: a magnetic resonance imaging study

Twenty-eight individuals with familial schizophrenia, from 16 unrelated families (12 sibling pairs and 4 individuals whose siblings refused scanning), and 21 normal control subjects were examined by cerebral magnetic resonance imaging (MRI). Measurements of the cerebrum, temporal lobes, and cerebral lateral ventricles were obtained using consecutive coronal sections containing these structures. Temporal lobe volume was significantly decreased by approximately 10% in these early onset schizophrenic siblings compared with normal controls. These findings add to recent post-mortem and neuroradiological evidence for morphological alteration in the temporal lobes in schizophrenia.     

Neuropsychiatric and neurodevelopmental outcome of children at age 6 and 7 years who screened positive for language problems at 30 months

We present a prospective study at school age of neuropsychiatric and neurodevelopmental outcome of language delay suspected at child health screening around 30 months of age. In a community sample, 25 children (21 males, 4 females) screening positive and 80 children (38 males, 42 females) screening negative for speech and language problems at age 30 months were examined in detail for language disorders at age 6 years. The screen-positive children were then followed for another year and underwent in-depth neuropsychiatric examination by assessors blind to the results of previous testing. Detailed follow-up results at age 7 years were available for 21 children. Thirteen of these 21 children (62%) had a major neuropsychiatric diagnosis (autism, atypical autism, Asperger's syndrome, attention-deficit-hyperactivity disorder [ADHD]), or combinations of these. Two further children (10%) had borderline IQ with no other major diagnosis. We conclude that children in the general population who screen positive for speech and language problems before age 3 years appear to be at very high risk of autism spectrum disorders or ADHD, or both, at 7 years of age. Remaining language problems at age 6 years strongly predict the presence of neuropsychiatric or neurodevelopmental disorders at age 7 years.     

The effect of the quality of sibling relationships on the life satisfaction of adults with schizophrenia

OBJECTIVE: This study examined the importance of the quality of the sibling relationship to the life satisfaction of adults with schizophrenia. METHODS: Data were drawn from a longitudinal survey of aging families of adults with schizophrenia. Ninety-three dyads of adults with schizophrenia and their siblings participated. Participants independently completed a self-administered mail questionnaire. Data on the quality of the sibling relationship were taken from the siblings' scores on the Positive Affect Index, and data on life satisfaction of the adult with schizophrenia were measured by the self and present life subscale of the Satisfaction With Life Scale. RESULTS: Adults with schizophrenia had higher levels of life satisfaction when their siblings reported having a closer and more supportive relationship with their sibling with schizophrenia. CONCLUSIONS: Our findings provide evidence of the saliency of the sibling relationship to quality of life of adults with schizophrenia in midlife.