Pre- and perinatal hypoxia associated with hippocampus/amygdala volume in bipolar disorder.

BACKGROUND: Pre- and perinatal adversities may increase the risk for schizophrenia and bipolar disorder. Hypoxia-related obstetric complications (OCs) are associated with brain anatomical abnormalities in schizophrenia, but their association with brain anatomy variation in bipolar disorder is unknown. METHOD: Magnetic resonance imaging brain scans, clinical examinations and data from the Medical Birth Registry of Norway were obtained for 219 adults, including 79 patients with a DSM-IV diagnosis of bipolar disorder (age 29.4 years, s.d. = 11.8 years, 39% male) and 140 healthy controls (age 30.8 years, s.d. = 12.0 years, 53% male). Severe hypoxia-related OCs throughout pregnancy/birth and perinatal asphyxia were each studied in relation to a priori selected brain volumes (hippocampus, lateral ventricles and amygdala, obtained with FreeSurfer), using linear regression models covarying for age, sex, medication use and intracranial volume. Multiple comparison adjustment was applied. RESULTS: Perinatal asphyxia was associated with smaller left amygdala volume (t = -2.59, p = 0.012) in bipolar disorder patients, but not in healthy controls. Patients with psychotic bipolar disorder showed distinct associations between perinatal asphyxia and smaller left amygdala volume (t = -2.69, p = 0.010), whereas patients with non-psychotic bipolar disorder showed smaller right hippocampal volumes related to both perinatal asphyxia (t = -2.60, p = 0.015) and severe OCs (t = -3.25, p = 0.003). No associations between asphyxia or severe OCs and the lateral ventricles were found. CONCLUSIONS: Pre- and perinatal hypoxia-related OCs are related to brain morphometry in bipolar disorder in adulthood, with specific patterns in patients with psychotic versus non-psychotic illness.

Cortical folding in Broca's area relates to obstetric complications in schizophrenia patients and healthy controls.

BACKGROUND: The increased occurrence of obstetric complications (OCs) in patients with schizophrenia suggests that alterations in neurodevelopment may be of importance to the aetiology of the illness. Abnormal cortical folding may reflect subtle deviation from normal neurodevelopment during the foetal or neonatal period. In the present study, we hypothesized that OCs would be related to cortical folding abnormalities in schizophrenia patients corresponding to areas where patients with schizophrenia display altered cortical folding when compared with healthy controls. METHOD: In total, 54 schizophrenia patients and 54 healthy control subjects underwent clinical examination and magnetic resonance image scanning on a 1.5 T scanner. Information on OCs was collected from original birth records. An automated algorithm was used to calculate a three-dimensional local gyrification index (lGI) at numerous points across the cortical mantle. RESULTS: In both schizophrenia patients and healthy controls, an increasing number of OCs was significantly related to lower lGI in the left pars triangularis (p<0.0005) in Broca's area. For five other anatomical cortical parcellations in the left hemisphere, a similar trend was demonstrated. No significant relationships between OCs and lGI were found in the right hemisphere and there were no significant case-control differences in lGI. CONCLUSIONS: The reduced cortical folding in the left pars triangularis, associated with OCs in both patients and control subjects suggests that the cortical effect of OCs is caused by factors shared by schizophrenia patients and healthy controls rather than factors related to schizophrenia alone.

Unwanted pregnancy as a risk factor for offspring schizophrenia-spectrum and affective disorders in adulthood: a prospective high-risk study.

BACKGROUND: This study investigated whether 'unwanted pregnancy' (i.e. a negative or ambivalent attitude towards the pregnancy/reproduction) is associated with schizophrenia-spectrum and affective disorders in the offspring in adulthood, and if so, whether other pregnancy, perinatal, childhood or genetic-risk factors account for this association. METHOD: In a prospective study beginning during pregnancy, unwanted pregnancy (in combination with other early life risk factors) was studied in relation to adult mental disorders in 75 genetic high-risk (HR) and 91 normal-risk (NR) offspring, defined through maternal psychosis history. Early life risk factors were studied through personal interviews, observations and medical records, and offspring mental disorders were independently diagnosed through follow-up examination at about 22 years of age. RESULTS: Unwanted pregnancy by itself was significantly related to adult offspring schizophrenia-spectrum disorders in both the total sample and the HR subgroup, but the effect was found to be limited to the HR group and occurred in interaction with genetic risk. Other co-temporaneous pregnancy stressors and later perinatal complications, malformations and early childhood environmental stressors could not explain this relationship. Unwanted pregnancy also interacted with genetic-risk status in relating to affective disorders in the offspring. CONCLUSIONS: Unwanted pregnancy, when occurring together with genetic risk for psychosis, was found to be related to both adult schizophrenia-spectrum and affective mental disorders in the offspring. Although the effect of unwanted pregnancy could be mediated by other yet-unidentified factors, unwanted pregnancy might be a functional, discrete environmental psychosocial factor with its own deleterious impact on offspring mental development, when co-occurring with genetic risk.

Community-based environmental management in Atlantic Canada: the impacts and spheres of influence of the Atlantic Coastal Action Program.

The Atlantic Coastal Action Program (ACAP) is a unique, community-based program initiated by Environment Canada in 1991 to help Atlantic Canadians restore and sustain watersheds and adjacent coastal areas. ACAP is the eastem-most Environment Canada Ecosystem Initiative. The ACAP family is currently made up of 14 ecosystem-based organizations in the four Atlantic provinces. Each one of these non-profit organizations operates independently, but is formally linked under the umbrella of ACAP to represent a force stronger than the individual parts. In Environment Canada's experience, the program consistently demonstrates the value of a community-based approach and produces results on an ecosystem basis. This paper will examine some of the impacts of ACAP in terms of economics, credible community science, and environmental results which most often align with Environment Canada's objectives. It will explore the influences of the community-based approach to environmental management on multiple scales (local, regional, etc.). Through examples, the paper will demonstrate the effectiveness of ACAP in influencing some of the policies, programs and attitudes of various levels of government and industry in the region, as well as describe how the community-based model has been exported internationally. The paper will conclude with a discussion on a planned path forward for ACAP.

A prospective study of offspring of women with psychosis: visual dysfunction in early childhood predicts schizophrenia-spectrum disorders in adulthood.

OBJECTIVE: Children with visual dysfunction have perinatal, neurological, visual-perceptual and cognitive abnormalities, similar to schizophrenia patients. We prospectively investigated whether visual dysfunction in childhood selectively predicts adult schizophrenia-spectrum disorders, and is related to childhood neurological abnormality. METHOD: Offspring of mothers with and without a history of psychosis were prospectively assessed with vision tests at 4 years, neurological examinations at 6 years, and interviews for psychiatric disorders at follow-up (93% effective, n=166) at 22 years. RESULTS: In the total sample and high-risk (HR) offspring, visual dysfunction at 4 years, and its severity, were associated only with schizophrenia-spectrum disorders in adulthood, and with neurological abnormality at 6 years. CONCLUSION: Visual dysfunction at 4 years of age selectively predicts schizophrenia-spectrum disorders in adulthood among HR offspring, this likely reflecting disturbed neurological development.

Craniofacial dysmorphology in Swedish schizophrenia patients.

OBJECTIVE: To perform detailed assessments of craniofacial dysmorphology in individuals with schizophrenia and controls in Sweden, in order to further elucidate the neurodevelopmental origins of schizophrenia. METHOD: We performed detailed, anthropometric assessments of craniofacial dysmorphology in male patients with schizophrenia (n=24), healthy controls (n=16), and patients' siblings with schizophrenia (n=2) in Sweden, while remaining as blind as possible to schizophrenia/control status. RESULTS: Individuals with schizophrenia evidenced significantly more craniofacial dysmorphology than controls, especially in the ears and mouth. At a group level, there was a dose-response type relationship between total dysmorphology score and patient/control status. CONCLUSION: The consistency of results across multiple studies supports the hypothesis that individuals with schizophrenia have increased rates of prenatal developmental disturbances. The presence of a dose-response type relationship between total dysmorphology score and patient/control status supports the importance of neurodevelopmental disturbance as a contributory cause of schizophrenia.

Obstetrical complications, parenting practices and risk of criminal behaviour among persons who develop major mental disorders.

OBJECTIVE: The present study examined whether socio-economic status (SES) of the family of origin, inadequate parenting, and pre and perinatal factors are antecedents of criminality among men and women who develop a major mental disorder. METHOD: The sample included the 82 men and 79 women from the 1953 Stockholm birth cohort who developed a major mental disorder by age 30. Information was extracted from obstetric files, health, social and work records and official criminal records. RESULTS: Among males, neonatal complications increased the risk of offending two-fold, the risk of violent offending 2.5 times, and the risk of early start offending 3 times. Neither pregnancy or birth complications, inadequate parenting, or SES of the family of origin increased the risk for offending. Among females, none of the factors that were examined were associated with offending. CONCLUSION: Complications in the neonatal period are associated with offending among men who develop major mental disorders.

Membrane-bound TNF supports secondary lymphoid organ structure but is subservient to secreted TNF in driving autoimmune inflammation.

Mice without secreted TNF but with functional, normally regulated and expressed membrane-bound TNF (memTNF(Delta/Delta) mice) were created by knocking-in the uncleavable Delta 1-9,K11E TNF allele. In contrast to TNF-deficient mice (TNF(-/-)), memTNF supported many features of lymphoid organ structure, except generation of primary B cell follicles. Splenic chemokine expression was near normal. MemTNF-induced apoptosis was mediated through both TNF-R1 and TNF-R2. That memTNF is suboptimal for development of inflammation was revealed in experimental autoimmune encephalomyelitis. Disease severity was reduced in memTNF(Delta/Delta) mice relative to wild-type mice, and the nature of spinal cord infiltrates resembled that in TNF(-/-) mice. We conclude that memTNF supports many processes underlying lymphoid tissue structure, but secreted TNF is needed for optimal inflammatory lesion development.

Obstetric complications, parenting, and risk of criminal behavior.

BACKGROUND: The results of studies that have examined the relationship between prenatal and perinatal complications and adult criminality and violence are contradictory. Supporting evidence for this relationship comes from studies of samples drawn from a single cohort. The present study was designed to examine the associations between prenatal and perinatal complications and criminality, defining more precisely than past investigations subject characteristics and the types of offenses. METHODS: The cohort includes the 15 117 persons born in Stockholm, Sweden, in 1953 and followed up to age 30 years. Information was extracted from obstetric files, health, social, work, and criminal records. Obstetric complications were defined as deviations from normal development occurring at any point from conception through the neonatal period. Inadequate parenting was indexed by social intervention. RESULTS: Inadequate parenting was experienced by 19.1% of the men and 18.1% of the women, and was shown to increase the risk of offending (men, 1.39 times [95% confidence interval [CI], 1.28-1.50]; women, 2.09 [95% CI, 1.70-2.56]) and of violent offending (men, 2.02 times [95% CI, 1.67-2.44]; women, 2.09 [95% CI, 1.70-2.56]). Obstetric complications in the absence of family problems did not increase the risk of offending. A combination of pregnancy complications and inadequate parenting affected 3.1% of the men and 4.0% of the women, and increased the risk of offending (1.64 times [95% CI, 1.43-1.89]; 1.79 times [95% CI, 1.16-2.75], respectively) and violent offending (2.86 times [95% CI, 2.09-3.91]; 1.81 times [95% CI, 0.57-5.79]). CONCLUSIONS: A combination of pregnancy complications and inadequate parenting increased the risk of violent and nonviolent offending only slightly more than inadequate parenting alone. However, inadequate parenting was experienced by 5 times more cohort members than was the combination of inadequate parenting and pregnancy complications.

Increased rates of psychosis among immigrants to Sweden: is migration a risk factor for psychosis?

BACKGROUND: Previous studies have shown high rates of psychosis among Afro-Caribbean immigrants to the UK and immigrants to the Netherlands. Rates of schizophrenia-like psychoses (SLP), i.e. schizophrenia or other non-affective psychosis, among the native-born and immigrant populations were assessed in Malmö, the city in Sweden with the highest proportion of immigrants. METHODS: All adult patients admitted for in-patient psychiatric treatment in Malmö during the course of a 1-year period (N = 1162) were studied with regard to ethnicity and SLP diagnosis. A smaller sample consisting only of first-onset SLP cases (regardless of in- or out-patient status) was also studied (N = 56). Risks for admission and first-onset were calculated on the basis of current background population figures for Malmö. RESULTS: Compared with those who were native-born, immigrants had increased risk for admission for SLP, with a similar tendency for increased risk for first-onset of SLP. Relative risk for SLP admission was most markedly increased in immigrants from East-Africa. Background factors specifically associated with migration (e.g. extreme duress) did not appear to contribute strongly to SLP in immigrants. CONCLUSION: While the current results add to the growing body of evidence showing increased risk for psychosis in immigrants, vulnerability to psychosis may have been determined by factors other than the migration process.

Substance abuse in schizophrenia: a review of the literature and a study of correlates in Sweden.

The purpose of the current study is twofold: (a) to provide an overall synthesis of recent research on substance abuse in schizophrenia and (b) to present findings in a Swedish patient sample. Studies conducted since 1990 have found a wide range of abuse prevalence rates, with male gender and younger age as primary correlates. Less certainty exists regarding substance abuse as an independent risk factor for schizophrenia and its further impact on illness course. In a sample of 87 patients attending a psychiatric clinic in Malmö, lifetime prevalence of substance abuse was 48.3%, with abuse debut primarily preceding first contact for psychotic symptoms. Significant correlates of abuse were male gender, family history of substance abuse, and increased rates of hospitalization and criminality, with poorer outcome found in previous as well as current abusers. Alcohol abuse, either solely or in combination with other substances, was the main type of substance abuse. Although the specific factors (social, behavioural, genetic) that predispose schizophrenic patients to substance abuse remain unclear, the predominantly male profile of abusers might suggest a link between substance abuse and the poorer clinical outcome frequently observed, especially in male schizophrenic patients.

Neurodevelopmental origins of tardivelike dyskinesia in schizophrenia patients and their siblings.

The question of whether dyskinesia of the type found in tardive dyskinesia (TD) related to schizophrenia has a neurodevelopmental background was studied in a sample of 60 younger schizophrenia patients (mean age 38 years) and 21 of their non-ill siblings. TD-like dyskinesia was studied in relation to selected risk factors in the patients, and to neurological abnormality and parkinsonism in both patients and siblings. One or more signs of TD-like dyskinesia in patients were predicted by male gender, a history of obstetric complications, shorter illness duration, and shorter neuroleptic exposure. One or more signs of TD-like dyskinesia were found in 28.5 percent of the siblings and tended to be associated with neurological abnormality. Little co-occurrence of TD-like dyskinesia was found in the sibling and the patient in the same family. Patients' TD-like dyskinesia was significantly associated with hard neurological signs (independent of involuntary movements) but not with soft signs or primitive reflexes per se. TD-like dyskinesia showed a significant positive relationship to parkinsonism in patients. TD-like dyskinesia in younger schizophrenia patients appears to have neurodevelopmental antecedents and seems to represent one aspect of the total neurological abnormality associated with schizophrenia.

Minor physical anomalies and obstetric complications in schizophrenia.

OBJECTIVE: To evaluate the possibility of using congenital minor physical anomalies (MPA) and obstetric complications (OC) as individual-orientated, early life markers signalling increased risk for schizophrenia. METHOD: Previous findings using Waldrop and colleagues' MPA scale (and additional items) and systematic study of OC history are summarised concerning schizophrenia patients and individuals at heightened genetic risk for schizophrenia. RESULTS: Significantly increased rates of both MPA and OC are consistently found in patients with schizophrenia. Minor physical anomalies are stable characteristics over time and can be studied efficiently from early childhood onward. Minor physical anomalies predict a variety of mental disorders in normal-risk children, but the predictive efficiency of MPA for schizophrenia in genetic high-risk samples and in the general population is unknown. Obstetric complications predict serious mental disturbance and neurodisorder in genetic high-risk cases, as well as doubling or tripling the individual's risk for schizophrenia in the general population. Obstetric complication results are sensitive to methodology and are best investigated using prospectively recorded information and an efficient OC scale for scoring the information. CONCLUSIONS: Both MPA and OC should be included in batteries of methods for identifying individuals at an increased risk for schizophrenia. However, increased rates of MPA and OC are not pathognomonic for schizophrenia, but rather characterise individuals at risk of a much broader range of mental and physical abnormality, as well as normality. Minor physical anomalies and OC are not in themselves stigmatising, but their possible identification as markers for 'increased risk for schizophrenia' should be used judiciously. Further research is recommended regarding the MPA and OC patterns related to schizophrenia.

Neuromotor markers of risk for schizophrenia.

OBJECTIVE: To evaluate the possibility of using neuromotor deviation (NMD) as an individual-orientated, early life marker for increased risk for schizophrenia. METHOD: Previous findings based on systematic examination of NMD are summarised concerning schizophrenia patients and individuals at heightened genetic risk for schizophrenia. RESULTS: Significantly increased rates of NMD are found in patients with schizophrenia, both after and long before disease onset. Neuromotor deviation can be efficiently studied at all ages from infancy to adulthood, and is typically not in itself stigmatising. Neuromotor deviation may represent an unstable characteristic of individuals from infancy to middle-to-late childhood, possibly attaining greater stability thereafter. Neuromotor deviation may also be more stable over time in the high-risk offspring of parents with schizophrenia than in other children. Neuromotor deviation in childhood predicts subsequent serious mental disturbance in genetic high-risk children. The efficiency of NMD for predicting schizophrenia in unselected samples is unknown, as is the optimal age(s) for assessing NMD to predict schizophrenia in high-risk and normal-risk groups. Neuromotor deviation is also found in the well relatives of schizophrenia patients, individuals developing a broad range of mental and physical disorders, and mentally normal individuals in the general population. CONCLUSIONS: Neuromotor deviation should definitely be included in batteries of methods for identifying individuals with notably heightened risk of schizophrenia. However, NMD is not pathognomonic for schizophrenia, and the investigation of NMD during childhood and adolescence must thus be used judiciously in order to avoid possible stigmatisation. Further research should be done concerning the specific forms and developmental timing of NMD as related to schizophrenia.

DAP12-deficient mice fail to develop autoimmunity due to impaired antigen priming.

DAP12 is an ITAM-bearing membrane adaptor molecule implicated in the activation of NK and myeloid cells. In mice rendered DAP12 deficient by targeted gene disruption, lymphoid and myeloid development was apparently normal, although the activating Ly49 receptors on NK cells were downregulated and nonfunctional. To analyze the consequences of DAP12 deficiency in vivo, we examined the susceptibility of DAP12-/- mice to experimental autoimmune encephalomyelitis (EAE). DAP12-/- mice were resistant to EAE induced by immunization with myelin oligodendrocyte glycoprotein (MOG) peptide. Resistance was associated with a strongly diminished production of IFNgamma by myelin-reactive CD4+ T cells due to inadequate T cell priming in vivo. These data suggest that DAP12 signaling may be required for optimal antigen-presenting cell (APC) function or inflammation.

Labour and delivery complications and schizophrenia. Case-control study using contemporaneous labour ward records.

BACKGROUND: Controversy continues regarding an association between obstetric complications and risk of schizophrenia in early adult life. AIMS: To compare the rate of labour and delivery complications among persons who developed schizophrenia with controls; to establish whether any complication is associated with later schizophrenia. METHOD: We located the labour ward records of 431 individuals with schizophrenia and of same-gender controls from the same hospital birth series. Mothers were matched by age, socio-economic group and parity. Individual complications were evaluated blindly using two obstetric complication scales. RESULTS: Overall, the rate of labour and delivery complications for those who developed schizophrenia did not differ from that of controls. Males who had presented to psychiatric services before the age of 30 had a greater frequency of and more severe labour/delivery complications than their matched controls. CONCLUSIONS: Other than among young-onset males we found no increase in labour and delivery complications among cases.

Labour and delivery complications at birth and later mania. An Irish case register study.

BACKGROUND: Several reports postulate that manic depression and schizophrenia share environmental risk factors. Although obstetric adversity has been suggested as a risk factor for schizophrenia, few studies have examined its relationship to bipolar affective disorder. AIMS: To assess the rate of obstetric complications incurred by patients with mania compared with controls. METHOD: From the Dublin Psychiatric Case Register we identified individuals with a discharge diagnosis of mania and traced their birth records. Each case was matched with a control of the same gender, born in the same hospital, in the same year, matched for maternal age, parity and social class. Two obstetric complications scales were used to make blind evaluations of labour and delivery data. RESULTS: Patients with mania did not experience a greater frequency or severity of labour and delivery complications than their matched controls. Rates of obstetric adversity were unrelated to the presence or absence of family history of psychiatric disorder. Obstetric adversity was unrelated to the age at first diagnosis. CONCLUSIONS: These findings suggest that obstetric adversity is not a risk factor for later mania.

Are neurological abnormalities in schizophrenic patients and their siblings the result of perinatal trauma?

OBJECTIVE: Previous findings of increased neurological abnormalities in schizophrenic patients and their non-psychotic siblings raise the question of possible causes. The purpose of the present study was to examine the role of perinatal trauma in the aetiology of neurological abnormality. METHOD: Obstetric information obtained from hospital records for 55 schizophrenic patients and 19 non-psychotic siblings was scored blindly and separately from a neurological assessment of hard and soft signs. RESULTS: Obstetric complications (OCs) were significantly increased in patients but not in siblings compared to their respective neonatal control groups. Neurological abnormalities were related to OCs in siblings but not in patients. Neurological abnormalities in patients were negatively related to reduced neonatal head circumference. CONCLUSION: Early somatic trauma may increase the probability of neurological abnormality in individuals who are genetically 'at risk'.

Minor physical anomalies in schizophrenia: cognitive, neurological and other clinical correlates.

Minor physical anomalies (MPAs) are minor congenital malformations which are found with significantly increased frequency among both patients with schizophrenia and their siblings, suggesting the effect of early developmental disturbance in their families. The aim of this study was to explore the relationship between these signs of early dysmorphogenesis and cognitive and neurological dysfunction in the patients and their siblings as well as the clinical characteristics of the patients. Sixty patients with schizophrenia, 21 nonpsychotic siblings and 75 normal comparison subjects were studied. Increased rates of cognitive and neurological dysfunction and high MPA scores were found in both the patients and their siblings. High rates of MPAs were not significantly related to cognitive or neurological dysfunction in the patients or siblings, or to premorbid history or other characteristics of the clinical disease process in the patients. These results suggest that MPAs are possibly markers of general early neuromaldevelopment rather than markers of a specific cognitive/neurological or clinical subtype of schizophrenia.

Obstetric complications and congenital malformation in schizophrenia.

Recent years have witnessed increasingly intense research activity concerning early life somatic trauma and dysmorphogenesis which are associated with the later development of schizophrenia. The two somatic factors that have received the most extensive scientific attention as antecedents of schizophrenia are obstetric complications (OCs) and the congenital malformations termed 'minor physical anomalies' (MPAs). Head circumference (HC) at birth has also been studied as a measure of prenatal cerebral development. A great number of studies indicate clearly that schizophrenia patients have a significantly increased history of OCs, representing many different OCs from pregnancy, labor-delivery and the neonatal period. The probable common denominator of these OCs is oxygen deprivation. Especially labor-delivery OCs relate strongly to brain structure abnormality in ill twins from monozygotic pairs discordant for schizophrenia. Schizophrenia patients very consistently have evidenced an increased frequency of MPAs in the global head, eyes, mouth, ears, hands, feet and limbs. Specific MPAs occur with considerable frequency even among normal comparison subjects, but combination models for specific MPAs efficiently discriminate most patients from comparison subjects. Schizophrenia patients also have significantly reduced HC at birth, independently of gestational age, suggesting a disturbance in prenatal cerebral development, and most frequently observed in female patients. Evidence has thus accumulated, increasingly, for the role of various forms of early trauma and dysmorphogenesis in subsequent schizophrenia, and efforts continue to determine the manner in which these early trauma influence both the early developing brain and the brain of the adult patient with manifest schizophrenia.