Lauren M. Ellman

Gene-Environment Interaction and Covariation in Schizophrenia: The Role of Obstetric Complications

While genetic factors account for a significant proportion of liability to schizophrenia, a body of evidence attests to a significant environmental contribution. Understanding the mechanisms through which genetic and environmental factors coalesce in influencing schizophrenia is critical for elucidating the pathways underlying psychotic illness and for developing primary prevention strategies. Although obstetric complications (OCs) remain among the most well-documented environmental indicators of risk for schizophrenia, the pathogenic role they play in the etiology of schizophrenia continues to remain poorly understood. A question of major importance is do these factors result from a genetic diathesis to schizophrenia (as in gene-environment covariation), act additively or interactively with predisposing genes for the disorder in influencing disease risk, or independently cause disease onset? In this review, we evaluate 3 classes of OCs commonly related to schizophrenia including hypoxia-associated OCs, maternal infection during pregnancy, and maternal stress during pregnancy. In addition, we discuss several mechanisms by which OCs impact on genetically susceptible brain regions, increasing constitutional vulnerability to neuromaturational events and stressors later in life (ie, adolescence), which may in turn contribute to triggering psychosis.

Inflammatory Cytokines and Neurological and Neurocognitive Alterations in the Course of Schizophrenia

A growing body of evidence suggests that immune alterations, especially those related to inflammation, are associated with increased risk of schizophrenia and schizophrenia-related brain alterations. Much of this work has focused on the prenatal period, because infections during pregnancy have been repeatedly (albeit inconsistently) linked to risk of schizophrenia. Given that most infections do not cross the placenta, cytokines associated with inflammation (proinflammatory cytokines) have been targeted as potential mediators of the damaging effects of infection on the fetal brain in prenatal studies. Moreover, additional evidence from both human and animal studies suggests links between increased levels of proinflammatory cytokines, immune-related genes, and schizophrenia as well as brain alterations associated with the disorder. Additional support for the role of altered immune factors in the etiology of schizophrenia comes from neuroimaging studies, which have linked proinflammatory cytokine gene polymorphisms with some of the structural and functional abnormalities repeatedly found in schizophrenia. These findings are reviewed and discussed with a life course perspective, examining the contribution of inflammation from the fetal period to disorder presentation. Unexplored areas and future directions, such as the interplay between inflammation, genes, and individual-level environmental factors (e.g., stress, sleep, and nutrition), are also discussed.

Structural brain alterations in schizophrenia following fetal exposure to the inflammatory cytokine interleukin-8.

BACKGROUND Maternal infection during pregnancy has been repeatedly associated with increased risk for schizophrenia. Nevertheless, most viruses do not cross the placenta; therefore, the damaging effects to the fetus appear to be related to maternal antiviral responses to infection (e.g. proinflammatory cytokines). Fetal exposure to the proinflammatory cytokine interleukin-8 (IL-8) has been significantly associated with risk of schizophrenia in offspring. This study sought to determine the association between fetal exposure to IL-8 and structural brain changes among schizophrenia cases and controls. METHODS Subjects were 17 cases diagnosed with schizophrenia from the Developmental Insult and Brain Anomaly in Schizophrenia (DIBS) study. Psychiatric diagnoses were determined among offspring with semi-structured interviews and medical records review. IL-8 was determined from assays in archived prenatal sera and volumetric analyses of neuroanatomical regions were obtained from T1-weighted magnetic resonance imaging in adulthood. Eight controls were included for exploratory purposes. RESULTS Among cases, fetal exposure to increases in IL-8 was associated with significant increases in ventricular cerebrospinal fluid, significant decreases in left entorhinal cortex volumes and significant decreases in right posterior cingulate volumes. Decreases that approached significance also were found in volumes of the right caudate, the putamen (bilaterally), and the right superior temporal gyrus. No significant associations were observed among controls. CONCLUSION Fetal exposure to elevations in maternal IL-8 led to structural neuroanatomic alterations among cases in regions of the brain consistently implicated in schizophrenia research. In utero exposure to elevations in IL-8 may partially account for brain disturbances commonly found in schizophrenia.

Fetal heart rate reactivity differs by women's psychiatric status: An early marker for developmental risk?

OBJECTIVE To determine whether there are differences in fetal heart rate (FHR) reactivity associated with womens psychiatric status. METHOD In 57 women in their 36th to 38th week of pregnancy (mean age 27 +/- 6 years), electrocardiogram, blood pressure (BP), respiration (RSP), and FHR were measured during baseline and a psychological challenge (a Stroop color-word matching task). Subjects underwent the Structured Clinical Interview for DSM-IV (SCID) and completed the Spielberger State-Trait Anxiety Inventory prior to testing. RESULTS There was a significant main effect of maternal diagnostic group on FHR reactivity during the Stroop task even after controlling for birth weight and womens BP reactivity (F4,44 = 2.68, p =.04). Fetuses of depressed women had greater heart rate increases compared to fetuses of women with anxiety disorders and those of healthy, low-anxiety women (post hoc comparisons using the Fisher protected least significant difference test; t = 4.12, p <.05; t = 4.72, p <.01, respectively). There was a similar pattern comparing fetuses of healthy, high-anxiety women to the same two groups (t = 3.29, p <.05; t = 3.99, p <.05, respectively). There were no group differences in FHR during a resting baseline period (F4,52 = 1.2, p =.35). CONCLUSIONS Maternal mood disturbance is associated with alterations in childrens physiological reactivity prior to birth.

Enhanced stress reactivity in paediatric anxiety disorders: implications for future cardiovascular health

The aim was to clarify the developmental nature of associations between psychiatric illness and risk for cardiovascular disease by investigating differences in cardiac functioning between youth with anxiety disorders and healthy controls. Twenty-two children meeting DSM-IV criteria for either separation anxiety disorder, overanxious disorder, panic disorder/panic attacks, or social phobia and 12 healthy controls underwent continuous electrocardiogram and respiration rate monitoring during a 15 min baseline period and 15 min of exposure to 5% CO(2). Heart rate (HR) and high frequency heart rate variability (HRV), a non-invasive measure of cardiac parasympathetic control, were calculated. Youth with anxiety disorders had higher and less fluctuating HR during baseline. Data also suggested that probands showed diminished overall changes in HRV during baseline and CO(2) inhalation relative to controls. However, as respiration rate affects HRV, these findings were confounded by changes in respiration elicited by CO(2) inhalation. The data suggest that youth with anxiety disorders experience an elevated and less fluctuating HR in the face of a novel situation, possibly due to a failure to appropriately modulate HRV. In adults, sustained elevations in HR in conjunction with deficient vagal modulation predicts risk for future cardiovascular disease. As such, the current data suggest that the presence of an anxiety disorder may identify youth who exhibit autonomic profiles that place them at risk for cardiac disease.

Effects of women's stress-elicited physiological activity and chronic anxiety on fetal heart rate.

ABSTRACT. This study examined the effects of pregnant women’s acute stress reactivity and chronic anxiety on fetal heart rate (HR). Thirty-two healthy third trimester pregnant women were instrumented to monitor continuous electrocardiography, blood pressure, respiration, and fetal HR. Subjects completed the trait anxiety subscale of the State Trait Anxiety Index, then rested quietly for a 5-minute baseline period, followed by a 5-minute Stroop color-word matching task and a 5-minute recovery period. Fetal HR changes during women’s recovery from a stressful task were associated with the women’s concurrently collected HR and blood pressure changes (r = .63, p < .05). Fetal HR changes during recovery, as well as during women’s exposure to the Stroop task, were correlated with their mothers’ trait anxiety scores (r = .39, p < .05 and r = −.52, p < .01, respectively). Finally, a combination of measures of women’s cardiovascular activity during recovery and trait anxiety scores accounted for two thirds of the variance in fetal HR changes during the same recovery period (R2 = .69, p < .001). The results from this study link changes in fetal behavior with acute changes in women’s cardiovascular activity after psychological stress and women’s anxiety status. This indicates that variations in women’s emotion-based physiological activity can affect the fetus and may be centrally important to fetal development.

Cognitive functioning prior to the onset of psychosis: the role of fetal exposure to serologically determined influenza infection.

BACKGROUND Previous studies have linked prenatal influenza exposure to increased risk of schizophrenia; however, no study has examined the neurodevelopmental sequelae of this prenatal insult before the onset of psychotic symptoms using serological evidence of infection. This study sought to examine the contribution of prenatal influenza A and B exposure to cognitive performance among children who developed psychoses in adulthood versus nonpsychiatric control children. METHODS Subjects were 111 cases (70 with schizophrenia and 41 with affective psychoses) and 333 matched control subjects followed from gestation until age 7 through the Collaborative Perinatal Project. The Wechsler Intelligence Scale for Children (age 7) was administered and adult psychiatric morbidity was assessed by medical records review and confirmed by a validation study. Assays were conducted from archived prenatal maternal sera collected at birth, and influenza infection was determined by immunoglobulin G (IgG) antibody titers >75th percentile. RESULTS Significant decreases in verbal IQ and the information subtest, as well as similar nonsignificant reductions in full scale IQ scores and vocabulary, comprehension, digit span, and picture arrangement subtests were found among cases who were prenatally exposed to influenza B versus cases who were not exposed. Fetal exposure to influenza B did not lead to any significant differences in cognitive performance among control children. CONCLUSIONS Cumulatively, these findings suggest that a genetic and/or an environmental factor associated with psychosis rendered the fetal brain particularly vulnerable to the effects of influenza B, leading to poorer cognitive performance even before symptom onset.

The Promise of Epidemiologic Studies: Neuroimmune Mechanisms in the Etiologies of Brain Disorders

We present our views on current and past epidemiological contributions to our understanding of neuroimmune mechanisms for neurodevelopmental disorders, such as schizophrenia. We also discuss future directions for epidemiological studies and ways in which newer cohorts are well positioned to address questions that were previously not feasible to explore.

Trauma and the psychosis spectrum: A review of symptom specificity and explanatory mechanisms

Traumatic life events have been robustly associated with various psychosis outcomes, including increased risk of psychotic disorders, the prodrome of psychosis, and dimensional measures of psychotic symptoms, such as attenuated positive psychotic symptoms. However, trauma exposure has been linked to various mental disorders; therefore, the specificity of trauma exposure to psychosis remains unclear. This review focuses on two understudied areas of the trauma and psychosis literature: 1) the specificity between trauma and psychosis in relation to other disorders that often result post-trauma, and 2) proposed mechanisms that uniquely link trauma to psychosis. We begin by discussing the underlying connection between trauma exposure and the entire psychosis spectrum with a focus on the influence of trauma type and specific psychotic symptoms. We then consider how the principles of multifinality and equifinality can be useful in elucidating the trauma-psychosis relationship versus the trauma-other disorder relationship. Next, we discuss several cognitive and neurobiological mechanisms that might uniquely account for the association between trauma and psychosis, as well as the role of gender. Lastly, we review important methodological issues that complicate the research on trauma and psychosis, ending with clinical implications for the field.

Genetic Risk for Schizophrenia, Obstetric Complications, and Adolescent School Outcome: Evidence for Gene-Environment Interaction

Low birth weight (LBW) and hypoxia are among the environmental factors most reliably associated with schizophrenia; however, the nature of this relationship is unclear and both gene-environment interaction and gene-environment covariation models have been proposed as explanations. High-risk (HR) designs that explore whether obstetric complications differentially predict outcomes in offspring at low risk (LR) vs HR for schizophrenia, while accounting for differences in rates of maternal risk factors, may shed light on this question. This study used prospectively obtained data to examine relationships between LBW and hypoxia on school outcome at age 15-16 years in a Finnish sample of 1070 offspring at LR for schizophrenia and 373 offspring at HR for schizophrenia, based on parental psychiatric history. Controlling for offspring sex, maternal smoking, social support, parity, age, and number of prenatal care visits, HR offspring performed worse than LR offspring across academic, nonacademic, and physical education domains. LBW predicted poorer academic and physical education performance in HR offspring, but not in LR offspring, and this association was similar for offspring of fathers vs mothers with schizophrenia. Hypoxia predicted poorer physical education score across risk groups. Rates of LBW and hypoxia were similar for LR and HR offspring and for offspring of fathers vs mothers with schizophrenia. Results support the hypothesis that genetic susceptibility to schizophrenia confers augmented vulnerability of the developing brain to the effects of obstetric complications, possibly via epigenetic mechanisms.