Prenatal Exposure to Maternal Infection and Executive Dysfunction in Adult Schizophrenia

Abstract

Objective Executive dysfunction is one of the most prominent and functionally important cognitive deficits in schizophrenia. Although strong associations have been identified between executive impairments and structural and functional prefrontal cortical deficits, the etiological factors that contribute to disruption of this important cognitive domain remain unclear. Increasing evidence suggests that schizophrenia has a neurodevelopmental etiology, and several prenatal infections have been associated with risk of this disorder. To date, however, no previous study has examined whether in utero infection is associated with executive dysfunction in patients with schizophrenia. Method In the present study, we assessed the relationship between serologically documented prenatal exposure to influenza and toxoplasmosis and performance on the Wisconsin Card Sorting Test (WCST) and the Trail Making Test, part B (Trails B), as well as other measures of executive function, in 26 patients with schizophrenia from a large and well-characterized birth cohort. Results Cases who were exposed in utero to infection committed significantly more total errors on the WCST and took significantly more time to complete the Trails B than unexposed cases. Exposed cases also exhibited deficits on figural fluency, letter-number sequencing, and backward digit span. Conclusion Prenatal infections previously associated with schizophrenia are related to impaired performance on the WCST and Trails B. The pattern of results suggests that cognitive set-shifting ability may be particularly vulnerable to this gestational exposure. Further work is necessary to elucidate the specificity of prenatal infection to these executive function measures and examine correlates with neuroanatomic and neurophysiologic anomalies.

Cognitive control deficit in patients with first-episode schizophrenia is associated with complex deviations of early brain development

“…34 In addition to an association with deviations during adolescence, TMT impairment in patients with schizophrenia has also been associated with deviations during fetal life (in utero maternal infection exposures). 8 Furthermore, non-right-handedness, including mixed-and lefthandedness, which is considered to result from early neurodevelopmental "failure to establish cerebral asymmetry," 23 is more frequent in patients with schizophrenia than in healthy individuals 23 and is associated with executive impairments. 12 Finally, NSS, referred to as the minor, nonlocalizable defects in motor coordination, motor integration and sensory integration, 11 are a clinical marker of pre-and perinatal deviance; 22,35 are much more frequent in patients with schizophrenia and their siblings than in controls; 36 and are associated with cognitive deficits, including executive functions.…”

“…Serologically documented infections in utero were found to be associated with subsequent impaired performance in the executive domain in patients with schizophrenia. 8 An association between lower birth weight, a global proxy measure of uterine "optimality," 9 and neurocognitive deficits has also been found in patients with schizophrenia-spectrum disorders compared with controls. 10 In this context, the aim of our study was to investigate the influences of early brain deviation on executive deficit in patients with schizophrenia.…”

Sex as a Biological Variable: Who, What, When, Why, and How

“…Certainly, one can get to the same destination via different routes. For instance, in neuropsychiatric diseases such as autism, schizophrenia, or depression, although men and women may be given a similar diagnosis, there exist significant sex differences in overall rates, timing of onset, symptom presentation, and treatment efficacy (Heim and Nemeroff, 1999;Heim and Nemeroff, 2001;Sanchez et al, 2001;Goldstein et al, 2002;Heim et al, 2004;Bale, 2006;Brown and Susser, 2008;Bale, 2009;Brown et al, 2009;Heim et al, 2009;Bale et al, 2010;Heim et al, 2010;Brown, 2012;Davis and Pfaff, 2014;Goldstein et al, 2014). Further, mechanistic animal studies modeling endophenotypes of these disorders have demonstrated robust sex differences in the timing of susceptibility to insults to the developing brain where males appear more vulnerable prenatally and females postnatally (Mueller and Bale, 2006;Mueller and Bale, 2007;Ivy et al, 2008;Kapoor et al, 2008;Mueller and Bale, 2008;Kapoor et al, 2009;Ivy et al, 2010;Hsiao and Patterson, 2012).…”

In vivo type II T-helper cells shift in schizophrenia compared to sex- and age-matched healthy controls

“…Epidemiological studies relating to antibody titers against various viruses indicate that viral infection could be the cause of immune dysfunction in one subgroup of schizophrenics 2 . Several viral infections have been associated with the risk of this disorder [3][4][5] . During antiviral immunity, accurate control of the balance between the type I and type II Thelper cells (Th1 and Th2) is pivotal for optimizing immune response 6 .…”