Hostname: page-component-cd9895bd7-dzt6s Total loading time: 0 Render date: 2024-12-28T21:36:43.419Z Has data issue: false hasContentIssue false
  • English
  • Français

Prenatal maternal immune disruption and sex-dependent risk for psychoses

Published online by Cambridge University Press:  26 March 2014

J. M Goldstein ,
S. Cherkerzian ,
L. J. Seidman ,
J.-A. L. Donatelli ,
A. G. Remington ,
M. T. Tsuang ,
M. Hornig  and
S. L. Buka
J. M Goldstein*
Affiliation:
Connors Center for Women's Health and Gender Biology, Brigham and Women's Hospital, Boston, MA, USA Departments of Psychiatry and Medicine, Harvard Medical School, Boston, MA, USA Division of Psychiatric Neuroscience, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA
S. Cherkerzian
Affiliation:
Connors Center for Women's Health and Gender Biology, Brigham and Women's Hospital, Boston, MA, USA Departments of Psychiatry and Medicine, Harvard Medical School, Boston, MA, USA
L. J. Seidman
Affiliation:
Division of Psychiatric Neuroscience, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA Harvard Medical School, Department of Psychiatry, Massachusetts Mental Health Center; Division of Public Psychiatry, Beth Israel Deaconess Medical Center, Boston, MA, USA
J.-A. L. Donatelli
Affiliation:
Department of Epidemiology, Brown University, Providence, RI, USA
A. G. Remington
Affiliation:
Connors Center for Women's Health and Gender Biology, Brigham and Women's Hospital, Boston, MA, USA
M. T. Tsuang
Affiliation:
Beth Israel Deaconess Hospital, Department of Psychiatry, Division of Public Psychiatry, Massachusetts Mental Health Center and Harvard Medical School, Boston, MA, USA Center for Behavioral Genomics, Department of Psychiatry; Institute for Genomic Medicine, University of California at San Diego, La Jolla, CA, USA Harvard Institute of Psychiatric Epidemiology and Genetics, Harvard School of Public Heath, Boston, MA, USA
M. Hornig
Affiliation:
Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, NY, USA
S. L. Buka
Affiliation:
Department of Epidemiology, Brown University, Providence, RI, USA
*
*Address for correspondence: Dr J. M. Goldstein, Brigham and Women's Hospital, One Brigham Circle, Division of Women's Health, 1620 Tremont Street, 3rd Floor, Boston, MA 02120, USA. (Email: jill_goldstein@hms.harvard.edu)
Get access Rights & Permissions [Opens in a new window]

Abstract

Background.

Previous studies suggest that abnormalities in maternal immune activity during pregnancy alter the offspring's brain development and are associated with increased risk for schizophrenia (SCZ) dependent on sex.

Method.

Using a nested case–control design and prospectively collected prenatal maternal sera from which interleukin (IL)-1β, IL-8, IL-6, tumor necrosis factor (TNF)-α and IL-10 were assayed, we investigated sex-dependent associations between these cytokines and 88 psychotic cases [SCZ = 44; affective psychoses (AP) = 44] and 100 healthy controls from a pregnancy cohort followed for > 40 years. Analyses included sex-stratified non-parametric tests adjusted for multiple comparisons to screen cytokines associated with SCZ risk, followed by deviant subgroup analyses using generalized estimating equation (GEE) models.

Results.

There were higher prenatal IL-6 levels among male SCZ than male controls, and lower TNF-α levels among female SCZ than female controls. The results were supported by deviant subgroup analyses with significantly more SCZ males with high IL-6 levels (>highest quartile) compared with controls [odd ratio (OR)75 = 3.33, 95% confidence interval (CI) 1.13–9.82], and greater prevalence of low TNF-α levels (<lowest quartile) among SCZ females compared with their controls (OR25 = 6.30, 95% CI 1.20–33.04) and SCZ males. Higher levels of IL-6 were only found among SCZ compared with AP cases. Lower TNF-α levels (non-significant) also characterized female AP cases versus controls, although the prevalence of the lowest levels was higher in SCZ than AP females (70% v. 40%), with no effect in SCZ or AP males.

Conclusions.

The results underscore the importance of immunologic processes affecting fetal brain development and differential risk for psychoses depending on psychosis subtype and offspring sex.

Keywords

Fetal programminginflammationpsychosesschizophreniasex differences
Type
Original Articles
Information
Psychological Medicine , Volume 44 , Issue 15 , November 2014 , pp. 3249 - 3261
Copyright
Copyright © Cambridge University Press 2014 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Abbs, B, Liang, L, Makris, N, Tsuang, MT, Seidman, LJ, Goldstein, JM (2011). Covariance modeling of MRI brain volumes in memory circuitry in schizophrenia: sex differences are critical. NeuroImage 56, 1865–1874.Google Scholar
Aguilar-Valles, A, Luheshi, GN (2011). Alterations in cognitive function and behavioral response to amphetamine induced by prenatal inflammation are dependent on the stage of pregnancy. Psychoneuroendocrinology 36, 634–648.Google Scholar
Anisman, H, Merali, Z (2002). Cytokines, stress, and depressive illness. Brain, Behavior, and Immunity 16, 513–524.Google Scholar
Behrens, MM, Ali, SS, Dugan, LL (2008). Interleukin-6 mediates the increase in NADPH-oxidase in the ketamine model of schizophrenia. Journal of Neuroscience 28, 13957–13966.Google Scholar
Behrens, MM, Sejnowski, TJ (2009). Does schizophrenia arise from oxidative dysregulation of parvalbumin-interneurons in the developing cortex? Neuropharmacology 57, 193–200.Google Scholar
Borovikova, LV, Ivanova, S, Zhang, M, Yang, H, Botchkina, GI, Watkins, LR, Wang, H, Abumrad, N, Eaton, JW, Tracey, KJ (2000). Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405, 458–462.Google Scholar
Brown, AS, Begg, MD, Gravenstein, S, Schaefer, CA, Wyatt, RJ, Bresnahan, M, Babulas, VP, Susser, ES (2004 a). Serologic evidence of prenatal influenza in the etiology of schizophrenia. Archives of General Psychiatry 61, 774–780.Google Scholar
Brown, AS, Derkits, EJ (2010). Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. American Journal of Psychiatry 167, 261–280.Google Scholar
Brown, AS, Hooton, J, Schaefer, CA, Zhang, H, Petkova, E, Babulas, V, Perrin, M, Gorman, JM, Susser, ES (2004 b). Elevated maternal interleukin-8 levels and risk of schizophrenia in adult offspring. American Journal of Psychiatry 161, 889–895.Google Scholar
Brown, AS, Vinogradov, S, Kremen, WS, Poole, JH, Deicken, RF, Penner, JD, McKeague, IW, Kochetkova, A, Kern, D, Schaefer, CA (2009). Prenatal exposure to maternal infection and executive dysfunction in adult schizophrenia. American Journal of Psychiatry 166, 683–690.CrossRefGoogle ScholarPubMed
Buka, SL, Tsuang, MT, Torrey, EF, Klebanoff, MA, Bernstein, D, Yolken, RH (2001 a). Maternal infections and subsequent psychosis among offspring: a forty year prospective study. Archives of General Psychiatry 58, 1032–1037.Google Scholar
Buka, SL, Tsuang, MT, Torrey, EF, Klebanoff, MA, Wagner, RL, Yolken, RH (2001 b). Maternal cytokine levels during pregnancy and adult psychosis. Brain, Behavior, and Immunity 15, 411–420.Google Scholar
Carlson, NG, Wieggel, WA, Chen, J, Bacchi, A, Rogers, SW, Gahring, LC (1999). Inflammatory cytokines IL-1 alpha, IL-1 beta, IL-6, and TNF-alpha impart neuroprotection to an excitotoxin through distinct pathways. Journal of Immunology 163, 3963–3968.Google Scholar
Carter, CJ (2009). Schizophrenia susceptibility genes directly implicated in the life cycles of pathogens: cytomegalovirus, influenza, herpes simplex, rubella, and Toxoplasma gondii . Schizophrenia Bulletin 35, 1163–1182.Google Scholar
Castle, DJ, Wessely, S, Murray, RM (1993). Sex and schizophrenia: effects of diagnostic stringency, and associations with premorbid variables. British Journal of Psychiatry 162, 653–664.Google Scholar
Correale, J, Arias, M, Gilmore, W (1998). Steroid hormone regulation of cytokine secretion by proteolipid protein-specific CD4+ T cell clones isolated from multiple sclerosis patients and normal control subjects. Journal of Immunology 161, 3365–3374.CrossRefGoogle ScholarPubMed
Dahlgren, J, Samuelsson, AM, Jansson, T, Holmäng, A (2006). Interleukin-6 in the maternal circulation reaches the rat fetus in mid-gestation. Pediatric Research 60, 147–151.Google Scholar
Dalman, C, Allebeck, P, Cullberg, J, Grunewald, C, Koster, M (1999). Obstetric complications and the risk of schizophrenia: a longitudinal study of a national birth cohort. Archives of General Psychiatry 56, 234–240.Google Scholar
Dammann, O, Leviton, A (1997). Maternal intrauterine infection, cytokines, and brain damage in the preterm newborn. Pediatric Research 42, 1–8.Google Scholar
De Miranda, J, Yaddanapudi, K, Hornig, M, Villar, G, Serge, R, Lipkin, WI (2010). Induction of Toll-like receptor 3-mediated immunity during gestation inhibits cortical neurogenesis and causes behavioral disturbances. MBio 1, e00176–10.Google Scholar
Drexhage, RC, Knijff, EM, Padmos, RC, Heul-Nieuwenhuijzen, L, Beumer, W, Versnel, MA, Drexhage, HA (2010). The mononuclear phagocyte system and its cytokine inflammatory networks in schizophrenia and bipolar disorder. Expert Review of Neurotherapeutics 10, 59–76.Google Scholar
Eide, M, Moster, D, Irgens, L, Reichborn-Kjennerud, T, Stoltenberg, C, Skjærven, R, Susser, E, Abel, K (2013). Degree of fetal growth restriction associated with schizophrenia risk in a national cohort. Psychological Medicine 43, 2057–2066.Google Scholar
Elenkov, IJ (2008). Neurohormonal-cytokine interactions: implications for inflammation, common human diseases and well-being. Neurochemistry International 52, 40–51.Google Scholar
Faraone, SV, Tsuang, MT (1985). Quantitative models of the genetic transmission of schizophrenia. Psychological Bulletin 98, 41–66.Google Scholar
Ganguli, R, Yang, Z, Shurin, G, Chengappa, KN, Brar, JS, Gubbi, A, Rabin, BS (1994). Serum interleukin-6 concentration in schizophrenia: elevation associated with duration of illness. Psychiatry Research 51, 1–10.Google Scholar
Gilmore, JH, Jarskog, LF (1997). Exposure to infection and brain development: cytokines in the pathogenesis of schizophrenia. Schizophrenia Research 24, 365–367.Google Scholar
Gilmore, JH, Jarskog, LF, Vadlamudi, S (2003). Maternal infection regulates BDNF and NGF expression in fetal and neonatal brain and maternal-fetal unit of the rat. Journal of Neuroimmunology 138, 49–55.Google Scholar
Gilmore, JH, Jarskog, LF, Vadlamudi, S, Lauder, JM (2004). Prenatal infection and risk for schizophrenia: IL-1beta, IL-6, and TNFalpha inhibit cortical neuron dendrite development. Neuropsychopharmacology 29, 1221–1229.Google Scholar
Goldstein, JM, Buka, SL, Seidman, LJ, Tsuang, MT (2010). Specificity of familial transmission of schizophrenia psychosis spectrum and affective psychoses in the New England family study's high-risk design. Archives of General Psychiatry 67, 458–467.Google Scholar
Goldstein, JM, Cherkerzian, S, Seidman, LJ, Petryshen, TL, Fitzmaurice, G, Tsuang, MT, Buka, SL (2011). Sex-specific rates of transmission of psychosis in the New England high-risk family study. Schizophrenia Research 128, 150–155.Google Scholar
Goldstein, JM, Seidman, LJ, Goodman, JM, Koren, D, Lee, H, Weintraub, S, Tsuang, MT (1998). Are there sex differences in neuropsychological functions among patients with schizophrenia? American Journal of Psychiatry 155, 1358–1364.Google Scholar
Goldstein, JM, Seidman, LJ, Horton, NJ, Makris, N, Kennedy, DN, Caviness, VS Jr., Faraone, SV, Tsuang, MT (2001). Normal sexual dimorphism of the adult human brain assessed by in vivo magnetic resonance imaging. Cerebral Cortex 11, 490–497.CrossRefGoogle ScholarPubMed
Goldstein, JM, Walder, DJ (2006). Sex differences in schizophrenia: the case for developmental origins and etiological implications. In The Early Course of Schizophrenia (ed. Sharma, T. and Harvey, P. D.), pp. 147–173. Oxford University Press: Oxford, UK.Google Scholar
Gottesman, II (1991). Schizophrenia Genesis: The Origin of Madness. W.H. Freeman and Company: New York.Google Scholar
Handa, RJ, Burgess, LH, Kerr, JE, O'Keefe, JA (1994). Gonadal steroid hormone receptors and sex differences in the hypothalamo-pituitary-adrenal axis. Hormones and Behavior 28, 464–476.Google Scholar
Harbuz, MS, Stephanou, A, Sarlis, N, Lightman, SL (1992). The effects of recombinant human interleukin (IL)-1 alpha, IL-1 beta or IL-6 on hypothalamo-pituitary-adrenal axis activation. Journal of Endocrinology 133, 349–355.Google Scholar
Hochberg, Y (1988). A sharper Bonferroni procedure for multiple tests of significance. Biometrika 75, 800–802.Google Scholar
Hornig, M (2013). The role of microbes and autoimmunity in the pathogenesis of neuropsychiatric illness. Current Opinion in Rheumatology 25, 488–795.Google Scholar
Hornig, M, Weissenbock, H, Horscroft, N, Lipkin, WI (1999). An infection-based model of neurodevelopmental damage. Proceedings of the National Academy of Sciences USA 96, 12102–12107.Google Scholar
Hsiao, EY, McBride, SW, Chow, J, Mazmanian, SK, Patterson, PH (2012). Modeling an autism risk factor in mice leads to permanent immune dysregulation. Proceedings of the National Academy of Sciences USA 109, 12776–12781.Google Scholar
Hu, Z, Yuri, K, Ozawa, H, Lu, H, Kawata, M (1997). The in vivo time course for elimination of adrenalectomy-induced apoptotic profiles from the granule cell layer of the rat hippocampus. Journal of Neuroscience 17, 3981–3989.Google Scholar
Jáuregui, OI, Costanzo, EY, de Achával, D, Villarreal, MF, Chu, E, Mora, MC, Vigo DE Castro, MN, Leiguarda, RC, Bär, KJ, Guinjoan, SM (2011). Autonomic nervous system activation during social cognition tasks in patients with schizophrenia and their unaffected relatives. Cognitive and Behavioral Neurology 24, 194–203.Google Scholar
Kawata, M (1995). Roles of steroid hormones and their receptors in structural organization in the nervous system. Neuroscience Research 24, 1–46.Google Scholar
Kendler, KS, Gruenberg, AM, Tsuang, MT (1985). Subtype stability in schizophrenia. American Journal of Psychiatry 142, 827–832.Google Scholar
Kim-Fine, S, Regnault, TR, Lee, JS, Gimbel, SA, Greenspoon, JA, Fairbairn, J, Summers, K, de Vrijer, B (2012). Male gender promotes an increased inflammatory response to lipopolysaccharide in umbilical vein blood. Journal of Maternal-Fetal and Neonatal Medicine 25, 2470–2474.Google Scholar
Klebanoff, MA, Zhang, J, Zhang, C, Levine, RJ (2009). Maternal serum theobromine and the development of preeclampsia. Epidemiology and Community Health 20, 727–732.Google Scholar
Mandal, M, Marzouk, AC, Donnelly, R, Ponzio, NM (2010). Preferential development of Th17 cells in offspring of immunostimulated pregnant mice. Journal of Reproductive Immunology 87, 97–100.Google Scholar
Martins, TB (2002). Development of internal controls for the Luminex instrument as part of a multiplex seven-analyte viral respiratory antibody profile. Clinical and Diagnostic Laboratory Immunology 9, 41–45.Google Scholar
Marx, CE, Jarskog, LF, Lauder, JM, Lieberman, JA, Gilmore, JH (2001). Cytokine effects on cortical neuron MAP-2 immunoreactivity: implications for schizophrenia. Biological Psychiatry 50, 743–749.Google Scholar
McGrath, J, Murray, R (2003). Risk factors for schizophrenia: from conception to birth. In Schizophrenia (ed. Hirsh, S. R. and Weinberger, D. R.), pp. 232–250. Blackwell Science: Malden, MA.Google Scholar
Meyer, U, Nyffeler, M, Engler, A, Urwyler, A, Schedlowski, M, Knuesel, I, Yee, BK, Feldon, J (2006). The time of prenatal immune challenge determines the specificity of inflammation-mediated brain and behavioral pathology. Journal of Neuroscience 26, 4752–4762.Google Scholar
Miller, V, Kahnke, T, Neu, N, Sanchez-Morrissey, S, Brosch, K, Kelsey, K, Seegal, R (2010). Developmental PCB exposure induces hypothyroxinemia and sex-specific effects on cerebellum glial protein levels in rats. International Journal of Developmental Neuroscience 28, 553–560.Google Scholar
Moreli, JB, Morceli, G, De Luca, AK, Magalhães, CG, Costa, RA, Damasceno, DC, Rudge, MV, Calderon, IM (2012). Influence of maternal hyperglycemia on IL-10 and TNF-α production: the relationship with perinatal outcomes. Journal of Clinical Immunology 32, 604–610.Google Scholar
Müller, N, Dobmeier, P, Empl, M, Riedel, M, Schwarz, M, Ackenheil, M (1997). Soluble IL-6 receptors in the serum and cerebrospinal fluid of paranoid schizophrenic patients. European Psychiatry 12, 294–299.Google Scholar
Mutlu, O, Gumuslu, E, Ulak, G, Celikyurt, IK, Kokturk, S, Kir, HM, Akar, F, Erden, F (2012). Effects of fluoxetine, tianeptine and olanzapine on unpredictable chronic mild stress-induced depression-like behavior in mice. Life Sciences 91, 1252–1262.Google Scholar
Niswander, KR, Gordon, M (1972). The Collaborative Perinatal Study of the National Institute of Neurological Diseases and Stroke: The Women and Their Pregnancies. Government Printing Office, U.S. Department of Health, Education, and Welfare: Washington, DC.Google Scholar
Nunes-Freitas, AL, Ribeiro-Carvalho, A, Lima, CS, Dutra-Tavares, AC, Manhães, AC, Lisboa, PC, Oliveira, E, Gaspar de Moura, E, Filgueiras, CC, Abreu-Villaça, Y (2011). Nicotine exposure during the third trimester equivalent of human gestation: time course of effects on the central cholinergic system of rats. Toxicological Sciences 123, 144–154.Google Scholar
O'Connell, P, Woodruff, PW, Wright, I, Jones, P, Murray, RM (1997). Developmental insanity or dementia praecox: was the wrong concept adopted? Schizophrenia Research 23, 97–106.Google Scholar
Patterson, PH (2007). Maternal effects on schizophrenia risk. Science 318, 576–577.Google Scholar
Patterson, PH (2009). Immune involvement in schizophrenia and autism: etiology, pathology and animal models. Behavioral Brain Research 204, 313–321.Google Scholar
Sargent, I (1992). Maternal and fetal immune responses during pregnancy. Experimental and Clinical Immunogenetics 10, 85–102.Google Scholar
Schobitz, B, de Kloet, ER, Sutanto, W, Holsboer, F (1993). Cellular localization of interleukin 6 mRNA and interleukin 6 receptor mRNA in rat brain. European Journal of Neuroscience 5, 1426–1435.Google Scholar
Scott, NM, Hodyl, NA, Murphy, VE, Osei-Kumah, A, Wyper, H, Hodgson, DM, Smith, R, Clifton, VL (2009). Placental cytokine expression covaries with maternal asthma severity and fetal sex. Journal of Immunology 182, 1411–1420.Google Scholar
Seckl, JR (2001). Glucocorticoid programming of the fetus: adult phenotypes and molecular mechanisms. Molecular and Cellular Endocrinology 185, 61–71.Google Scholar
Seckl, JR, Walker, BR (2001). Minireview: 11beta-hydroxysteroid dehydrogenase type 1 – a tissue-specific amplifier of glucocorticoid action. Endocrinology 142, 1371–1376.Google Scholar
Seidman, LJ, Cherkerzian, S, Goldstein, JM, Agnew-Blais, J, Tsuang, MT, Buka, SL (2013). Neuropsychological performance and family history in children at age 7 who develop adult schizophrenia or bipolar psychosis in the New England Family Studies. Psychological Medicine 43, 119–131.Google Scholar
Smith, AJ, Li, M, Becker, S, Kapur, S (2007 a). Linking animal models of psychosis to computational models of dopamine function. Neuropsychopharmacology 32, 54–66.Google Scholar
Smith, SE, Li, J, Garbett, K, Mirnics, K, Patterson, PH (2007 b). Maternal immune activation alters fetal brain development through interleukin-6. Journal of Neuroscience 27, 10695–10702.Google Scholar
Sparkman, NL, Buchanan, JB, Heyen, JR, Chen, J, Beverly, JL, Johnson, RW (2006). Interleukin-6 facilitates lipopolysaccharide-induced disruption in working memory and expression of other proinflammatory cytokines in hippocampal neuronal cell layers. Journal of Neuroscience 26, 10709–10716.Google Scholar
Stratton, MS, Searcy, BT, Tobet, SA (2011). GABA regulates corticotropin releasing hormone levels in the paraventricular nucleus of the hypothalamus in newborn mice. Physiology and Behavior 104, 327–333.Google Scholar
Stroud, LR, Solomon, C, Shenassa, E, Papandonatos, G, Niaura, R, Lipsitt, LP, Lewinn, K, Buka, SL (2007). Long-term stability of maternal prenatal steroid hormones from the National Collaborative Perinatal Project: still valid after all these years. Psychoneuroendocrinology 32, 140–150.Google Scholar
Sugino, H, Futamura, T, Mitsumoto, Y, Maeda, K, Marunaka, Y (2009). Atypical antipsychotics suppress production of proinflammatory cytokines and up-regulate interleukin-10 in lipopolysaccharide-treated mice. Progress in Neuro-Psychopharmacology and Biological Psychiatry 33, 303–307.Google Scholar
Szelenyi, J, Vizi, ES (2007). The catecholamine cytokine balance: interaction between the brain and the immune system. Annals of the New York Academy of Sciences 1113, 311–324.Google Scholar
Tobet, SA (2002). Genes controlling hypothalamic development and sexual differentiation. European Journal of Neuroscience 16, 373–376.Google Scholar
Tobet, SA, Hanna, IK (1997). Ontogeny of sex differences in the mammalian hypothalamus and preoptic area. Cellular and Molecular Neurobiology 17, 565–601.Google Scholar
Tsuang, MT, Faraone, SV, Lyons, MJ (1993). Identification of the phenotype in psychiatric genetics. European Archives of Psychiatry and Clinical Neuroscience 243, 131–142.Google Scholar
Twohig, JP, Cuff, SM, Yong, AA, Wang, EC (2011). The role of tumor necrosis factor receptor superfamily members in mammalian brain development, function and homeostasis. Reviews in the Neurosciences 22, 509–533.CrossRefGoogle ScholarPubMed
Urakubo, A, Jarskog, LF, Lieberman, JA, Gilmore, JH (2001). Prenatal exposure to maternal infection alters cytokine expression in the placenta, amniotic fluid, and fetal brain. Schizophrenia Research 47, 27–36.Google Scholar
Vignali, DA (2000). Multiplexed particle-based flow cytometric assays. Journal of Immunological Methods 243, 243–255.Google Scholar
Watanabe, Y, Someya, T, Nawa, H (2010). Cytokine hypothesis of schizophrenia pathogenesis: evidence from human studies and animal models. Psychiatry and Clinical Neurosciences 64, 217–230.CrossRefGoogle ScholarPubMed
Yeargin-Allsopp, M, Rice, C, Karapurkar, T, Doernberg, N, Boyle, C, Murphy, C (2003). Prevalence of autism in a US metropolitan area. Journal of the American Medical Association 289, 49–55.Google Scholar
Yoon, BH, Romero, R, Yang, SH, Jun, JK, Kim, IO, Choi, JH, Syn, HC (1996). Interleukin-6 concentrations in umbilical cord plasma are elevated in neonates with white matter lesions associated with periventricular leukomalacia. American Journal of Obstetrics and Gynecology 174, 1433–1440.Google Scholar
Zalcman, S, Green-Johnson, JM, Murray, L, Nance, DM, Dyck, D, Anisman, H, Greenberg, AH (1994). Cytokine-specific central monoamine alterations induced by interleukin-1, -2 and -6. Brain Research 643, 40–49.Google Scholar
Zietz, B, Hrach, S, Scholmerich, J, Straub, RH (2001). Differential age-related changes of hypothalamus-pituitary-adrenal axis hormones in healthy women and men – role of interleukin 6. Experimental and Clinical Endocrinology and Diabetes 109, 93–101.Google Scholar
Zuckerman, L, Weiner, I (2003). Post-pubertal emergence of disrupted latent inhibition following prenatal immune activation. Psychopharmacology (Berlin) 169, 308–313.Google Scholar
Supplementary material: File

Goldstein et al. supplementary material

Supplementary table

Download Goldstein et al. supplementary material(File)
File 33.3 KB
Supplementary material: File

Goldstein et al. supplementary material

Supplementary table

Download Goldstein et al. supplementary material(File)
File 13.3 KB
Supplementary material: File

Goldstein et al. supplementary material

Supplementary table

Download Goldstein et al. supplementary material(File)
File 14.6 KB
Supplementary material: File

Goldstein et al. supplementary material

Supplementary data and tables

Download Goldstein et al. supplementary material(File)
File 94.7 KB