ORIGINAL ARTICLE Brain morphological changes associated with exposure to HSV1 in first-episode schizophrenia KMR Prasad 1 , BH Shirts 1 , RH Yolken 2 , MS Keshavan 1,3 and VL Nimgaonkar 1 1 Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; 2 Stanley Division of Developmental Neurovirology, Johns Hopkins University School of Medicine, Baltimore, MD, USA and 3 Department of Psychiatry and Behavioral Neuroscience, Wayne State University School of Medicine, Detroit, MI, USA Infectious agents have been proposed as one of the risk factors for schizophrenia. However, the data on the association of infectious agents with in vivo brain changes are scant. We evaluated the association of serological evidence of exposure to herpes simplex virus 1 (HSV1) with in vivo brain structural variations among first-episode antipsychotic-naive schizophrenia/ schizoaffective disorder patients and control subjects. We assayed HSV1 immunoglobulin G (IgG) antibody in serum samples from 30 patients and 44 healthy subjects and obtained structural magnetic resonance imaging scans from the same individuals. There were proportionately more patients with elevated HSV1 antibody ratios than healthy comparison subjects (v 2 = 3.98, 1 df, P = 0.046) and patients had significantly higher HSV1 IgG antibody ratios compared with healthy subjects. Using optimized voxel-based morphometry, we examined diagnosis by HSV1 serological status interaction followed by within- and between- group comparison across the serological status. We observed a diagnosis by HSV1 serological status interaction and a significant main effect of HSV1 serological status in the prefrontal gray matter. Patients exposed to HSV1 had decreased gray matter in Brodmann area 9 (dorsolateral prefrontal cortex) and 32 (anterior cingulate cortex) compared with patients without serological evidence of exposure to HSV1. HSV1-associated differences in brain structure were not detected among healthy subjects. These findings suggest that HSV1 exposure in schizophrenia is associated with specific regional gray matter differences that may not be attributable to medications, illness chronicity or comorbid substance use. This study provides suggestive evidence for a link between HSV1 exposure and some of the cerebral morphological changes often reported in schizophrenia. Molecular Psychiatry (2007) 12, 105–113. doi:10.1038/sj.mp.4001915; published online 10 October 2006 Keywords: herpes simplex virus; schizophrenia; etiology; neuroanatomy; neuroimaging; morphometry Introduction Plausible environmental as well as genetic etiological factors for schizophrenia have been proposed, but the pathogenic mechanisms are still unclear. Exposure to infectious agents has been proposed as one of the putative environmental factors. The support for the role of infectious risk factors comes from direct and indirect lines of investigation. A review of more than 250 studies concluded that there was nearly 5–8% excess winter or spring births for individuals who later develop schizophrenia. 1 Several factors, includ- ing infectious agents may explain this excess. Other studies have noted higher numbers of these births during the periods of increased activity of infectious agents. 2 Herpes virus DNA has been identified in the brains of schizophrenia patients 3,4 and elevated anti- body levels to herpes simplex virus (HSV) in schizo- phrenia patients in some, 5–8 but not all studies. 9–11 Among the infectious agents reported so far, herpes viruses are particularly interesting. They belong to herpesviridae family and are characterized by an electron opaque core of double stranded DNA surrounded by a protein capsid, an amorphous tegument surrounding the capsid with an outer spiky envelope. 12 Following infection, the viral DNA inte- grates into the host cell DNA and establishes latency in the nervous system with periodic lytic cycles 13 that can remain lifelong. Among the herpes viruses, HSV1, HSV2, cytomegalovirus (CMV), Epstein–Barr virus (EBV), varicella-zoster virus (VZV) and human herpes virus 6 (HHV6) have neurotrophic potential. 12 The central nervous system infection of CMV, 14 EBV 15 and VZV 16 in immunocompetent persons is rare. HSV2 Received 13 March 2006; revised 8 August 2006; accepted 25 August 2006; published online 10 October 2006 Correspondence: Dr KMR Prasad, Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. E-mail: PrasadKM@upmc.edu Molecular Psychiatry (2007) 12, 105–113 & 2007 Nature Publishing Group All rights reserved 1359-4184/07 $30.00 www.nature.com/mp