Brain Advance Access originally published online on July 31, 2008
Brain 2008 131(9):2489-2498; doi:10.1093/brain/awn167
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Enuresis as a premorbid developmental marker of schizophrenia*
1Clinical Brain Disorders Branch, 2Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland, Baltimore and 3Genes, Cognition, and Psychosis Program, NIMH/DIRP/NIH, Bethesda, MD, USA
Correspondence to: Thomas M. Hyde, MD, PhD, Clinical Brain Disorders Branch, NIMH/DIRP/NIH, 10 Center Drive, MSC 1385, Bethesda, MD 20892, USA E-mail: hydet{at}mail.nih.gov
There is comparatively little information about premorbid maturational brain abnormalities in schizophrenia (SCZ). We investigated whether a history of childhood enuresis, a well-established marker of neurodevelopmental delay, is associated with SCZ and with measures of brain abnormalities also associated with SCZ. A Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) based history of enuresis, volumetric brain MRI scans and neuropsychological testing were obtained in patients with SCZ, their non-psychotic siblings (SIB) and non-psychiatric controls (NC). The subjects were 211 patients (79.6% male), 234 of their SIB (43.2% male) and 355 controls (39.2% male). Frequency of enuresis was compared across groups and correlated with cognitive measures. Total and regional brain volumes were determined using voxel-based morphometry on matched subsets of probands (n = 82) with or without enuresis (n = 16, n = 66, respectively) and controls (n = 102) with or without enuresis (n = 11, n = 91, respectively). Patients with SCZ had higher rates of childhood enuresis (21%) compared with SIB (11%; 
2 = 6.42, P = 0.01) or controls (7%; 2 = 23.65, P < 0.0001) and relative risk for enuresis was increased in SIB (
S = 2.62). Patients with enuresis performed worse on two frontal lobe cognitive tests [Letter Fluency (t = 1.97, P = 0.05, df = 200) and Category Fluency (t = 2.15, P = 0.03, df = 200)] as compared with non-enuretic patients. Voxel-based morphometry analysis revealed grey matter volume reductions in several frontal regions (right BA 9, right BA 10 and bilateral BA 45) and right superior parietal cortex (BA 7) in patients with a history of enuresis as compared with non-enuretic patients (all t > 3.57, all P < 0.001). The high frequency of childhood enuresis associated with SCZ and abnormalities in prefrontal function and structure in patients with a childhood history of enuresis suggest that childhood enuresis may be a premorbid marker for neurodevelopmental abnormalities related to SCZ. These findings add to the evidence implicating prefrontal dysmaturation in this disorder, potentially related to genetic risk factors.
Key Words: schizophrenia; enuresis; development; neuroimaging; frontal lobes
Abbreviations: DSM-IV, Diagnostic and Statistical Manual of Mental Disorders; SCZ, schizophrenia; SIB, non-psychotic sibling; NC, non-psychiatric control; VBM, voxel-based morphometry
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Received April 8, 2008. Revised June 25, 2008. Accepted June 30, 2008.
Present address: Central Institute of Mental Health, Mannheim, Germany.
Present address: Merck & Co., Inc., Clinical Neuroscience, North Wales, PA, USA.
*This study was presented as a poster at the 62nd Society of Biological Psychiatry Scientific Convention and Meeting; May 17–19, 2007; San Diego, CA, USA.