DTI microstructural abnormalities in adolescent siblings of patients with childhood-onset schizophrenia.

Psychiatry Research: Neuroimaging 258 (2016) 23–29 Contents lists available at ScienceDirect Psychiatry Research Neuroimaging journal homepage: www.elsevier.com/locate/psychresns DTI microstructural abnormalities in adolescent siblings of patients with childhood-onset schizophrenia crossmark Dana Waltzman a,b, , Barbara Jean Knowlton c , Jessica Rachel Cohen d , Susan Yost Bookheimer e , Robert Martin Bilder e , Robert Franklin Asarnow c,e a War Related Illness and Injury Study Center, Veterans Aﬀairs Palo Alto Health Care System (VAPAHCS), United States Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, United States c Department of Psychology, University of California Los Angeles, United States d Department of Psychology and Neurosciences, University of North Carolina at Chapel Hill, United States e David Geﬀen School of Medicine at University of California Los Angeles, United States b 1. Introduction Diﬀusion tensor imaging (DTI) is a non-invasive magnetic reso- nance imaging technique that provides information about the micro- structural tissue architecture in diﬀerent cerebral tissues in vivo. DTI measures the random molecular motion of water molecules (i.e. diﬀusion) by applying many diﬀusion-encoding gradients in diﬀerent orientations (Beaulieu, 2002). DTI studies have demonstrated de- creased white matter fractional anisotropy (FA) in adult onset schizo- phrenia (AOS) patients compared to healthy subjects (Camchong et al., 2009; Ellison-Wright and Bullmore, 2009; Hao et al., 2009; Hoptman et al., 2008; Munoz Maniega et al., 2008), though one study (Hoptman et al., 2008) showed an increase in FA. Childhood onset schizophrenia (COS) is clinically continuous with the adult onset form of schizophrenia (Rapoport et al., 2005), in which psychosis develops before the age of 13. In addition, COS is a rare and more severe form of AOS and has a more pronounced genetic risk (Asarnow and Asarnow, 1994; Asarnow and Forsyth, 2013; Asarnow et al., 2001; Nicolson and Rapoport, 1999). There have been extremely few DTI studies in this population; Moran et al. (2015) and Clark et al. (2011) found decreased FA in COS patients, and Ashtari et al. (2007) found decreased FA in early onset schizophrenia (deﬁned as onset before the age of 18) patients. Since schizophrenia is a highly heritable disorder with a strong genetic disposition, studying non-aﬀected relatives can reveal insights into the disorder without the confounding eﬀects of medication. Gogtay et al. (2012) and Moran et al. (2015) found a delayed white matter growth trajectory and decreased FA in adolescent COS siblings, Boos et al. (2013) and Hoptman et al. (2008), found increased FA in adult ﬁrst-degree relatives of AOS, while others (Harms et al., 2015; Koivukangas et al., 2015) found no diﬀerences in AOS relatives compared to controls. Patients with schizophrenia and their ﬁrst degree relatives also show substantial deﬁcits in cognitive skill learning (Foerde et al., 2008; Gimenez et al., 2003; Purdon et al., 2003; Schroder et al., 1996; Wagshal et al., 2012; Weickert et al., 2010). The corticostriatal system plays an important role in skill learning (Knowlton et al., 1996; Poldrack and Gabrieli, 2001), suggesting that the pathophysiology of schizophrenia involves dysfunction of corticostriatal circuits (Buchanan et al., 1993; Buchsbaum, 1990; Kleist, 1960). One cognitive skill learning task that has been used extensively in the neuropsycho- logical literature is the Weather Prediction Task (WPT) (Knowlton et al., 1994). The WPT requires participants to learn the probabilistic associations between visually presented cues and binary outcomes, followed by feedback as to whether they chose the correct outcome. Performance on the WPT is impaired in patients with schizophrenia (Foerde et al., 2008; Horan et al., 2008; Keri et al., 2005; Weickert et al., 2002) and their adult and adolescent relatives (Wagshal et al., 2012; Weickert et al., 2010). In addition, in previous fMRI and volumetric studies (Wagshal et al., 2015, 2013) examining a subset of these subjects, we have also demonstrated the COS siblings showed a relative deactivation in frontal and striatal regions, as well as in the cerebellum, compared to controls after extensive training on the WPT and that poorer performance in later learning on the WPT was related to a smaller volume in the cerebellum in COS siblings. Taken together, the results from past studies support the idea that corticostriatal and cerebellar impairments in unaﬀected siblings of COS patients are behaviorally relevant and may reﬂect genetic risk for schizophrenia. Microstructural abnormalities may also play a role in the pathophysiology of schizophrenia and underlie some of the deﬁcits experienced by relatives of schizophrenia patients as well. DTI is traditionally used for characterizing microstructural properties of white matter tracts, but has recently been employed in a novel way to detect microstructural abnormalities and overall cellular damage in subcor- tical gray matter regions as well (Bozzali et al., 2002; Cavallari et al., 2014; Caverzasi et al., 2014; Ciccarelli et al., 2001; Hannoun et al., 2012; Hasan et al., 2009, 2012, 2011; Muller et al., 2007; Piras et al., 2010; Spoletini et al., 2011; Vrenken et al., 2006). DTI can capture Corresponding author at: War Related Illness and Injury Study Center, Veterans Aﬀairs Palo Alto Health Care System (VAPAHCS), United States. E-mail address: dana2@stanford.edu (D. Waltzman). http://dx.doi.org/10.1016/j.pscychresns.2016.10.010 Received 29 April 2016; Received in revised form 25 October 2016; Accepted 28 October 2016 Available online 01 November 2016 0925-4927/ Published by Elsevier Ireland Ltd.