Brain neurodevelopmental markers related to the deficit subtype of schizophrenia
Introduction
Detailed examination of specific schizophrenia subtypes is one possible approach to reduce heterogeneity, which could partly explain the discrepant neurobiological findings of the disorder (Keshavan et al., 2008, van Os and Kapur, 2009). Deficit schizophrenia is a clinical subtype characterized by primary and prominent negative symptoms that persist even during periods of relative remission (Carpenter et al., 1988). While etiologic factors related to this specific subtype remain elusive, the association of deficit schizophrenia with poor premorbid adjustment (Bucci et al., 2016, Kirkpatrick and Galderisi, 2008), neurological abnormalities (Peralta et al., 2014), and general cognitive impairments (reviewed by Mucci et al., in press) may support the hypothesis of its pervasive neurodevelopmental abnormalities (Galderisi et al., 2002, Peralta et al., 2014). Furthermore, a recent magnetic resonance imaging (MRI) study of network-level properties of cortical thickness demonstrated altered intracortical relationships, which may reflect reduced network differentiation during early neurodevelopment, in deficit schizophrenia (Wheeler et al., 2015). To our knowledge, however, no MRI studies have examined gross brain morphology closely associated with early neurodevelopment specifically in deficit schizophrenia.
Previous MRI studies of gross brain morphology in schizophrenia have implicated the role of aberrant neurodevelopmental processes in the pathophysiology of schizophrenia (Pantelis et al., 2005). A smaller adhesio interthalamica (AI), which is a narrow bridge connecting the medial surfaces of the thalami that develops during early gestation (O'Rahilly and Muller, 1990, Rosales et al., 1968), and increased prevalence of large (e.g., ≥6 mm in anterior-posterior length) cavum septi pellucidi (CSP) due to incomplete fusion of the septum pellucidum around birth (Rakic and Yakovlev, 1968) are thought to reflect early developmental characteristics in midline brain regions in schizophrenia (Landin-Romero et al., 2016, Trzesniak et al., 2011a, 2011b). However, a large number of MRI studies including our own study (Takahashi et al., 2007, Takahashi et al., 2013b) reported normal size of the CSP in schizophrenia (reviewed by Trzesniak et al., 2011b). The surface morphology of the orbitofrontal cortex (OFC) is also a potential neurodevelopmental marker because it is largely established by birth (Armstrong et al., 1995, Chi et al., 1977); schizophrenia patients are generally characterized by a shallower olfactory sulcus (Nishikawa et al., 2016, Takahashi et al., 2013a, Takahashi et al., 2014), decreased Type I and increased Type III expression in the variation of the OFC ‘H-shaped’ sulcus [Type I, II, and III; defined by Chiavaras and Petrides (2000)] (Chakirova et al., 2010, Nakamura et al., 2007, Takayanagi et al., 2010), as well as a decreased number of intermediate and posterior orbital sulci (IOS/POS) (Bartholomeusz et al., 2013, Takahashi et al., 2016). We have previously demonstrated that AI length and number of POS are related to the severity of negative symptoms in schizophrenia (Takahashi et al., 2008a, Takahashi et al., 2016). Further, nucleus accumbens atrophy (De Rossi et al., 2016) as well as microstructural disruption of the forceps minor (Spalletta et al., 2015) in deficit schizophrenia may imply significant role of the OFC abnormalities in this clinical subtype, because both of these structures are functionally and structurally connected with the OFC (Catani and Thiebaut de Schotten, 2008, Diekhof et al., 2012). However, it remains largely unknown whether the deficit and non-deficit subtypes of schizophrenia have differences in the morphology of potential neurodevelopmental markers located in the midline and OFC regions.
This MRI study aimed to expand our previous studies of a range of neurodevelopmental markers [AI (Takahashi et al., 2008a, Takahashi et al., 2008b), CSP (Takahashi et al., 2007), olfactory sulcus (Nishikawa et al., 2016, Takahashi et al., 2013a), and OFC surface morphology (Nishikawa et al., 2016, Takahashi et al., 2016)] in schizophrenia by investigating the characteristics of these neurodevelopmental markers in well-defined deficit subtype schizophrenia in comparison with non-deficit subtype as well as healthy controls. On the basis of hypothesized pervasive neurodevelopmental abnormalities in deficit schizophrenia (Galderisi et al., 2002, Peralta et al., 2014), we predicted that the deficit patients would exhibit greater changes in brain neurodevelopmental markers compared with the non-deficit patients. We also investigated the association between brain neurodevelopmental markers and clinical variables in each schizophrenia subgroup. Given the role of gross brain morphology as a stable trait marker that mainly reflects early neurodevelopment, we predicted that it would not be related to the symptom severity (especially positive symptoms) at scanning and potential confounding factors after illness onset (e.g., medication, illness duration).
Section snippets
Subjects
Seventy-five patients with schizophrenia (38 deficit and 37 non-deficit subtypes) fulfilling the ICD-10 research criteria (World Health Organization, 1993), who were recruited from the inpatient and outpatient clinics of the Department of Neuropsychiatry of Toyama University Hospital, were included in this study. The patients were diagnosed following a structured clinical interview by psychiatrists using the Comprehensive Assessment of Symptoms and History (CASH; Andreasen et al., 1992).
Demographic characteristics
Demographic and clinical characteristics of the study participants are summarized in Table 1. Age, gender, and parental education did not differ significantly between the groups, but the healthy controls had attained a higher level of education compared with the schizophrenia subgroups. The handedness distribution differed between the groups. The deficit and non-deficit schizophrenia subgroups did not differ in onset age, illness duration, and medication. There were significant
Discussion
To our knowledge, this is the first MRI study that demonstrated greater morphologic changes in several neurodevelopmental markers in deficit schizophrenia. The length of the AI was significantly shorter in patients with deficit schizophrenia compared to those with non-deficit schizophrenia and control subjects. Furthermore, alteration of the OFC sulcogyral pattern (H-shaped variation and sulcus count) was more evident in the deficit schizophrenia group than in the non-deficit group. However,
Conclusion
The present MRI study of gross brain morphology demonstrated that the deficit schizophrenia group was characterized by shorter AI and more evident changes in the OFC sulcogyral pattern compared with the non-deficit group. Given the potential role of these brain structures as a marker of early neurodevelopment, our findings may support the hypothesis, based on the clinical characteristics of deficit schizophrenia, that this specific subtype is associated with pervasive neurodevelopmental
Contributors
In this study, Drs. Suzuki and Takayanagi conceived the idea and methodology of the study. Dr. Takahashi conducted the statistical analyses and wrote the manuscript. Drs. Takahashi, Takayanagi, Furuichi, Kido, Nishikawa, Sasabayashi, and Nakamura recruited subjects, and were involved in clinical and diagnostic assessments. Drs. Takahashi, Nishikawa, and Nakamura analyzed the MRI data. Ms. Komori assisted in the management of clinical data of the study participants. Dr. Noguchi provided
Conflict of interest
None.
Acknowledgements
This work was supported by JSPS KAKENHI Grant number JP26461738 to Y.T., JP26461739 to T.T., and JP24390281 to M.S., and by the Health and Labour Sciences Research Grants for Comprehensive Research on Persons with Disabilities from the Japan Agency for Medical Research and Development (AMED) Grant Number 16dk0307029h0003 to M.S. The authors would like to thank the radiological technologists, especially Mr. Koichi Mori and Mr. Sadanori Ito, who assisted in the MRI data collection at Toyama
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