Altered depth of the olfactory sulcus in ultra high-risk individuals and patients with psychotic disorders
Introduction
The olfactory sulcus appears during fetal development at around 16 weeks of gestation (Chi et al., 1977) and its depth is considered to relate to olfactory function in healthy subjects (Hummel et al., 2003). Given the evidence that schizophrenia patients exhibit olfactory dysfunction as a possible vulnerability marker (Brewer et al., 2001, Brewer et al., 2003, Turetsky et al., 2009b, Kamath et al., in press), as well as the fetal stage of the sulcus formation at which neurodevelopmental disruption could increase the risk for schizophrenia (Fatemi and Folsom, 2009), olfactory sulcus morphology might be a potential early neurodevelopmental marker of schizophrenia. However, magnetic resonance imaging (MRI) studies of the olfactory sulcus in schizophrenia have yielded inconsistent results. We demonstrated an abnormally shallow olfactory sulcus in first-episode psychosis patients (Takahashi et al., 2013a), while both normal (Nguyen et al., 2011) and shallow (Turetsky et al., 2009a) sulcus depths were reported in chronic patients. This inconsistency may be partly due to methodological issues such as different sample characteristics (e.g., illness stage, medication) and tracing methodologies. Although a recent MRI study found no progressive changes in the sulcus depth in first-episode schizophrenia (Takahashi et al., 2013a), the nature of the sulcus morphology in the course of the illness remains unclear. In addition, to our knowledge, no MRI studies have investigated whether the olfactory sulcus abnormalities in schizophrenia are diagnostically specific or common to various psychotic disorders (e.g., affective psychosis).
Our previous MRI studies in ultra high-risk (UHR) individuals (Yung et al., 2004a), 35% of whom made the transition to psychosis according to their long-term outcome (Nelson et al., 2013), revealed abnormalities in sulcus/gyral folding in the anterior cingulate cortex (ACC) (Yücel et al., 2003) or in the size of the adhesio interthalamica (AI) (Takahashi et al., 2008a) regardless of later transition status, which could represent pre-existing vulnerability to psychopathology as a consequence of early neurodevelopmental insult (Pantelis et al., 2005). On the other hand, we found no abnormality in the cavum septum pellucidum (CSP) that is also related to fetal neurodevelopment (Rakic and Yakovlev, 1968) in UHR individuals (Takahashi et al., 2008b), suggesting different biological processes responsible for these gross brain abnormalities. A recent MRI study demonstrated decreased olfactory sulcus depth in a Japanese high-risk sample (Takahashi et al., 2013b), supporting the notion that olfactory impairment appears to be a promising vulnerability marker of the psychosis risk status especially for those who subsequently develop schizophrenia (Brewer et al., 2003, Turetsky et al., 2012). However, that preliminary MRI study could not take account of sample outcome (e.g., with and without later transition) due to small sample size and needs replication in a larger well-defined high-risk cohort.
The present study aimed to investigate the olfactory sulcus morphology in a large sample of patients at various stages of psychotic illness and with various diagnoses [first-episode psychosis (FEP), chronic schizophrenia, and ultra high-risk individuals who did (UHR-P) and did not (UHR-NP) develop psychosis] compared with healthy controls. On the basis of a possible role of the olfactory sulcus depth as an early neurodevelopmental marker, as well as previous MRI (Turetsky et al., 2009a, Takahashi et al., 2013a, Takahashi et al., 2013b) and olfactory ability (Brewer et al., 2001, Brewer et al., 2003, Turetsky et al., 2009b, Turetsky et al., 2012) findings, we predicted that the UHR-P subjects, FEP patients, and chronic schizophrenia patients would have a shallower olfactory sulcus to a similar degree as compared with controls. We also investigated the association between the olfactory sulcus morphology and clinical features (clinical variables and diagnosis) as well as other brain structures potentially related to early neurodevelopment (i.e., ACC folding, AI length, and CSP length).
Section snippets
Subjects
Eighty-nine patients with chronic schizophrenia, 162 patients with first-episode psychosis (FEP), 135 individuals at ultra high-risk (UHR) for developing psychosis, and 87 healthy comparisons participated in this study (Table 1). Inclusion criteria and demographic characteristics of the study participants have been described in detail elsewhere (Velakoulis et al., 1999, Garner et al., 2005, Velakoulis et al., 2006).
Briefly, the patients with chronic schizophrenia were recruited from the Adult
Demographic characteristics
Comparison of the groups revealed no difference in handedness and ICV, but there were significant group differences in age, gender, height, and premorbid IQ (Table 1). The two UHR groups (UHR-P versus -NP) did not differ with respect to global psychopathological state according to the BPRS or negative symptoms according to the SANS.
Depth and length of the olfactory sulcus
ANCOVA of the olfactory sulcus length revealed no significant effect involving diagnosis (Table 1), but that for depth showed significant main effects of diagnosis [F
Discussion
To our knowledge, this is the first MRI study to report morphologic changes of the olfactory sulcus across various illness stages including those of a sample at clinical high-risk of psychosis that was followed-up longitudinally. The UHR subjects who developed psychosis (UHR-P) had a significantly shallower olfactory sulcus as compared with both UHR who did not develop psychosis (UHR-NP) and control subjects, suggesting that such anomaly already exists prior to the onset as a possible risk
Role of funding source
This research was supported in part by Grants-in-Aid for Scientific Research (C) (Nos. 22591275 and, 24591699) and Grants-in-Aid for Scientific Research (B) (No. 24390281) from the Japanese Society for the Promotion of Science, Health and Labour Sciences Research Grants (Comprehensive Research on Disability, Health and Welfare, H23-Seishin-Ippan-002 and H23-Seishin-Ippan-009), and Research Grants from the JSPS Asian Core Program and the Research Group For Schizophrenia, Japan. This research was
Contributors
In this study, Drs. Suzuki, Pantelis, and Brewer conceived the idea and methodology of the study. Dr. Takahashi conducted the statistical analyses and wrote the manuscript. Drs. McGorry, Yung, Brewer, Nelson, Lin, Phillips, and Proffitt recruited subjects, and were involved in clinical and diagnostic assessments. Drs. Takahashi and Nakamura analyzed the MRI data. Drs. Suzuki, Pantelis, Velakoulis, Wood, and Yücel contributed to writing and editing of the manuscript. All authors contributed to
Conflict of interest
All authors declare that they have no conflicts of interest.
Acknowledgements
The authors are grateful to the clinical staff of the Personal Assessment and Crisis Evaluation (PACE) Clinic, Early Psychosis Prevention and Intervention Centre (EPPIC), and Adult Mental Health Rehabilitation services of the North Western Mental Health Program for their assistance in diagnostic and psychopathological assessments of the study participants.
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