Grey matter morphological anomalies in the caudate head in first-episode psychosis patients with delusions of reference

https://doi.org/10.1016/j.pscychresns.2015.04.011Get rights and content

Highlights

  • Grey matter density values were compared in psychosis patients and healthy controls.

  • Caudate grey matter density reduced in patients with delusions of reference (DOR).

  • Grey matter density of the bilateral caudate head were negatively correlated with the DOR severity.

  • Decreased grey matter density in caudate nucleus may underlie DOR in early psychosis.

Abstract

Delusions of reference (DOR) are theoretically linked with aberrant salience and associative learning. Previous studies have shown that the caudate nucleus plays a critical role in the cognitive circuits of coding prediction errors and associative learning. The current study aimed at testing the hypothesis that abnormalities in the caudate nucleus may be involved in the neuroanatomical substrate of DOR. Structural magnetic resonance imaging of the brain was performed in 44 first-episode psychosis patients (with diagnoses of schizophrenia or schizophreniform disorder) and 25 healthy controls. Patients were divided into three groups according to symptoms: patients with DOR as prominent positive symptom; patients with prominent positive symptoms other than DOR; and patients with minimal positive symptoms. All groups were age-, gender-, and education-matched, and patient groups were matched for diagnosis, duration of illness, and antipsychotic treatment. Voxel-based morphometric analysis was performed to identify group differences in grey matter density. Relationships were explored between grey matter density and DOR. Patients with DOR were found to have reduced grey matter density in the caudate compared with patients without DOR and healthy controls. Grey matter density values of the left and right caudate head were negatively correlated with DOR severity. Decreased grey matter density in the caudate nucleus may underlie DOR in early psychosis.

Introduction

Delusions of reference (DOR) are one of the most common psychotic symptoms in early schizophrenia (World Health Organization, 1975). Its roles as both a prodromal sign (Yung et al., 2005) and signal of relapse (Birchwood et al., 1989) suggest a close linkage with the psychotic state. Importantly, DOR are found in many delusional themes (Kraepelin, 1921) and may be particularly involved in the early delusion-formation stage (Corlett et al., 2006). Some investigators also speculate that different types of delusions such as paranoid ideation, delusions of misidentification and cotard delusion may have different pathological bases (Corlett et al., 2010). Investigation into the neural substrates of DOR may provide insight into understanding delusion formation in psychosis.

In DOR, subjects find their attention drawn toward irrelevant stimuli and events in the environment and impute personal meaning to them (Corlett et al., 2010). Theoretically, aberrant salience and associative learning may be involved. It has been proposed that dopamine mediates the conversion of the neural representation of an external stimulus from neutral information into its appropriate significance (Berridge and Robinson, 1998). In particular, the dopamine system plays a critical role in salience attribution. Authors such as Kapur (2003) and Corlett et al. (2006) have proposed that delusions are the cognitive effort by the patient to make sense of these aberrantly salient experiences which may have resulted from abnormal mesocorticolimbic dopamine system through disrupted prediction-error signalling. Prediction errors, signalled by midbrain dopamine neurons that are densely connected with the prefrontal cortex and basal ganglia, are considered to play a direct role in forming and strengthening associations (Schultz and Dickinson, 2000). Converging neurobiological evidence has shown a central role of the caudate nucleus in perception and prediction errors coding, associative learning, and working memory (Levy et al., 1997, Williams and Eskandar, 2006, Schiffer and Schubotz, 2011). Studies have showed that the caudate nucleus, which has dense fibre projections from the prefrontal lobe, is the primary target of the cognitive/limbic association cortex (Alexander et al., 1990, Levy et al., 1997). A functional imaging study has provided initial evidence of the association of DOR with abnormal brain activity in the frontal cortex, insula, and striatal areas (Menon et al., 2011). In theory, therefore, abnormality in the caudate nucleus may also be involved. However, very few research studies have been done on the neuropathology of DOR and their neuroanatomical substrate remains unclear.

In the current study, we studied the neuropathology of DOR in patients with schizophrenia using the voxel-based morphometry (VBM) technique in magnetic resonance imaging (MRI). We hypothesized that an abnormality of the caudate nucleus may be involved in the neuroanatomical substrate of DOR. Considering that structural heterogeneity may be correlated with psychopathological dimensions in psychosis (Koutsouleris et al., 2008), we investigated neuropathology in the following three groups of patients with different symptom profiles: (1) patients with DOR as prominent positive symptom, (2) patients with prominent positive symptoms other than DOR, and (3) patients with minimal positive symptoms. To determine the severity of DOR, we used a recently validated instrument, the Ideas of Reference Interview Scale (IRIS), which provides a theoretically based assessment tool to quantify the amount of aberrant salience in DOR (Wong et al., 2012). The IRIS has been validated in a Chinese patient population with demonstrated sensitivity, specificity, and reliability. We also explored possible relationships between grey matter density and DOR severity.

Section snippets

Participants and measures

Sixty-nine subjects (44 first-episode psychosis patients and 25 healthy controls) participated in the study. All participants were right-handed Han Chinese aged 18–45 years old, who had at least 9 years of formal education to ensure adequate understanding and expressive capacity, with no history of substance abuse or dependence, brain trauma or neurological disease, or contraindications to MRI. Participants׳ IQ was estimated using the information and digit-symbol coding subscales of the

Demographic and clinical characteristics

Analysis of variance (ANOVA) and chi-square tests showed no significant differences in the age, years of education and gender across all four groups (all p>0.05) (Table 1). The three patient groups differed significantly in SAPS (F (2, 41)=14.79, p<0.001) and SANS (F (2, 41)=36.05, p<0.001) scores, but not in duration of illness (F (2, 41)=1.96, p=0.15), treatment duration (F (2, 41)=1.12, p=0.34), or antipsychotic dosage (F (2, 41)=1.53, p=0.23). The DOR group had a significantly higher IRIS

Discussion

Using a specific measurement of DOR, the present study found that patients with DOR had reduced grey matter density in the caudate compared with patients without DOR and healthy controls. These abnormalities seem independent of antipsychotic treatment. Our findings may contribute to the understanding of the current literature on caudate changes in psychotic patients. Increasing evidence has pointed to a smaller caudate nucleus in psychosis (Ellison-Wright et al., 2008). The decrease in caudate

Acknowledgements

This research was supported by grants from the National Natural Science Foundation of China (81301161 to Dr. HJ Tao, 81271485 to Dr. ZN Liu, 30971053 to Dr. ZM Xue) and Hunan Provincial Innovation Foundation for Postgraduate Student (CX2010B078 to Dr. H.J. Tao).

The authors gratefully acknowledge the assistance of Lin Xu from Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, PR China, and Zhong He from the Department

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    These authors contributed equally to this work.

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