Grey matter morphological anomalies in the caudate head in first-episode psychosis patients with delusions of reference
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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2019, Medical HypothesesCitation Excerpt :Other neuropathological localizations have resulted in false narratives. Delusions have been associated with lesions in the heads of the caudate nuclei (CN) [55], and in schizophrenia, studies associate delusions of reference and negative symptoms with decreased gray matter density in the CN [56,57]. Right CN strokes can present with content-specific delusions and reduced metabolism in the inferior prefrontal cortex [55]; however, left CN head strokes can also present with recurrent delusions, disturbed sleep, and decreased cerebral blood flow in the frontal lobes [58].
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2018, Schizophrenia ResearchCitation Excerpt :Latent Toxoplasma infection has been associated for the first time with the delusion of reference in the present study. Delusion of reference has been specifically associated with the dysregulation of the mesolimbic dopaminergic system (Heinz and Schlagenhauf, 2010), with altered brain functional connectivity (Larivière et al., 2017) and gray matter abnormalities in the caudate head (Tao et al., 2015). The cysts of latent Toxoplasma have been located in amygdala and ventral striatum, two areas that have been associated with delusion of reference in schizophrenia (Menon et al., 2011).
Correlation Between Levels of Delusional Beliefs and Perfusion of the Hippocampus and an Associated Network in a Non–Help-Seeking Population
2018, Biological Psychiatry: Cognitive Neuroscience and NeuroimagingCitation Excerpt :Consistent with the results of the ROI analysis, we found evidence, using voxelwise regression, for significant correlations between total PDI score and perfusion of the hippocampus bilaterally (Talairach coordinates [x, y, z] of peak with the left hippocampus = –22, –31, –10, p = .004; peak with the right hippocampus = 32, –29, –4, p = .01) (Figure 3). In a secondary ROI analysis, we tested for associations between delusional thinking and perfusion of 13 brain regions with close connections to the hippocampus, some of which have been previously linked to delusions or psychosis (83–87), including the medial prefrontal cortex/cingulate gyrus, thalamus, and striatum and regions of the medial and lateral temporal lobe (the amygdala, parahippocampal gyrus, and lateral temporal cortex). This analysis revealed significant correlations between total PDI score and perfusion of the thalamus and caudal anterior and posterior cingulate cortices, as well as the middle and superior temporal cortices and parahippocampal gyrus (Table 2 and Supplemental Table S3).
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These authors contributed equally to this work.