Reduced paralimbic system gray matter volume in schizophrenia: Correlations with clinical variables, symptomatology and cognitive function

Highlights

• Gray matter volumes (GMVs) in the paralimbic system were significantly reduced in schizophrenia.

• Abnormalities of GMVs in the paralimbic system were correlated with symptomatology and cognitive function.

• Abnormalities of GMVs in paralimbic system were correlated with processing speed.

• Abnormalities of GMVs in bilateral orbitofrontal cortex were correlated with memory function.

• The paralimbic system plays an important role in the pathophysiology of schizophrenia.

Abstract

Background

Psychopathy is associated with dysfunction in regions that compose the paralimbic system, such as the orbitofrontal cortex (OFC), insular cortex (IC), temporal pole (TP), parahippocampal gyrus (PHG) and cingulate cortex (CC). However, findings of structural alterations in these regions are inconsistent in schizophrenia, and correlations between paralimbic system measures and symptomatology and cognitive function have not been investigated.

Method

93 patients with schizophrenia and 99 healthy controls received structural magnetic resonance imaging and clinical and cognitive assessment. We compared gray matter volume (GMV) between the two groups using voxel-based morphometry, and evaluated correlations between abnormal GMVs and clinical variables, symptomatology and cognitive function. The assessment of cognition included measures of processing speed, verbal fluency and memory.

Results

Patients with schizophrenia demonstrated significant GMV decreases in the paralimbic system, including bilateral OFC, IC and TP (p < 0.05, FWE corrected). GMV decreases were also observed in bilateral superior temporal gyri (STG). The GMVs in bilateral OFC, left IC, left TP and bilateral STG were positively correlated with processing speed, and the GMVs in bilateral OFC were positively correlated with memory function in all participants. In our patient group, the GMV deficits were also associated with earlier age of onset, longer duration of illness, greater number of hospitalizations and more severe positive symptoms.

Conclusions

GMVs in the paralimbic system were significantly reduced in schizophrenia, and these abnormalities were correlated with clinical variables, symptomatology and cognitive function. These results suggest the paralimbic system plays an important role in the pathophysiology of schizophrenia.

Introduction

Schizophrenia is one of the most serious and disabling psychiatric disorders, affecting 1% of the population and remaining one of the top ten causes of health burden in the world (Salomon et al., 2012). Schizophrenia is characterized by positive symptoms, negative symptoms and cognitive impairments (Mueser and McGurk, 2004, Fatouros-Bergman et al., 2014). Evidence from structural and functional neuroimaging and electrophysiology suggests that the paralimbic system is involved in psychopathology and cognitive impairment (Kiehl, 2006). However, the role of the paralimbic system in the occurrence of schizophrenia is not clear.

The paralimbic system includes the orbitofrontal cortex (OFC), insular cortex (IC), temporal pole (TP), parahippocampal gyrus (PHG) and cingulate cortex (CC). These regions develop in concert in the embryonic period and share cytoarchitecture and connectivity (Mesulam, 1998, Mesulam, 2000). The paralimbic system is a transition zone from agranular to granular cortex (Mesulam, 1998). Enormous inter-individual variability in paralimbic sulcogyral morphology reflects neurodevelopmental processes, including neuronal migration, local neuronal connection, synaptic development, lamination and formation of cytoarchitecture (Rakic, 1988, Armstrong et al., 1995). Meanwhile, the paralimbic system is also a gradually transitive cytoarchitectonic zone between the primitive allocortex of limbic structure and primary sensory-motor areas, which acts as neural bridges that link the inside to the external environment. With information provided by the external environment, the internal milieu is responsible for regulation of emotion, motivation, memory and autonomic-endocrine function (Mesulam, 1998). The paralimbic system plays an important role in the process of mediating internal and environmental targets. Thus, the paralimbic system is engaged in various functions, such as mood regulation, social behavior, attentional and mnemonic processes, reward processing, motivation, and decision-making (Olson et al., 2007, Nakamura et al., 2008, Larquet et al., 2010, Keller et al., 2013, van Eijndhoven et al., 2013), and therefore has been thought to play an important role in the pathophysiology of psychopathy (Kiehl, 2006).

However, studies focused on paralimbic regions in schizophrenia are relatively few, and the published research findings were inconsistent. Structural neuroimaging studies of schizophrenia with small sample sizes have reported reduced gray matter volume (GMV) in one or more paralimbic regions, including GMV in OFC decreases in 24 patients with schizophrenia (Nakamura et al., 2008), GMV in TP decreases in 27 first-episode patients with schizophrenia (Kasai et al., 2003), and GMV in IC decreases in 20 patients with schizophrenia (Saze et al., 2007). However, Lacerda et al. (2007) reported that OFC volume was increased in 43 first-episode schizophrenic patients and correlated with negative symptoms. Similarly, Hoptman et al. (2005) found that GMV of left OFC was increased in 49 chronic schizophrenia or schizoaffective disorder patients, and the OFC volume increase was associated with greater levels of aggression. Additionally, several studies reported that patients with schizophrenia did not significantly differ from controls in TP morphometric variables, and clinical variables were not significantly related to the GMV of TP (Crespo-Facorro et al., 2004, Roiz-Santiáñez et al., 2010). Taken together, these studies suggested that paralimbic regional abnormalities might exist in patients with schizophrenia. However, further investigation is necessary to resolve the inconsistency between studies. In addition, correlations between alterations in the paralimbic system and symptom severity and cognition have not been investigated.

In the present study, we used high-resolution structural magnetic resonance imaging (sMRI) and voxel-based morphometry (VBM) to study abnormalities of GMV in schizophrenia patients, and evaluated correlations between abnormal GMVs and clinical variables, symptomatology and cognitive function. We hypothesized that GMV decreases would be present in the paralimbic system in patients with schizophrenia, and that these alterations would be associated with clinical variables, psychopathology and cognitive deficits.