Evidence for progressive brain abnormalities in early schizophrenia: A cross-sectional structural and functional connectivity study

Abstract

It has long been debated whether a progressive process is involved in schizophrenia. The aim of the current study was to determine whether a progressive process was involved in patients with early schizophrenia, who were drug naive or had received short-term minimal antipsychotic treatment to avoid the distortion through medication effects. Twenty-eight patients with schizophrenia with illness-duration of up to 3 years and twenty-six matched healthy controls were recruited. Structural and functional brain networks were examined based on diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI). The intergroup differences and correlation with illness duration in the patient group were surveyed. The schizophrenic patients showed lower fractional anisotropy (FA) values in the corpus callosum and corona radiata. Negative correlations of illness duration with FA values were observed in similar regions. During functional analysis, reduced functional connectivity between bilateral temporoparietal-junction (TPJ) and the posterior cingulate cortex (PCC) were found in the default mode network (DMN) in schizophrenic patients. In addition, the left TPJ showed gradually weaker functional connectivity with PCC and the medial prefrontal cortex (MPFC) in DMN as the duration of schizophrenia increased. The results suggested that early in the disease process patients have decreased connectivity in both structural and functional networks and that the weaker structural and functional connectivity negatively correlated with illness duration, which provided evidence for progressive brain abnormalities in early schizophrenia.

Introduction

Schizophrenia is a complex and strongly heritable disorder with general cognitive impairments. Kraepelin first described schizophrenia as “dementia praecox” (Kraepelin et al., 1919). It occurs in familial aggregates carrying genetic vulnerability to schizophrenia and the onset of illness is usually during puberty.

Recently, numerous studies on brain volume have shown decreased gray matter in the hippocampus (Steen et al., 2006), the frontal, the temporal, and the parietal lobes (Whitford et al., 2006, Olabi et al., 2011) as well as enlargement in ventricular size (Kempton et al., 2010) in patients with schizophrenia. In addition, the white matter fibers connecting different brain regions show a consistent decrease in integrity in the fornix, corpus callosum, cingulum bundle, internal capsule, external capsule, superior and inferior occipito-frontal fasciculus, arcuate fasciculus, and uncinate fasciculus in schizophrenia (Kubicki et al., 2005).

In further studies, Mori et al. found a progressive process in the structural network of patient with chronic schizophrenia (Mori et al., 2007); meanwhile Friedman et al. found a significantly decreased fractional anisotropy (FA) in widespread areas of white matter in patients with chronic schizophrenia compared to first-episode patients who had received medication with illness duration less than 3 years (Friedman et al., 2008). The progressive structural brain impairment is always associated with incremental degeneration of brain function. Deterioration of a number of cognitive performances such as executive control, lexico-semantic processing, and working memory has been associated with reduced activity within the related cortex in patients with schizophrenia (Seok Jeong et al., 2005, Lam et al., 2012, Faget-Agius et al., 2013), indicating that a progressive process might be involved in schizophrenia.

Importantly, previous investigations have also shown negative findings when studying the progressive changes of the brain in longitudinal studies of schizophrenia. For example, no progressive changes were found among patients with schizophrenia at 8-month, 1.5-year, or 2.7-year follow-up visits (Puri et al., 2001, James et al., 2002, Dickey et al., 2004).

However, researchers have found that antipsychotic medication may cause changes in brain structures. Meanwhile, Lieberman suggested that there is a limited progressive process involved in the early stages of schizophrenia (Lieberman, 1999). The effects from chronicity and long-term medication may lead to this inconformity (Lieberman et al., 2005).

We used a cross-sectional design to avoid the limitations of previous studies that had a longitudinal design and chronic patients with long-term treatment in whom it was difficult to exclude the effects of the medication. Twenty-eight first-episode schizophrenia patients, who were drug-naïve or had minimal antipsychotic treatment for less than 10 days were recruited. The illness-duration of all schizophrenic patients was as long as 3 years. Twenty-six age- and gender-matched healthy controls were also enrolled. Table 1 presents the participants' demographics. The structural connectivity and functional connectivity of all participants were measured via DTI and fMRI separately. The present study aimed to examine whether there is a progressive decline along the course of schizophrenia by correlating structural and functional connectivity with the illness duration.