Corpus callosum shape alterations in individuals prior to the onset of psychosis

Abstract

Reductions in the size of the anterior callosum have been described for both first-episode schizophrenia-spectrum psychosis and established schizophrenia, but have not been examined in individuals at ultra-high risk for psychosis (UHR). We compared 100 UHR individuals (27 of whom later developed psychosis) with 38 age-matched control subjects on measures of size and shape of the corpus callosum to determine if changes previously demonstrated in first-episode and established schizophrenia are present in the pre-psychotic phase. Each individual's callosum was extracted from the mid-sagittal slice from T1-weighted magnetic resonance images, and total area, length and curvature of the callosum was compared using one-way ANOVA, and 39 regional thicknesses via a non-parametric permutation method to account for non-independence of adjacent measures. Total area, length and curvature did not differ between the groups. Compared to both the UHR-NP group and controls, the UHR-P group showed significant regional reductions in the region of the anterior genu of the callosum. The UHR-NP group did not differ from controls. Positive and negative symptoms did not affect regional thickness in either of the patient groups. Cox regression showed that mean anterior genu thickness was highly predictive of a transition to psychosis. Reductions in the thickness of the anterior callosum differentiate between high-risk individuals who transition to psychosis and those who do not, and is highly predictive of transition. These changes may reflect primary pathology of orbitofrontal and medial frontal cortex, or deficits in anterior interhemispheric myelination.

Introduction

The identification of individuals, who later develop psychotic illness, whilst in the pre-psychotic phase may allow for the targeting of interventions to prevent, delay or attenuate the course of a psychotic disorder (Wyatt, 1991). This recognition of the role that early intervention may have on modifying the illness course has prompted the search for factors that may identify individuals who are at very high risk of psychotic illness (Yung et al., 1998), enabling “indicated prevention” to be undertaken in this group through intervention in the pre-psychotic phase (Mrazek and Haggerty, 1994). In 1994, the Personal Assessment and Crisis Evaluation (PACE) Clinic was established in Melbourne, Australia to facilitate prospective study of the development of psychotic illnesses, and uses a ‘close-in strategy’ to identify combinations of putative state and trait risk factors that define a target population at ‘ultra-high risk’ (UHR) of an impending psychotic episode (McGorry et al., 2001, Yung et al., 1995). This strategy has been shown to identify a group of young people with a 40% chance of developing a psychotic illness within a 12-month period (Yung et al., 2003a). Subjects receive an MRI brain scan at baseline and are followed clinically for a minimum of 1 year, and a range of neurobiological indices are measured at baseline and follow-up with the aim of identifying factors that predict a transition from the UHR phase to frank psychotic illness.

Through careful follow-up of UHR individuals in the PACE cohort, factors such as olfactory identification (Brewer et al., 2003), verbal memory and spatial working memory function (Brewer et al., 2005, Wood et al., 2003), and hypothalamic–pituitary axis function (Thompson et al., 2007) have been shown to be at least partially predictive of the transition to psychosis. Additionally, we have been able to identify a number of neuroimaging indices that differentiated patients in the UHR group who later became psychotic (UHR-P) from those who remained non-psychotic at follow-up (UHR-NP), including pituitary volume (Garner et al., 2005) and thickness of the anterior cingulate cortex (Fornito et al., 2007, Fornito et al., in press). In a longitudinal neuroimaging study that followed a group of UHR individuals from the pre-psychotic phase, we showed that those in the UHR-P group showed right medial and lateral temporal, right inferior frontal, and bilateral cingulate cortex reductions when compared to the UHR-NP group (Pantelis et al., 2003), and have also shown that accelerated grey matter loss occurs in prefrontal cortical regions from the pre-psychotic period through the transition to psychosis (Sun et al., 2007a, Sun et al., 2007b).

The common neuroanatomical origin of the majority of these indices, which appear to be strong neurocognitive and neuroimaging trait markers for the development of psychotic illness (Brewer et al., 2006, Pantelis et al., 2007), appears to be in the anterior cortex. We have recently shown that reductions in the genu of the corpus callosum are present in both first-episode and established schizophrenia patients (Walterfang et al., in press), which carry fibres that connect contralateral inferior frontal and prefrontal regions. Subtle reductions in callosal size are well-described in schizophrenia (Woodruff et al., 1995), although no studies have examined this structure in the pre-psychotic phase. Given our findings of inferior frontal reductions in those UHR individuals who later became psychotic compared to those who did not (Pantelis et al., 2003), we speculated that these anterior callosal changes seen at the first-episode of schizophrenia may be present in pre-psychotic individuals and may differentiate them from individuals identified in the UHR group who do not progress to psychosis.