Progression of neuroanatomical abnormalities in psychotic disorder and the effect of psychotropic medication

Introduction: Schizophrenia is a particularly severe and disabling mental disorder affecting 20 million people worldwide. The vast majority of structural and diffusion neuroimaging studies on neuroanatomy and cognition have been conducted cross-sectionally and it remains unclear whether risk factors, treatments or associated illness effects are driving changes. The overarching theme of this thesis is to longitudinally examine elements of neuroanatomical progression and its cognitive or clinical correlates in samples of patients across different phases of psychosis spanning first episode of illness and treatment refractory schizophrenia, using structural and diffusion MRI techniques. Specifically, Manuscript 1 aims to assess whether impaired executive functioning and emotional intelligence at first presentation of psychotic episode are associated with progressive prefrontal and orbitofrontal cortical thinning and whether negative symptom severity is linked to progressive prefrontal cortical thinning in the years following the first-episode of psychosis. Manuscript 2 and 3, using a unique sample of treatment-resistant clozapine-naïve schizophrenia patients, investigate whether subcortical structures, white matter microstructure and structural network organisation demonstrate any progressive changes after 6 months of clozapine treatment and whether any such changes are related to clinical variables including treatment response and amount of clozapine taken. Method: Manuscript 1. 1.5T structural MRI images were acquired at baseline and after 3.5 years for 20 individuals with first-episode psychosis (FEP) and 18 healthy volunteers (HC). At baseline and follow-up, the longitudinal pipeline of Freesurfer was employed to parcellate prefrontal cortex and the MATRICS Consensus Cognitive Battery (MCCB) was used to assess executive functioning and emotional intelligence. At both timepoints the severity of negative and positive symptoms was assessed using the Positive and Negative Syndrome Scale (PANSS). Baseline cognitive performance was compared between diagnostic groups using Multivariate Analysis of Covariance (MANCOVA). Partial correlations investigated relationships between cognition and negative symptoms at baseline and cortical thickness change over time. Manuscript 2 & 3. Thirty-three patients with treatment-resistant schizophrenia (TRS) and 31 healthy volunteers successfully participated at both baseline, prior to clozapine initiation in patients, and 6 months follow-up clinical assessments and structural MRI scanning (Manuscript 2). Of these 64 participants, diffusion MRI data were available at both time points for 22 patients and 23 healthy controls (Manuscript 3). The severity of positive and negative symptoms was assessed at both time points using the PANSS, the Scale for the Assessment of Positive Symptoms (SAPS) and the Scale for the Assessment of Negative Symptoms (SANS). Social, occupational and psychological functioning was assessed using a Global Assessment of Functioning Score. In Manuscript 2 the longitudinal pipeline of Freesurfer v.5.3.0 was employed to bilaterally segment eight subcortical regions-of-interest: lateral ventricle, thalamus, hippocampus, caudate, putamen, globus pallidus, amygdala and nucleus accumbens. Two-way repeated MANCOVA was used to assess group differences in subcortical volumes over time and partial correlations to determine association with clinical variables. In Manuscript 3 the Tract-based spatial statistics approach (TBSS) was used to compare changes over time between groups in fractional anisotropy (FA). Changes in structural network organisation and subnetwork connectivity weighted by FA and number of streamlines (NOS) were assessed using graph theory and network-based statistics. Results: In Manuscript 1 we demonstrated that patients in their first-episode of psychotic illness perform significantly worse on several tests assessing different aspects of executive functions compared to healthy controls, including category fluency, attention, working memory and reasoning & problem solving. The poorer performance at baseline in spatial working memory was a significant predictor of loss of total prefrontal cortical thickness in the initial years after illness onset. We also found that impairment of emotional intelligence at illness onset was significantly associated with a progressive reduction of orbitofrontal thickness in patients after their first-episode of psychosis. Finally, we demonstrated a correlation between neuroanatomical progression and clinical variables, specifically, worsening of negative symptoms was associated with prefrontal thickness reduction as the illness progresses. In Manuscript 2, in treatment-resistant schizophrenia patients we showed a substantial progressive volumetric reduction of the thalamus, hippocampus, caudate, putamen and enlargement of lateral ventricles over a 6-month period compared to controls. Furthermore, patients who had the greatest symptomatic and functional improvement displayed the largest thalamo-striatal reductions. We also found that patients who were exposed to higher amounts of clozapine displayed a greater reduction of thalamus volume. In Manuscript 3, treatment-resistant schizophrenia patients showed progressive focal FA abnormalities in the white matter of key anterior tracts, such as genu and body of the corpus callosum and bilaterally in the anterior and superior corona radiata compared to controls. The brain structural network organisation was preserved in patients compared to controls. The FA reduction was independent of any clinical measures or serum level of clozapine. Conclusion: Taken together our results indicate that at onset of psychosis working memory and emotional intelligence impairment represents a trait marker of progressive prefrontal thinning as the illness progresses, while worsening of negative symptoms is associated with prefrontal thickness reduction over time, indicating a functional consequence of anatomical progression in psychosis. In those with the chronic treatment-resistant stage of the illness, there is a consistent progressive volume reduction in several subcortical structures as well as progressive focal abnormalities in the white matter microstructure of key anterior tracts, but a preserved brain structural network. However, our findings suggest a divergence of neuroanatomical progression, where progressive atrophy in the thalamo-striatal circuits are linked to clinical and functional improvement, whereas no such association is found with longitudinal progression in lateral ventricles, hippocampus and white matter. This thesis confirms the importance of investigating the neurocognitive dimension at illness onset in order to enhance understanding of the functional consequences of illness progression as well as identifying potential markers at illness onset. It also highlights the potential role of the thalamo-striatal circuits in tracking recovery in treatment-resistant schizophrenia patients, suggesting that its investigation using large scale longitudinal design studies could significantly contribute to the identification of biomarkers in refractory schizophrenia