Characterising changes in brain structure and neuropsychological function in the psychoses of epilepsy

Abstract

Psychosis of epilepsy (POE) is a poorly understood condition which can have a devastating impact on people with epilepsy. Despite over a century of investigation into the relationship between epilepsy and psychosis, the structural neurobiological basis and neuropsychological deficits of POE remain unclear. Research in schizophrenia, the paradigmatic psychotic disorder, strongly suggests that psychosis is underpinned by abnormal neurodevelopmental processes which lead to altered brain structure and psychotic symptoms in later life. Moreover, both epilepsy and psychosis are increasingly understood as disorders of large-scale brain networks such as the default mode network (DMN) and the cognitive control network (CCN). The neurodevelopmental model of psychosis on the one hand, and the contemporary understanding of epilepsy and psychosis as network disorders on the other, underpin the primary aim of this thesis, which was to investigate changes in brain structure and neuropsychological function in POE. Understanding the structural neurobiological and neuropsychological deficits of POE is critical as it may provide insights into its neurobiological and developmental mechanisms. Following the introductory chapters (1-3), a systematic review of the neuroimaging literature in POE was undertaken. The results of this review informed the 3 structural neuroimaging studies and 1 neuropsychological study that followed.

Study 1 comprised the first examination of volumetric changes in hippocampal subregions in POE, undertaken in the largest POE sample to date (n = 50). It addresses the methodological limitations of past studies of the hippocampus in POE, which were identified via the systematic review. The results of Study 1 showed hippocampal volume loss on a postero-anterior gradient, with severe decreases in the tail, and moderate volume decreases in the body, but no difference in the hippocampal head in POE relative to matched epilepsy controls (EC). These findings suggest that posterior hippocampal atrophy may be a structural biomarker of POE.

The hippocampus can be further subdivided into distinct subfields which, along with the hippocampal fissure, were not captured by the assessment of hippocampal subregions undertaken in Study 1. Specific subfields, and the hippocampal fissure, have been shown to be affected in other non-epilepsy related psychotic disorders, and have not previously been examined in POE. Therefore, Study 2 comprised the first assessment of hippocampal subfields and the hippocampal fissure in POE. The results revealed an enlarged right hippocampal fissure in POE, with no difference in subfield volumes relative to EC. Moreover, because the volume of the right hippocampal fissure was not related to duration of epilepsy or age of habitual seizure onset, hippocampal fissure enlargement is likely underpinned by abnormal neurodevelopment. Together, Studies 1 and 2 provide strong evidence for structural hippocampal abnormalities in POE.

Study 3 examined changes in cortical thickness, area, and volume in POE relative to EC, comparing patients with postictal psychosis (PIP) and interictal psychosis (IP) - the two main POE subtypes. This study was also motivated by the findings of the systematic review, which highlighted that only two studies have examined cortical changes in POE, one showing cortical thickening in PIP and the other showing cortical thinning in IP. Study 3 directly investigated this distinction, revealing cortical thickening in nodes of the CCN and DMN in POE overall, with more extensive thickening in visual processing regions in IP.

Study 4 comprised an examination of the neuropsychological performance of POE patients and was informed by the structural changes identified in Studies 1-3. The results revealed that patients with POE displayed significantly poorer performance on tasks supported by nodes of the DMN (verbal memory and visual memory) relative to EC and healthy controls (HC), and on tasks supported by the CCN (working memory and verbal fluency), relative to HC.

Considered together, the results of this thesis advance our knowledge of the structural neurobiological basis and neuropsychological deficits of POE. Specifically, they suggest that hippocampal abnormalities and cortical thickening in nodes of key brain networks are involved in its neuropathogenesis, and underpin altered neuropsychological function. The findings of this thesis also provide initial evidence that these structural changes may reflect the impact of epilepsy on neurodevelopmental processes, and provide some new insights into the neurobiological mechanisms underpinning POE. A neurodevelopmental model of POE is proposed, wherein altered hippocampal development and interruption of normal synaptic pruning leads to cortical thickening within specific large-scale brain networks. These structural changes may underpin the cognitive deficits and psychiatric symptoms of POE.