The illumination of the developing brain: Using MRI signal intensity contrasts to probe microstructural brain maturation, and associations with psychopathology and cognition

Abstract

Childhood and adolescence captures a remarkable period of change, and is the central period for major reorganization and optimization of the cerebral cortex. This maturation is mirrored by major cognitive improvements within the youth period. At a neurobiological level, several genetic regional and age specific processes are at work, in dynamic interplay with the environment. It is therefore understood that certain genetic and environmental risk factors could cause developmental processes to go awry, thereby fostering mental health issues, of which childhood and adolescence is a particular sensitive period. Intracortial myelination is one such candidate process. In youth, increasing levels of myelin induce what appears as “brain illumination”, or an increase in the intensity of T1 weighted magnetic resonance image. There are newer microstructural MRI measures that are based on this intensity variation, but unfortunately there is a near a complete lack of highly powered developmental studies that employ these measures.

The current thesis is an exploration of typical cerebral cortical development, through the intensity contrast measures grey/white contrast (GWC) and T1w/T2w ratio. The relationship between these cortical patterns and cognitive abilities is also central for the current thesis, as well as using these patterns as a standard, in the search for spatiotemporal patterns associated with emerging psychopathology. This exploration was done within large typically developing- and population based youth samples including very young children. Moreover, the current thesis uses, for the first time, data-driven GWC decomposition, and multimodal morphometric and GWC fusion, in addition to the more conventional vertex-wise assessments of T1w/T2w ratio.

By integrating three papers, the current thesis will present and discuss three main findings. For the first time it will be presented that in development, higher age is associated with globally lower GWC. A specific regional bi-directional associations will also be presented, that beyond the global finding, possibly reflect protracted and accelerated development, which in sum indeed spatiotemporally converges with the protracted process of intracortical myelination. Using a larger developmental sample with a lower age range, co-authors of the paper II and I, also replicate prior reports of almost globally higher T1w/T2w ratio with higher age, now covering a larger portion of the cortex. We also report a negative association between T1w/T2w ratio and cognitive abilities, which could possibly indicate that excess levels of intracortical myelin beyond a certain developmental norm is disadvantageous. The current thesis will also present and discuss the findings that clinical components capturing anxiety and prodromal psychosis are associated with highly overlapping regional GWC.

While performing research for the current thesis, I encountered several methodological challenges that will be thoroughly highlighted. Including studying development with a cross sectional design, MRI acquisition and analytical youth-related issues, and the close relationship with the developmental age range and cognitive abilities. Other central challenges included interpreting the GWC and T1w/T2w ratio results in a biologically meaningful way.

The current thesis conclude that GWC and T1w/T2w ratio shows a biologically relevant signal that is sensitive to individual differences in age-, cognitive abilities- and levels of symptoms of psychopathology. Future highly powered longitudinal studies are needed to replicate the findings within the current thesis, and studies are also urgently needed to give a better understanding of the biological underpinnings of intensity contrast measures as they are currently highly debated.