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

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

New insights into the dynamic development of the cerebral cortex in childhood and adolescence: Integrating macro- and microstructural MRI findings

Through dynamic transactional processes between genetic and environmental factors, childhood and adolescence involve reorganization and optimization of the cerebral cortex. The cortex and its development plays a crucial role for prototypical human cognitive abilities. At the same time, many common mental disorders appear during these critical phases of neurodevelopment. Magnetic resonance imaging (MRI) can indirectly capture several multifaceted changes of cortical macro- and microstructure, of high relevance to further our understanding of the neural foundation of cognition and mental health. Great progress has been made recently in mapping the typical development of cortical morphology. Moreover, newer less explored MRI signal intensity and specialized quantitative T2 measures have been applied to assess microstructural cortical development. We review recent findings of typical postnatal macro- and microstructural development of the cerebral cortex from early childhood to young adulthood. We cover studies of cortical volume, thickness, area, gyrification, T1-weighted (T1w) tissue contrasts such a grey/white matter contrast, T1w/T2w ratio, magnetization transfer and myelin water fraction. Finally, we integrate imaging studies with cortical gene expression findings to further our understanding of the underlying neurobiology of the developmental changes, bridging the gap between ex vivo histological- and in vivo MRI studies

Maturation of cortical microstructure and cognitive development in childhood and adolescence: A T1w/T2w ratio MRI study

The restructuring and optimization of the cerebral cortex from early childhood and through adolescence is an essential feature of human brain development, underlying immense cognitive improvements. Beyond established morphometric cortical assessments, the T1w/T2w ratio quantifies partly separate biological processes, and might inform models of typical neurocognitive development and developmental psychopathology. In the present study, we computed vertex‐wise T1w/T2w ratio across the cortical surface in 621 youths (3–21 years) sampled from the Pediatric Imaging, Neurocognition, and Genetics (PING) study and tested for associations with individual differences in age, sex, and both general and specific cognitive abilities. The results showed a near global linear age‐related increase in T1w/T2w ratio across the brain surface, with a general posterior to anterior increasing gradient in association strength. Moreover, results indicated that boys in late adolescence had regionally higher T1w/T2w ratio as compared to girls. Across individuals, T1w/T2w ratio was negatively associated with general and several specific cognitive abilities mainly within anterior cortical regions. Our study indicates age‐related differences in T1w/T2w ratio throughout childhood, adolescence, and young adulthood, in line with the known protracted myelination of the cortex. Moreover, the study supports T1w/T2w ratio as a promising surrogate measure of individual differences in intracortical brain structure in neurodevelopment

Probing brain developmental patterns of myelination and associations with psychopathology in youths using gray/white matter contrast

Background: Cerebral myeloarchitecture shows substantial development across childhood and adolescence, and aberrations in these trajectories are relevant for a range of mental disorders. Differential myelination between intracortical and subjacent white matter can be approximated using signal intensities in T1-weighted magnetic resonance imaging. Methods: To test the sensitivity of gray/white matter contrast (GWC) to age and individual differences in psychopathology and general cognitive ability in youths (8–23 years), we formed data-driven psychopathology and cognitive components using a large population-based sample, the Philadelphia Neurodevelopmental Cohort (N = 6487, 52% female). We then tested for associations with regional GWC defined by an independent component analysis in a subsample with available magnetic resonance imaging data (n = 1467, 53% female). Results: The analyses revealed a global GWC component, which showed an age-related decrease from late childhood and across adolescence. In addition, we found regional anatomically meaningful components with differential age associations explaining variance beyond the global component. When accounting for age and sex, both higher symptom levels of anxiety or prodromal psychosis and lower cognitive ability were associated with higher GWC in insula and cingulate cortices and with lower GWC in pre- and postcentral cortices. We also found several additional regional associations with anxiety, prodromal psychosis, and cognitive ability. Conclusions: Independent modes of GWC variation are sensitive to global and regional brain developmental processes, possibly related to differences between intracortical and subjacent white matter myelination, and individual differences in regional GWC are associated with both mental health and general cognitive functioning

Widespread Changes in White Matter Microstructure After a Day of Waking and Sleep Deprivation

Background Elucidating the neurobiological effects of sleep and waking remains an important goal of the neurosciences. Recently, animal studies indicated that sleep is important for cell membrane and myelin maintenance in the brain and that these structures are particularly susceptible to insufficient sleep. Here, we tested the hypothesis that a day of waking and sleep deprivation would be associated with changes in diffusion tensor imaging (DTI) indices of white matter microstructure sensitive to axonal membrane and myelin alterations. Methods Twenty-one healthy adult males underwent DTI in the morning [7:30AM; time point (TP)1], after 14 hours of waking (TP2), and then after another 9 hours of waking (TP3). Whole brain voxel-wise analysis was performed with tract based spatial statistics. Results A day of waking was associated with widespread increases in white matter fractional anisotropy, which were mainly driven by radial diffusivity reductions, and sleep deprivation was associated with widespread fractional anisotropy decreases, which were mainly explained by reductions in axial diffusivity. In addition, larger decreases in axial diffusivity after sleep deprivation were associated with greater sleepiness. All DTI changes remained significant after adjusting for hydration measures. Conclusions This is the first DTI study of sleep deprivation in humans. Although previous studies have observed localized changes in DTI indices of cerebral microstructure over the course of a few hours, further studies are needed to confirm widespread DTI changes within hours of waking and to clarify whether such changes in white matter microstructure serve as neurobiological substrates of sleepiness

Cerebellar Gray Matter Volume Is Associated With Cognitive Function and Psychopathology in Adolescence

Background Accumulating evidence supports cerebellar involvement in mental disorders, such as schizophrenia, bipolar disorder, depression, anxiety disorders, and attention-deficit/hyperactivity disorder. However, little is known about the cerebellum in developmental stages of these disorders. In particular, whether cerebellar morphology is associated with early expression of specific symptom domains remains unclear. Methods We used machine learning to test whether cerebellar morphometric features could robustly predict general cognitive function and psychiatric symptoms in a large and well-characterized developmental community sample centered on adolescence (Philadelphia Neurodevelopmental Cohort, n = 1401, age 8–23 years). Results Cerebellar morphology was associated with both general cognitive function and general psychopathology (mean correlations between predicted and observed values: r = .20 and r = .13; p < .001). Analyses of specific symptom domains revealed significant associations with rates of norm-violating behavior ( r = .17; p < .001) as well as psychosis ( r = .12; p < .001) and anxiety ( r = .09; p = .012) symptoms. In contrast, we observed no associations with attention deficits or depressive, manic, or obsessive-compulsive symptoms. Crucially, across 52 brain-wide anatomical features, cerebellar features emerged as the most important for prediction of general psychopathology, psychotic symptoms, and norm-violating behavior. Moreover, the association between cerebellar volume and psychotic symptoms and, to a lesser extent, norm-violating behavior remained significant when adjusting for several potentially confounding factors. Conclusions The robust associations with psychiatric symptoms in the age range when these typically emerge highlight the cerebellum as a key brain structure in the development of severe mental disorders