Dynamic changes of the structural and functional brain connectome in anorexia nervosa (revision)

• Applicant: Professor Stefan Ehrlich, Ph.D.
• Subject Area: Clinical Psychiatry, Psychotherapy, Child and Adolescent Psychiatry ; Biological Psychiatry
• Term: from 2017 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 320247098

Anorexia nervosa (AN) is a life-threatening eating disorder characterized by severe emaciation. In acute AN (acAN), reduction of brain mass is often readily visible in brain scans and several structural magnetic resonance imaging (sMRI) studies (including our own) have documented massive but reversible decreases in gray matter (GM) volume and thickness. These processes, which are accompanied by dramatic hormonal and metabolic changes are incredibly dynamic and unparalleled in psychiatry. Therefore, AN may be a valuable model disorder to study the brain's plasticity, i.e. changes in structural and functional neural connections (i.e. the connectome). Insights will contribute to the understanding of basic neural mechanisms and shed light on this enigmatic illness.The biological mechanisms underlying these (pseudo-)atrophic changes in AN remain elusive. For example, it is unclear whether they may be related to changes in white matter (WM), changes in the functional connectome (correlations between regional brain signal fluctuations measured using functional MRI (fMRI)) and how they might be linked to known cognitive impairments, clinical symptoms and weight restoration. We seek to elucidate (1) the specific patterns of structural brain alterations, specifically WM integrity and connectivity changes, associated with acAN using a combination of sMRI, diffusion tensor imaging (DTI) and modern mathematical and network theory analysis approaches. Critically, by following patients longitudinally during weight restoration therapy, we will assess the speed and degree of normalization. Second, we aim (2) to characterize changes in the functional connectome using highly time-resolved fMRI sequences to study static and dynamic resting state connectivity (i.e. the "chronnectome"). Ultimately, we aim (3) to understand the biological mechanisms underlying changes in the structural and functional brain connectome in the different states of AN. Using new myelin-sensitive MR sequences (mcDESPOT, quantitative T1 mapping) in addition to DTI and cross-modal analysis, we will study associations between GM- and WM-connectivity as well as local myelin changes more directly. We will also examine whether structural anomalies or changes of local fMRI signal patterns (e.g. amplitude of frequency fluctuations) are associated with abnormal static/dynamic functional connectivity and the changing hormonal parameters. Modern bioinformatics modelling techniques will reveal interdependencies between hormones and connectome characteristics and will identify predictors of weight gain and improvements in cognitive functioning. Using state of the art neuroimaging methodologies to triangulate the mechanisms underlying changes in the structural and functional connectome in AN will inform us not only about basic principles of the brain including how it is affected by energy depletion/repletion, but also has potential of revealing new targets for the development of better treatments for AN.

• DFG Programme: Research Grants