Beyond imaging of only synaptic dopamine transmission – longitudinal multimodal MRI imaging of dopamine system structure, connectivity, and metabolism from psychosis to psychotic remission in schizophrenia

• Applicants: Felix Brandl, Ph.D.; Privatdozent Dr. Christian Sorg
• Subject Area: Biological Psychiatry
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 550468338

Beyond mostly stable or slowly increasing negative and cognitive symptoms, schizophrenia is characterized by fluctuating psychotic symptoms. The dopamine hypothesis of psychosis in schizophrenia suggests that an impaired dopamine system underlies psychotic episodes, likewise with a fluctuating course. However, in-vivo evidence for an aberrant dopamine system in schizophrenia is limited to aberrant synaptic dopamine transmission as indexed by molecular imaging, for example 18F-DOPA-PET, which is largely restricted to measuring synaptic processes of dopamine transmission, but ignores other aspects of the dopamine system addressable by advanced MRI techniques. Therefore, this proposal is about the longitudinal assessment of patients with schizophrenia and healthy controls with dopamine system-focused MRI investigating non-synaptic-transmission-focused aspects of the dopamine system. It addresses three questions: (i) Are dopaminergic nucleus- and axon-focused MRI measures changed in patients with schizophrenia? Additionally, do potential changes correlate with striatal dopamine synthesis and storage (DSS) - the most consistent direct in-vivo evidence for impairments of dopaminergic transmission in schizophrenia - based on 18F-DOPA PET, which will be acquired in a subgroup of subjects? (ii) Do changes in dopaminergic nucleus- and axon-focused MRI measures vary longitudinally as a function of disease state? I.e., do they fluctuate between phases with marked psychotic symptoms and phases of psychotic remission? (iii) Are changes in dopaminergic nucleus- and axon-focused MRI measures linked with symptoms, particularly positive/psychotic symptoms? Ad (i): We focus on dopaminergic nucleus-focused and dopaminergic axon-focused MRI sequences. Regarding dopaminergic nucleus-focused MRI sequences, we focus on morphometry of T1w-MRI assessing volume and macrostructure of nuclei, neuromelanin MRI assessing long-term dopamine metabolism and function, and quantitative susceptibility mapping assessing dopamine-related iron content and metabolic integrity. Regarding dopaminergic axon-focused MRI sequences, we focus on diffusion MRI assessing structural tract-based connectivity, myelin MRI and biophysical modelling-based diffusion MRI assessing tract-based microstructure, resting-state functional MRI assessing blood oxygenation correlations (functional connectivity), and corresponding structure-function coupling of connectivity. Connectivity will be assessed between midbrain dopaminergic nuclei and primarily the striatum (the region with the densest dopaminergic projections) and secondarily the prefrontal cortex and certain thalamic nuclei. Ad (ii) and (iii): Previous evidence suggests that (dorsal) striatal DSS is, first, increased during psychosis and decreased during psychotic remission and, second, and associated with positive symptoms. We will test whether the same applies for dopamine system-focused MRI measures.

• DFG Programme: Research Grants