| dc.description.abstract |
The brain is one of the body’s most multifaceted and complex organs, its function still being incompletely understood. The development of imaging methods has massively benefitted the research of brain function in recent years, enabling the in vivo monitoring of brain function on different physiological, spatial and temporal levels. Brain imaging can be used to delineate effects ranging from task-based stimuli to drugs and pathologies on brain activation and connectivity. However, all imaging methods have specific caveats and can only provide readout on one single physiological level, which may be insufficient for various applications.
This work aimed to elucidate the complementary value positron emission tomography (PET) provides when acquired simultaneously to blood-oxygenation-level-dependent functional magnetic resonance imaging (BOLD-fMRI). Specifically, the readout generated using PET was used to delineate metabolic and molecular substrates of both neuronal activation and resting-state functional connectivity (rsFC) derived using BOLD-fMRI.
In the first study, rsFC derived from BOLD-fMRI and simultaneously acquired [18F]fluorodeoxyglucose ([18F]FDG) PET was compared on whole-brain and resting-state
network (RSN) levels. While BOLD-fMRI is considered gold standard and is most widely
used for the acquisition of rsFC, the generated readouts with this method suffer from the
convoluted nature of the BOLD signal and its indirect reflection of neuronal activity.
Calculating connectivity from [18F]FDG PET may serve to validate but also complement
readout generated from BOLD-fMRI. The data indicated similar organizations of the
connectomes acquired using the two techniques, but only moderate correlations and overlaps at whole-brain and network levels between both outputs. Three common networks and several modality-specific networks were identified. The mismatch between the results indicates functional connectivity acquired using [18F]FDG PET may offer significant complementary information and warrants further research into its substrate and physiological significance.
In the second study, the correlations between different distributions of D2 receptors (D2R)
and serotonin transporters (SERT), on one side, and three prominent RSNs, on the other, were investigated. Although monoaminergic systems are postulated to be of paramount importance for brain function and dysfunction, their relation to RSNs is poorly elucidated. The study revealed that D2R and SERT availabilities in two prominent dopaminergic and serotonergic projection areas, the striatum and medial prefrontal cortex, correlated in differentiated manners with the default-mode network (DMN), sensorimotor network (SMN) and salience network (SN). Specifically, the data showed strong negative correlation between striatal D2R availability and rsFC across all three RSNs. Additionally, prefrontal SERT correlated with prefrontal rsFC but negatively with rsFC across the rest of the networks and regions investigated. The generated data shed additional light into interactions between monoamines and RSNs and complement hypotheses regarding monoaminergic contributions to various pathologies, including Parkinson’s disease, major depressive disorder, schizophrenia and bipolar disorder.
The third study aimed to delineate the acute effects of methylenedioxymethamphetamine
(MDMA) on hemodynamics, metabolism and SERT availability, one of the main targets of
this compound. Along with other psychedelic compounds, MDMA has received significant
interest over the last decade due to its potential in the treatment of psychiatric disorders, such as major depressive disorder or post-traumatic stress disorder. To this extent, imaging studies have been previously performed to elucidate the mechanisms of action of MDMA and other psychedelics. However, most studies relied on hemodynamic MRI-based methods to detectneuronal activations or deactivations induced by acute administration of these compounds. The readout in this work mirrors decreases in BOLD signal reported previously in human studies. However, the global BOLD decreases were accompanied by increases in glucose consumption shown by simultaneously acquired [18F]FDG PET data. Additionally, comparable BOLD signal decreases were seen in extracerebral regions. The data indicateglobal hemodynamic suppression of non-neuronal nature, accompanied by neuronal activation induced by MDMA. In the brain, the BOLD decreases correlated with the magnitudes of changes in SERT occupancy, hinting towards additional local vascular effects induced by SERT blockage. The study indicated that hemodynamic decreases observed after MDMA administration do not map onto neuronal activity, but are probably induced by the vascular effects of endogenous serotonin or direct effects of MDMA on vascular serotonin receptors. The readout therefore puts into perspective and warrants a reevaluation of most studies investigating the effects of psychedelic drugs on neuronal activity through indirect hemodynamic effects.
The strongly complementary readouts of both modalities used in this work recommend further use of PET/MRI to study brain function at rest and under activation. Elucidating the intricate connections between neurotransmitter systems, hemodynamics, metabolism and large-scale functional networks will help to more thoroughly understand in vivo brain function and dysfunction, thereby supporting the targeted development of diagnostic and therapeutic strategies. |
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