Simultaneous fPET/fMRI unveils nigrostriatal pathway mechanisms during optogenetic stimulation.
Poster No:
2397
Submission Type:
Abstract Submission
Authors:
Fernando Bravo1, Sabrina Haas2, Tudor Ionescu2, Irene Gonzalez-Menendez2, Leticia Quintanilla-Martinez1, Gina Dunkel2, Laura Kuebler2, Bettina Weigelin2, Gerald Reischl2, Bernd Pichler2, Kristina Herfert1
Institutions:
1University of Tübingen, Tübingen, Germany, 2University of Tübingen, Tübingen, Germany
First Author:
Co-Author(s):
Introduction:
The dopaminergic system is a unique modulatory component of the brain governing motor behavior, cognition and emotion. It plays a major role in various neurological and psychiatric conditions such as Parkinson's disease and schizophrenia. The nigrostriatal pathway delineates a critical circuit for dopamine projections from the substantia nigra pars compacta (SNc) to the striatum, representing a doorway for understanding many of the disease-related dysfunctions. Stand-alone fMRI is unable to characterize this circuit's interplay between brain activation and its molecular underpinnings. Here, the use of simultaneous [18F]FDG-fPET/BOLD-fMRI allowed us to demonstrate excitation-inhibition mechanisms of the nigrostriatal pathway during optogenetic stimulation, which are concealed in isolated fMRI readouts.
Methods:
fMRI analysis: A block design was employed, modeling each of the six optogenetic stimulation and baseline blocks (Figure 1). Within-group subtractive/functional connectivity analyses were conducted in SPM12.
fPET analysis: To enable functional PET (fPET) (Villien et al., 2014) we employed an [18F]FDG bolus+constant infusion protocol. Without requiring a priori assumptions on the shape of the expected [18F]FDG-fPET response, independent component analysis (ICA) has been successfully applied to [18F]FDG-fPET during task-related designs (Li et al., 2020). We advanced the ICA approach through an automatic kurtosis-sorting of ICA components to isolate task-related signals without priori timing information (Lu & Rajapakse, 2003). ICA and molecular connectivity analyses were implemented with the GIFT v4.0b and CONN v22a toolboxes.
fPET analysis: To enable functional PET (fPET) (Villien et al., 2014) we employed an [18F]FDG bolus+constant infusion protocol. Without requiring a priori assumptions on the shape of the expected [18F]FDG-fPET response, independent component analysis (ICA) has been successfully applied to [18F]FDG-fPET during task-related designs (Li et al., 2020). We advanced the ICA approach through an automatic kurtosis-sorting of ICA components to isolate task-related signals without priori timing information (Lu & Rajapakse, 2003). ICA and molecular connectivity analyses were implemented with the GIFT v4.0b and CONN v22a toolboxes.
·Fig. 1: Time course of simultaneous optogenetic [18F]FDG-fPET/fMRI experiments. (a) Optical stimulation of the right SNc. (b) Control virus expression in the STR and SNc by fluorescence microscopy.
Results:
Comparison of hemodynamic and metabolic responses to stimulation: ICA revealed the optogenetic-stimulation response map as the first kurtosis-ranked component. Results showed significant [18F]FDG uptake in the expected right lateralised brain regions including the SNc, midbrain, thalamus, hypothalamus and striatum. Hemodynamic changes were observed in similar regions; however, important differences were found (Figure 2). BOLD-fMRI activation maps in the striatum showed a larger spatial extension than fPET glucose uptake maps, while the opposite was observed in the SNc. Ex vivo analysis of cFos expression in both corroborated our findings: increased cFos expression levels were evident in the dorsal striatum, but there were no discernible differences in the SNc. This occurred despite a high metabolic response in the SNc, suggesting an active suppression of neuronal firing during optogenetic stimulation. In agreement, metabolic connectivity analyses showed correlated glucose uptake in the right SNc, midbrain, thalamus and striatum; while functional connectivity evidenced BOLD signal interactions circumscribed to the right dorsal-ventral Striatum, supporting an active inhibition of nigrostriatal couplings during neuronal stimulation.
·Fig. 2: Overlay of [18F]FDG-fPET and BOLD-fMRI activation maps. Results threshold: p < unc. 0.001 (voxel-level), p < 0.05 FWE (cluster-level).
Conclusions:
Our study shed new light on the relationship between hemodynamic and metabolic responses during optogenetic stimulation of the dopaminergic pathway. fMRI results revealed a BOLD response which was strongly bound to the right striatum; fPET, on the other side, evidenced a significant [18F]FDG uptake along the entire dopaminergic circuit including the site of stimulation (SNc). The findings emphasize that a decrease or absence of the BOLD signal outside the striatal region does not necessarily correlate with neuronal inactivity. Dopamine release is modulated by numerous neuromodulators. One interpretation posits that optogenetic stimulation triggers the release of dopamine thereby activating dopamine D2 auto- and heteroreceptors and inhibiting further activation-induced dopamine release (Anzalone et al., 2012; Ford, 2014). This feedback control process may curtail the maximum attainable BOLD signal increase during stimulation (Benoit-Marand et al., 2001) and may be important to regulate neurotransmitter levels at the synapse for the effective operation of the dopaminergic system.
Modeling and Analysis Methods:
Activation (eg. BOLD task-fMRI)
Methods Development
PET Modeling and Analysis
Novel Imaging Acquisition Methods:
Multi-Modal Imaging 1
Physiology, Metabolism and Neurotransmission :
Cerebral Metabolism and Hemodynamics 2
Keywords:
Basal Ganglia
FUNCTIONAL MRI
Positron Emission Tomography (PET)
1|2Indicates the priority used for review
Provide references using author date format
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