Monitoring Pharmacological Manipulations in the Brain by fMRI in Combination with Neurochemistry and Electrophysiology: Setting the Technical Prerequisites for the Use of fMRI in Drug Screening and Diagnostics

In the drug development of neurological disorders and in the early diagnostic of such diseases fMRI can become a powerful tool due to its non-invasiveness. However the systematic use of this method needs a deeper understanding of the nature of the measured BOLD signal. The BOLD signal is not a direct measure of neuronal activation but relies on a cascade of metabolic and vascular responses generated by the energy demands of activated cells. We perform pharmacological manipulations to target single steps in this cascade and study the underlying mechanisms of neurovascular coupling. To correctly interpret drug induced BOLD fMRI changes we need corroborating evidence: In parallel to the BOLD fMRI studies we use electrophysiological measurements to define the underlying neuronal activity and neurochemical analysis to define the neurotransmitters or metabolites responsible for changes in the BOLD and electrophysiological signal. The correlation of these different signals and the drug induced changes thereof give further insights into the underlying mechanisms of neurovascular coupling and the generation of the BOLD signal. In our preliminary studies we set the technical prerequisites for a combined and parallel use of fMRI, EEG and systemic neurochemistry for drug screening and diagnostics in the future. We studied the impact of lidocaine on the electrophysiological signal, BOLD signal and EEG. This manipulation dissociates the BOLD and the EEG signals due to a different impact of neuronal synchrony on those signals. Simultaneous EEG-fMRI is becoming more and more a standard technique in clinics and therefore can have important implications in early diagnostics; our results will help to elucidate the relation and possible dissociations of simultaneous EEG-fMRI data. In addition, we examined the relation of different neurotransmitters and metabolites trough blood brain barrier. To study these relations we used microdialysis in brain and blood followed by neurochemical analyses. In the future these findings will help us to extrapolate brain concentrations of relevant compounds from non-invasively measured blood concentrations. This approach can be applied to study blood brain barrier penetrability parameters of drugs or if neurochemical changes in neurodegenerative diseases are reflected in the blood. Furthermore we can trace even subtle changes of plasma lactate concentrations with an increase of the BOLD signal. This finding indicates that the metabolite lactate plays an important role in the neurovascular coupling cascade: The physiologic formation of lactate during neuronal activation is one of the mechanisms causing the vasodilatation which is responsible for the BOLD effect. On the other hand during neurodegenerative diseases like Alzheimer’s this mechanisms are disrupted. Therefore our lactate challenge might be of diagnostic use having a different impact in healthy subjects versus Alzheimer patients