Frequency and state-dependent effects of VTA electrical stimulation on whole brain fMRI activity

Abstract

Event Abstract Back to Event Frequency and state-dependent effects of VTA electrical stimulation on whole brain fMRI activity Sjoerd Murris1*, John Arsenault1, 2 and Wim Vanduffel1, 2, 3 1 Department of Neurosciences, KU Leuven, Belgium 2 Athinoula A. Martinos Center for Biomedical Imaging, Harvard Medical School, United States 3 Harvard Medical School, United States The Ventral Tegmental Area (VTA) and neighbouring Substantia Nigra are integral structures at the heart of the dopamine system, underlying adaptive behaviour. Endogenous firing rates of dopamine cells in the VTA vary from fast phasic bursts to slow tonic activity, possibly supporting diverse cognitive functionss1. Artificial perturbations of the VTA through electrical and optogenetic stimulation methods generate different and sometimes even contrasting behavioural outcomes depending on stimulation parameters such as frequency, amplitude and pulse width2–4. Here we investigate the brain-wide functional effects of electrical stimulation frequency (10, 20, 50 and 100 Hz) of the VTA of two rhesus macaques implanted with chronic electrodes5. We stimulated both animals while measuring brain-wide fMRI signal changes during a passive fixation task or under anaesthesia. In the awake state, activity in many cortical and subcortical structures followed an inverted u-shape as a function of stimulation frequency, with highest evoked activity when stimulating at 20 and 50 Hz and less activity at 10 and 100 Hz. In addition, we tested whether the state of the animals had an effect on stimulation-induced network activity by performing the same experiment under ketamine-induced anaesthesia. Under anaesthesia, the hemodynamic responses in connected brain areas were slightly positive at 10Hz stimulation, but became negative and decreased linearly as a function of higher stimulation frequencies. In conclusion, brain wide network effects induced by electrical stimulation of the VTA are to a large degree frequency and state-dependent. The remarkably different stimulation-induced amplitudes and patterns of fMRI activity may explain varying and even opposing behavioural effects observed using Deep Brain Stimulation in patients. In addition, they call for a careful design and interpretation of electrical microstimulation procedures in fundamental research. Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Acknowledgements This work received funding from KU Leuven C14/17/109; Hercules II funds; Fonds Wetenschappelijk Onderzoek-Vlaanderen G0D5817N, G090714N and Odysseus G0007.12; and the European Union's Horizon 2020 Framework Programme for Research and Innovation under Grant Agreement No 785907 (Human Brain Project SGA2).