Molecular imaging to quantify neuromodulation of the medial prefrontal cortex in the rat

Datum: 2 mei 2016

Locatie: UAntwerp - Campus Drie Eiken - Building Q - Promotiezaal - Universiteitsplein 1 - 2610 WILRIJK

Tijdstip: 18 uur

Organisatie / co-organisatie: Faculty of Medicine and Health Sciences

Promovendus: Joke Parthoens

Promotor: Prof S. Staelens & Prof J. Verhaeghe

Korte beschrijving: PhD defence Joke Parthoens, Faculty of Medicine and Health Sciences



Abstract

Repetitive Transcranial Magnetic Stimulation (rTMS) of the dorsolateral Prefrontal Cortex (dlPFC) is a non-invasive neurostimulation technique that is used for the treatment of depression. In combination with PET, rTMS-induced changes in neuronal activity can be visualized. Our aims were to develop a miniaturized rat TMS coil to stimulate the medial prefrontal cortex (mPFC), the dlPFC analogue, and to validate rTMS with small animal PET (µPET). The ability of [18F]-FDG-µPET to quantify the effects of mPFC neurostimulation was first demonstrated for two focal but invasive neurostimulation techniques: intracranial microinjections of a GABAA agonist (muscimol) or antagonist (bicuculline) and Deep Brain Stimulation (DBS) at 60 Hz and 130 Hz.

Bicuculline induced widespread hypermetabolism, mainly in the target region and connected regions. Muscimol caused hypometabolism in the mPFC and cingulate cortex. This suggests an effect due to different dosing or that neuronal excitation spreads easier. DBS elicited hypo-and hypermetabolism at both frequencies. In the mPFC significant hypermetabolism was induced by 60Hz and hypometabolism by 130Hz (non-significant), suggesting the potential of 60Hz prefrontal DBS for the treatment of disorders associated with prefrontal hypofunction, such as depression and addiction. For subthreshold rTMS of the mPFC a miniaturized figure-of-eight coil was developped. Hypermetabolism was induced in the hippocampus by both frequencies (1Hz and 50Hz) and in the entorhinal cortex by 50Hz, demonstrating that these regions have the lowest stimulation threshold. For high-intensity rTMS, a liquid cooled circular rat coil was developed. Computer simulations revealed a ring-shaped E-field with intensities above 100V/m in the brain. MEP measurements showed motor thresholds at an average intensity of 27% of the machine output (MO), which could not be elicited unilaterally because of the lack of focality of stiumulation. At 27%MO continuous rTMS could be delivered at 1Hz and 272 pulses at 10-50Hz. Repetitive TMS at 1Hz, 10Hz and 50Hz combined with [18F]-FDG-µPET revealed that all frequencies induced hypometabolism in dorsal regions underneath the coil windings and hypermetabolism in the entorhinal cortex. These results demonstrate that the coil is able to stimulate at high intensities, but that new coil designs are needed to increase stimulation focality.