Physical Model for Investigating Intracranial Pressure with Clinical Pressure Sensors and Diagnostic Ultrasound: Preliminary Results.

INTRODUCTION: Intracranial pressure (ICP) is a commonly collected neurocritical parameter, but accurate signal modelling remains challenging. The goal of this project was to mimic clinical ICP waveforms using a physical model. MATERIALS AND METHODS: A physical head model was developed. The skull was segmented from a head computed tomography (CT) scan, remodelled, 3D-printed, and filled with a brain tissue mimicking material and a pressure generator. Pressure measurements and tissue displacement around an attached pressure sensor were explored. RESULTS: Analysis of the measured pressure demonstrated that the waveform did not perfectly resemble that of the clinical ICP. Through iterative improvements and using a revised second pressure generator, subpeaks could be seen in the waveform. A speckle image recorded using ultrasound during pressure application enabled visualization of tissue displacement around the pressure sensor. Comparison with measured ICP signals revealed that minuscule patterns were not distinct in the displacement images. DISCUSSION: We present the first steps towards mimicking clinical ICP using a physical head phantom model. The physical model enabled pressure tests and visualization of tissue displacement and will be foundational for further improvements.

The Chemogenetic Receptor Ligand Clozapine N-Oxide Induces in vivo Neuroreceptor Occupancy and Reduces Striatal Glutamate Levels.

Chemogenetic studies with the ligand clozapine N-oxide (CNO) are predicated upon the assumption that CNO is devoid of actions at natural neuroreceptors. However, recent evidence shows that CNO may be converted back to clozapine (CLZ) in vivo, which could yield plasma concentrations that may be sufficient to occupy inter alia dopamine D2/3 and serotonin 5HT2A receptors in living brain. To test this phenomenon, we measured striatal dopamine D2/3 receptor occupancy with [18F]fallypride PET and serotonin 5HT2A occupancy ex vivo using [18F]MH.MZ. We found a CNO dose-dependent effect on the availability of both neuroreceptor sites. In parallel MR spectroscopy experiments, we found that CNO reduced creatine + phosphcreatine (Cr+PCr) and increased N-acetylaspartate + N-acetylaspartylglutamate (NAA+NAAG) signals in the prefrontal cortex, and also reduced the glutamate signal in dorsal striatum, with peak effect at 2 mg/kg. Thus, our findings suggest that conversion of CNO to CLZ in living rats imparts significant occupancy at endogenous neuroreceptors and significant changes to neurometabolite levels.