G protein–coupled receptors (GPCRs), including dopamine receptors, represent a group of important pharmacological targets. An increased formation of dopamine receptor D2 homodimers has been suggested to be associated with the pathophysiology of schizophrenia. Selective labeling and ligand-induced modulation of dimerization may therefore allow the investigation of the pathophysiological role of these dimers. Using TIRF microscopy at the single molecule level, transient formation of homodimers of dopamine receptors in the membrane of stably transfected CHO cells has been observed. The equilibrium between dimers and monomers was modulated by the binding of ligands; whereas antagonists showed a ratio that was identical to that of unliganded receptors, agonist-bound D2 receptor-ligand complexes resulted in an increase in dimerization. Addition of bivalent D2 receptor ligands also resulted in a large increase in D2 receptor dimers. A physical interaction between the protomers was confirmed using high resolution cryogenic localization microscopy, with ca. 9 nm between the centers of mass.

In conventional neuroimaging, cerebrovascular reactivity (CVR) is quantified primarily using the blood-oxygenation level-dependent (BOLD) functional MRI (fMRI) signal, specifically, as the BOLD response to intravascular carbon dioxide (CO 2 ) modulations, in units of [%ΔBOLD/ mmHg]. While this method has achieved wide appeal and clinical translation, the tolerability of CO 2 -related tasks amongst patients and the elderly remains a challenge in more routine and largescale applications. In this work, we propose an improved method to quantify CVR by exploiting intrinsic fluctuations in CO 2 and corresponding changes in the resting-state BOLD signal (rsqCVR). Our rs-qCVR approach requires simultaneous monitoring of PETCO 2 , cardiac pulsation and respiratory volume. In 16 healthy adults, we compare our quantitative CVR estimation technique to the prospective CO 2 -targeting based CVR quantification approach (qCVR, the "standard"). We also compare our rs-CVR to non-quantitative alternatives including the restingstate fluctuation amplitude (RSFA), amplitude of low-frequency fluctuation (ALFF) and globalsignal regression. When all subjects were pooled, only RSFA and ALFF were significantly associated with qCVR. However, for characterizing regional CVR variations within each subject, only the PETCO 2 -based rs-qCVR measure is strongly associated with standard qCVR in 100% of the subjects (p<=0.1). In contrast, for the more qualitative CVR measures, significant withinsubject association with qCVR was only achieved in 50-70% of the subjects. Our work establishes the feasibility of extracting quantitative CVR maps using rs-fMRI, opening the possibility of mapping functional connectivity and qCVR simultaneously.

Measurements of cerebral perfusion using dynamic susceptibility contrast magnetic resonance imaging rely on the assumption of isotropic vascular architecture. However, a considerable fraction of vessels runs in parallel with white matter tracts. Here, we investigate the effects of tissue orientation on dynamic susceptibility contrast magnetic resonance imaging. Tissue orientation was measured using diffusion tensor imaging and dynamic susceptibility contrast was performed with gradient echo planar imaging. Perfusion parameters and the raw dynamic susceptibility contrast signals were correlated with tissue orientation. Additionally, numerical simulations were performed for a range of vascular volumes of both the isotropic vascular bed and anisotropic vessel components, as well as for a range of contrast agent concentrations. The effect of the contrast agent was much larger in white matter tissue perpendicular to the main magnetic field compared to white matter parallel to the main magnetic field. In addition, cerebral blood flow and cerebral blood volume were affected in the same way with angle-dependent variations of up to 130%. Mean transit time and time to maximum of the residual curve exhibited weak orientation dependency of 10%. Numerical simulations agreed with the measured data, showing that one-third of the white matter vascular volume is comprised of vessels running in parallel with the fibre tracts.