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Cancer-induced bone pain is abundant among advanced-stage cancer patients and arises from a primary tumor in the bone or skeletal metastasis of common cancer types such as breast, lung, or prostate cancer. Recently, antibodies targeting nerve growth factor (NGF) have been shown to effectively relieve neuropathic and inflammatory pain states in mice and in humans. Although efficacy has been shown in mice on a behavioral level, effectiveness in preventing pain-induced functional rearrangements in the central nervous system has not been shown. Therefore, we assessed longitudinal whole-brain functional connectivity using resting-state functional magnetic resonance imaging in a mouse model of cancer-induced bone pain. We found functional connectivity between major hubs of ascending and descending pain pathways such as the periaqueductal gray, amygdala, thalamus, and cortical somatosensory regions to be affected by a developing cancer pain state. These changes could be successfully prevented through prospective administration of a monoclonal anti-NGF antibody (mAb911). This indicates efficacy of anti-NGF treatment to prevent pain-induced adaptations in brain functional networks after persistent nociceptive input from cancer-induced bone pain. In addition, it highlights the suitability of resting-state functional magnetic resonance imaging readouts as an indicator of treatment response on the basis of longitudinal functional network changes.

Preclinical applications of resting-state functional magnetic resonance imaging (rsfMRI) offer the possibility to non-invasively probe whole-brain network dynamics and to investigate the determinants of altered network signatures observed in human studies. Mouse rsfMRI has been increasingly adopted by numerous laboratories world-wide. Here we describe a multi-centre comparison of 17 mouse rsfMRI datasets via a common image processing and analysis pipeline. Despite prominent cross-laboratory differences in equipment and imaging procedures, we report the reproducible identification of several large-scale resting-state networks (RSN), including a murine default-mode network, in the majority of datasets. A combination of factors was associated with enhanced reproducibility in functional connectivity parameter estimation, including animal handling procedures and equipment performance. Our work describes a set of representative RSNs in the mouse brain and highlights key experimental parameters that can critically guide the design and analysis of future rodent rsfMRI investigations.

The FMT/dFRI protocol presented is able to accurately map physiological processes and poses an attractive alternative to MRI for characterizing tumor neoangiogenesis.

Functional neuroimaging has emerged as attractive option for characterizing pain states complementing behavioral readouts or clinical assessment. In particular, resting-state functional magnetic resonance imaging (rs-fMRI) enables monitoring of functional adaptations across the brain, for example, in response to chronic nociceptive input. We have used rs-fMRI in a mouse model of chronic pain from breast cancer-derived tibial bone metastases to identify pain-induced alterations in functional connectivity. Combined assessment of behavioral readouts allowed for defining a trajectory as model function for extracting pain-specific functional connectivity changes from the fMRI data reflective of a chronic pain state. Cingulate and prefrontal cortices as well as the ventral striatum were identified as predominantly affected regions, in line with findings from clinical and preclinical studies. Inhibition of the peripheral bone remodeling processes by antiosteolytic therapy led to a reduction of pain-induced network alterations, emphasizing the specificity of the functional readouts for a developing chronic pain state.

26Hallucinogenic agents have been proposed as potent antidepressants; this includes the serotonin (5-HT) 27 receptor 2A agonist psilocybin. In human subjects, psilocybin alters functional connectivity (FC) within the 28 default-mode network (DMN), a constellation of inter-connected regions that is involved in self-reference 29 and displays altered FC in depressive disorders. In this study we investigated the effects of psilocybin on 30 FC in the analogue of the DMN in mouse, with a view to establishing an experimental animal model to 31 investigate underlying mechanisms. Psilocybin effects were investigated in lightly-anaesthetized mice using 32 resting-state fMRI. Dual-regression analysis identified reduced FC within the ventral striatum in psilocybin-33 relative to vehicle-treated mice. Refinement of the analysis using spatial references derived from both gene 34 expression maps and viral tracer projection fields revealed two distinct effects of psilocybin: it increased FC 35 between 5-HT-associated networks and elements of the murine DMN, thalamus, and midbrain; it decreased 36 FC within dopamine (DA)-associated striatal networks. These results suggest that interaction between 5-37 HT-and DA-regulated neural networks contributes to the neural and therefore psychological effects of 38 psilocybin. Furthermore, they highlight how information on molecular expression patterns and structural 39 connectivity can assist in the interpretation of pharmaco-fMRI findings.40