Prospective Administration of Anti-NGF Treatment Effectively Suppresses Functional Connectivity Alterations Following Cancer-Induced Bone Pain in Mice

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. While 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 fMRI 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 as well as 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 following persistent nociceptive input from cancer-induced bone pain. Additionally, it highlights the suitability of resting-state fMRI readouts as an indicator of treatment response on the basis of longitudinal functional network changes

Closed-loop cavitation control for focused ultrasound-mediated blood-brain-barrier opening by long-circulating microbubbles

Focused ultrasound (FUS) exposure in the presence of microbubbles (MBs) has been successfully used in the delivery of various sizes of therapeutic molecules across the blood-brain barrier (BBB). While acoustic pressure is correlated with the BBB opening size, real-time control of BBB opening to avoid vascular and neural damage is still a challenge. This arises mainly from the variability of FUS-MB interactions due to the variations of animal-specific metabolic environment and specific experimental setup. In this study, we demonstrate a closed-loop cavitation control framework to induce BBB opening for delivering large therapeutic molecules without causing macro tissue damages. To this end, we performed in mice long-term (5 min) cavitation monitoring facilitated by using long-circulating MBs. Monitoring the long-term temporal kinetics of the MBs under varying level of FUS pressure allowed to identify in-situ, animal specific activity regimes forming a pressure-dependent activity bands. This enables to determine the boundaries of each activity band (i.e. steady oscillation, transition, inertial cavitation) independent from the physical and physiological dynamics of the experiment. However, such a calibration approach is time consuming and to speed up characterization of the in-situ, animal specific FUS-MB dynamics, we tested a novel method called "pre-calibration" that closely reproduces the results of long-term monitoring but with a much shorter duration. Once the activity bands are determined from the pre-calibration method, an operation band can be selected around the desired cavitation dose. To drive cavitation in the selected operation band, we developed an adaptive, closed-loop controller that updates the acoustic pressure between each sonication based on measured cavitation dose. Finally, we quantitatively assessed the safety of different activity bands and validated the proposed methods and controller framework. The proposed framework serves to optimize the FUS pressure instantly to maintain the targete

A consensus protocol for functional connectivity analysis in the rat brain

International audienc