A surgery-informed precision approach to determining brain targets for real-time fMRI neurofeedback modulation in chronic pain

ObjectiveDespite the promising results of neurofeedback with real-time functional magnetic resonance imaging (rt-fMRI-NF) in the treatment of various psychiatric and neurological disorders, few studies have investigated its effects in acute and chronic pain and with mixed results. The lack of clear neuromodulation targets, rooted in the still poorly understood neurophysiopathology of chronic pain, has probably contributed to these inconsistent findings. In contrast, functional neurosurgery (funcSurg) approaches targeting specific brain regions have been shown to reduce pain in a considerable number of patients with chronic pain, however, their invasiveness limits their use to patients in critical situations. In this work, we sought to redefine, in an unbiased manner, rt-fMRI-NF future targets informed by the long tradition of funcSurg approaches. Methodsusing independent systematic reviews, we identified the targets of the rt-fMRI-NF (in acute and chronic pain) and funcSurg (in chronic pain) studies and characterized their underlying functional networks using a subset of high spatial resolution resting-state fMRI data (7T MRI data from the Human Connectome Project). After applying principal component analysis to reduce the number of identified networks, we performed a quantitative functional and anatomical annotation of these networks with a large-scale meta-analytic approach. Finally, we characterized the functional networks, defining their degree of overlap with canonical intrinsic brain networks (default mode, salience, and somatosensory) and their neurotransmitter profile. ResultsAs expected, the rt-fMRI-NF and funcSurg targets were different, except for the middle cingulate cortex, and showed different characteristics in terms of their functional connectivity. Our findings indicate that targets of rt-fMRI-NF primarily encompass hubs within the default mode network and, to a lesser extent, within the salience network. In contrast, funcSurg targets predominantly involve hubs within the sensorimotor system (primarily the motor system), with less robust involvement of the salience network. Notably, 3 out of 4 derived funcSurg rs-fMRI networks correlated significantly with the distribution map of noradrenaline transporters, further supporting the functional relevance of the funcSurg networks as targets for the treatment of chronic pain. ConclusionKey hubs of the sensorimotor networks, in particular the motor system, may represent promising targets for the therapeutic application of rt-fMRI-NF in chronic pain in particular in neuropathic pain patients. Our results also suggest that the antinociceptive effects of the funcSurg approaches could be, at least partially, linked to the restoration of abnormal noradrenergic system activation.