Dataset Information

Chronic generalized pain disrupts whole brain functional connectivity in mice.

ABSTRACT: Fibromyalgia (FM) is a generalized chronic pain condition whose pathophysiology is poorly understood, and both basic and translational research are needed to advance the field. Here we used the Sluka model to test whether FM-like pain in mice would produce detectable brain modifications using resting-state (rs) functional Magnetic Resonance Imaging (fMRI). Mice received intramuscular acid saline treatment, images were acquired at 7 T 5 days post-treatment, and pain thresholds tested 3 weeks post-scanning. Data-driven Independent Component Analysis revealed significant reduction of functional connectivity (FC) across several component pairs, with major changes for the Retrosplenial cortex (RSP) central to the default mode network, and to a lesser extent the Periaqueductal gray (PAG), a key pain processing area. Seed-to-seed analysis focused on 14 pain-related areas showed strongest FC reduction for RSP with several cortical areas (somatosensory, prefrontal and insular), and for PAG with both cortical (somatosensory) and subcortical (habenula, thalamus, parabrachial nucleus) areas. RSP-PAG FC was also reduced, and this decreased FC tended to be positively correlated with pain levels at individual subject level. Finally, seed-voxelwise analysis focused on PAG confirmed seed-to-seed findings and, also detected reduced PAG FC with the anterior cingulate cortex, increasingly studied in aversive pain effects. In conclusion, FM-like pain triggers FC alterations in the mouse, which are detected by rs-fMRI and are reminiscent of some human findings. The study reveals the causal fingerprint of FM-like pain in rodents, and indicates that both RSP and PAG connectional patterns could be suitable biomarkers, with mechanistic and translational value, for further investigations.

SUBMITTER: Nasseef MT

PROVIDER: S-EPMC8272737 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Previous functional magnetic resonance imaging (fMRI) studies have shown that brain responses to nociceptive pain, non-nociceptive somatosensory, visual, and auditory stimuli are extremely similar. Actually, perception of external sensory stimulation requires complex interactions among distributed cortical and subcortical brain regions. However, the interactions among these regions elicited by nociceptive pain remain unclear, which limits our understanding of mechanisms of pain from a brain network perspective. Task fMRI data were collected with a random sequence of intermixed stimuli of four sensory modalities in 80 healthy subjects. Whole-brain psychophysiological interaction analysis was performed to identify task-modulated functional connectivity (FC) patterns for each modality. Task-modulated FC strength and graph-theoretical-based network properties were compared among the four modalities. Lastly, we performed across-sensory-modality prediction analysis based on the whole-brain task-modulated FC patterns to confirm the specific relationship between brain patterns and sensory modalities. For each sensory modality, task-modulated FC patterns were distributed over widespread brain regions beyond those typically activated or deactivated during the stimulation. As compared with the other three sensory modalities, nociceptive stimulation exhibited significantly different patterns (more widespread and stronger FC within the cingulo-opercular network, between cingulo-opercular and sensorimotor networks, between cingulo-opercular and emotional networks, and between default mode and emotional networks) and global property (smaller modularity). Further, a cross-sensory-modality prediction analysis found that task-modulated FC patterns could predict sensory modality at the subject level successfully. Collectively, these results demonstrated that the whole-brain task-modulated FC is preferentially modulated by pain, thus providing new insights into the neural mechanisms of pain processing.

Project description:Placebo response in the clinical trial setting is poorly understood and alleged to be driven by statistical confounds, and its biological underpinnings are questioned. Here we identified and validated that clinical placebo response is predictable from resting-state functional magnetic-resonance-imaging (fMRI) brain connectivity. This also led to discovering a brain region predicting active drug response and demonstrating the adverse effect of active drug interfering with placebo analgesia. Chronic knee osteoarthritis (OA) pain patients (n = 56) underwent pretreatment brain scans in two clinical trials. Study 1 (n = 17) was a 2-wk single-blinded placebo pill trial. Study 2 (n = 39) was a 3-mo double-blinded randomized trial comparing placebo pill to duloxetine. Study 3, which was conducted in additional knee OA pain patients (n = 42), was observational. fMRI-derived brain connectivity maps in study 1 were contrasted between placebo responders and nonresponders and compared to healthy controls (n = 20). Study 2 validated the primary biomarker and identified a brain region predicting drug response. In both studies, approximately half of the participants exhibited analgesia with placebo treatment. In study 1, right midfrontal gyrus connectivity best identified placebo responders. In study 2, the same measure identified placebo responders (95% correct) and predicted the magnitude of placebo's effectiveness. By subtracting away linearly modeled placebo analgesia from duloxetine response, we uncovered in 6/19 participants a tendency of duloxetine enhancing predicted placebo response, while in another 6/19, we uncovered a tendency for duloxetine to diminish it. Moreover, the approach led to discovering that right parahippocampus gyrus connectivity predicts drug analgesia after correcting for modeled placebo-related analgesia. Our evidence is consistent with clinical placebo response having biological underpinnings and shows that the method can also reveal that active treatment in some patients diminishes modeled placebo-related analgesia. Trial Registration ClinicalTrials.gov NCT02903238 ClinicalTrials.gov NCT01558700.

Dataset Information

Chronic generalized pain disrupts whole brain functional connectivity in mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets