Sex-Specific Pharmacotherapy for Back Pain: A Proof-of-Concept Randomized Trial.

BACKGROUND: Preventing transition to chronic back pain (CBP) is a long-sought strategy that could rescue patients from prolonged suffering. Recent rodent and human brain imaging studies suggest involvement of sexually dimorphic, dopaminergic-motivational, mesolimbic circuits in the transition to chronic pain (tCBP), and hint that the combination of carbidopa/levodopa and naproxen (LDP + NPX) may block tCBP. Here we evaluated, in people with recent-onset back pain, whether a 3-month treatment with LDP + NPX is safe, blocks tCBP, and whether its efficacy is sex-dependent. METHODS: A total of 72 participants were enrolled and stratified by risk for tCBP using brain-imaging biomarkers. Low-risk participants entered a no-treatment arm. Others were randomized to placebo + naproxen or LDP + NPX for 3 months. RESULTS: Both treatments resulted in more than 50% pain relief for approximately 75% of participants. A strong sex by treatment interaction was observed for daily pain intensity (phone NRS, P = 0.007), replicated on 4-week average pain (Pain/4w, P = 0.00001), and in intent-to-treat analysis (Pain/4w, P = 0.000004). Nucleus accumbens functional connectivity with medial prefrontal cortex, a predefined objective biomarker, showed sex dependence at baseline (P = 0.03) and sex-by-treatment interaction effect 3 months after treatment cessation (P = 0.031). Treatment modified the psychological profile of participants, and disrupted brain modeling-based predicted back pain intensity trajectories. Forty participants were queried 3.3 years from trial start; back pain ratings were similar between end of treatment and at 3.3 years (P = 0.62), indicating persistence of relief for this duration. CONCLUSIONS: These results provide the first evidence for preventing transition to chronic back pain using sex-specific pharmacotherapy. These provocative observations require confirmation in a larger study. ClinicalTrials.gov identifier: NCT01951105.

BOLD temporal variability differentiates wakefulness from anesthesia-induced unconsciousness.

Even though a number of findings, based on information content or information integration, are shown to define neural underpinnings characteristic of a conscious experience, the neurophysiological mechanism of consciousness is still poorly understood. Here, we investigated the brain activity and functional connectivity changes that occur in the isoflurane-anesthetized unconscious state in contrast to the awake state in rats (awake and/or anesthetized, n = 68 rats). We examined nine information measures previously shown to distinguish between conscious states: blood oxygen level-dependent (BOLD) variability, functional connectivity strength, modularity, weighted modularity, efficiency, clustering coefficient, small-worldness, and spatial and temporal Lempel-Ziv complexity measure. We also identified modular membership, seed-based network connectivity, and absolute and normalized power spectrums to assess the integrity of the BOLD functional networks between awake and anesthesia. fMRI BOLD variability and related absolute power were the only information measures significantly higher during the awake state compared with isoflurane anesthesia across animals, and with varying levels of anesthesia, after correcting for motion and respiration confounds. Thus, we conclude that, at least under the specific conditions examined here, global measures of information integration/sharing do not properly distinguish the anesthetized state from wakefulness, and heightened overall, global and local, BOLD variability is the most reliable determinant of conscious brain activity relative to isoflurane anesthesia. NEW & NOTEWORTHY Multiple metrics previously suggested to be able to distinguish between states of consciousness were compared, within and across rats in awake and isoflurane anesthesia-induced unconsciousness. All measures tested showed sensitivity to confounds, correcting for motion and for respiration changes due to anesthesia. Resting state local BOLD variability and the related absolute power were the only information measures that robustly differentiated wakefulness states. These results caution against the general applicability of global information measures in identifying levels of consciousness, thus challenging the popular concept that these measures reflect states of consciousness, and also pointing to local signal variability as a more reliable indicator of states of wakefulness.

Identifying brain nociceptive information transmission in patients with chronic somatic pain.

INTRODUCTION: Recent advances regarding mechanisms of chronic pain emphasize the role of corticolimbic circuitry in predicting risk for chronic pain, independently from site of injury-related parameters. These results compel revisiting the role of peripheral nociceptive signaling in chronic pain. We address this issue by examining what brain circuitry transmit information regarding the intensity of chronic pain and how this information may be related to a common co-morbidity, depression. METHODS: Resting state functional MRI was used in a large group of chronic pain patients (n=40 chronic back pain, CBP, and n=44 osteoarthritis, OA patients), and in comparison to healthy subjects (n=88). We used a graph theoretical measure, degree count, to investigate voxel-wise information sharing/transmission in the brain. Degree count, a functional connectivity based measure, identifies the number of voxels functionally connected to every given voxel. Subdividing the chronic pain cohort into discovery, replication, and also for overall group we show that only degree counts of diencephalic voxels centered in the ventral lateral thalamus reflected intensity of chronic pain, independently of depression. RESULTS: Pain intensity was reliably associated with degree count of the thalamus, which was correlated negatively with components of the default mode network and positively with the periaqueductal grey (in contrast to healthy controls). Depression scores were not reliably associated with regional degree count. CONCLUSION: Collectively the results suggest that, across two types of chronic pain, nociceptive specific information is relayed through the spinothalamic pathway to the lateral thalamus, potentiated by pro-nociceptive descending modulation, and interrupting cortical cognitive processes.