Effect of a Biopsychosocial Intervention or Postural Therapy on Disability and Health Care Spending Among Patients With Acute and Subacute Spine Pain: The SPINE CARE Randomized Clinical Trial.

Importance: Low back and neck pain are often self-limited, but health care spending remains high. Objective: To evaluate the effects of 2 interventions that emphasize noninvasive care for spine pain. Design, Setting, and Participants: Pragmatic, cluster, randomized clinical trial conducted at 33 centers in the US that enrolled 2971 participants with neck or back pain of 3 months' duration or less (enrollment, June 2017 to March 2020; final follow-up, March 2021). Interventions: Participants were randomized at the clinic-level to (1) usual care (n = 992); (2) a risk-stratified, multidisciplinary intervention (the identify, coordinate, and enhance [ICE] care model that combines physical therapy, health coach counseling, and consultation from a specialist in pain medicine or rehabilitation) (n = 829); or (3) individualized postural therapy (IPT), a postural therapy approach that combines physical therapy with building self-efficacy and self-management (n = 1150). Main Outcomes and Measures: The primary outcomes were change in Oswestry Disability Index (ODI) score at 3 months (range, 0 [best] to 100 [worst]; minimal clinically important difference, 6) and spine-related health care spending at 1 year. A 2-sided significance threshold of .025 was used to define statistical significance. Results: Among 2971 participants randomized (mean age, 51.7 years; 1792 women [60.3%]), 2733 (92%) finished the trial. Between baseline and 3-month follow-up, mean ODI scores changed from 31.2 to 15.4 for ICE, from 29.3 to 15.4 for IPT, and from 28.9 to 19.5 for usual care. At 3-month follow-up, absolute differences compared with usual care were -5.8 (95% CI, -7.7 to -3.9; P < .001) for ICE and -4.3 (95% CI, -5.9 to -2.6; P < .001) for IPT. Mean 12-month spending was $1448, $2528, and $1587 in the ICE, IPT, and usual care groups, respectively. Differences in spending compared with usual care were -$139 (risk ratio, 0.93 [95% CI, 0.87 to 0.997]; P = .04) for ICE and $941 (risk ratio, 1.40 [95% CI, 1.35 to 1.45]; P < .001) for IPT. Conclusions and Relevance: Among patients with acute or subacute spine pain, a multidisciplinary biopsychosocial intervention or an individualized postural therapy intervention, each compared with usual care, resulted in small but statistically significant reductions in pain-related disability at 3 months. However, compared with usual care, the biopsychosocial intervention resulted in no significant difference in spine-related health care spending and the postural therapy intervention resulted in significantly greater spine-related health care spending at 1 year. Trial Registration: ClinicalTrials.gov Identifier: NCT03083886.

Cognition-Enhancing Vagus Nerve Stimulation Alters the Epigenetic Landscape.

Vagus nerve stimulation (VNS) has been shown to enhance learning and memory, yet the mechanisms behind these enhancements are unknown. Here, we present evidence that epigenetic modulation underlies VNS-induced improvements in cognition. We show that VNS enhances novelty preference (NP); alters the hippocampal, cortical, and blood epigenetic transcriptomes; and epigenetically modulates neuronal plasticity and stress-response signaling genes in male Sprague Dawley rats. Brain-behavior analysis revealed structure-specific relationships between NP test performance (NPTP) and epigenetic alterations. In the hippocampus, NPTP correlated with decreased histone deacetylase 11 (HDAC11), a transcriptional repressor enriched in CA1 cells important for memory consolidation. In the cortex, the immediate early gene (IEG) ARC was increased in VNS rats and correlated with transcription of plasticity genes and epigenetic regulators, including HDAC3. For rats engaged in NPTP, ARC correlated with performance. Interestingly, blood ARC transcripts decreased in VNS rats performing NPTP, but increased in VNS-only rats. Because DNA double-strand breaks (DSBs) facilitate transcription of IEGs, we investigated phosphorylated H2A.X (γH2A.X), a histone modification known to colocalize with DSBs. In agreement with reduced cortical stress-response transcription factor NF-κB1, chromatin immunoprecipitation revealed reduced γH2A.X in the ARC promoter. Surprisingly, VNS did not significantly reduce transcription of cortical or hippocampal proinflammatory cytokines. However, TNFRSF11B (osteoprotegerin) correlated with NPTP as well as plasticity, stress-response signaling, and epigenetic regulation transcripts in both hippocampus and cortex. Together, our findings provide the first evidence that VNS induces widespread changes in the cognitive epigenetic landscape and specifically affects epigenetic modulators associated with NPTP, stress-response signaling, memory consolidation, and cortical neural remodeling.SIGNIFICANCE STATEMENT Recent studies have implicated vagus nerve stimulation (VNS) in enhanced learning and memory. However, whereas epigenetic modifications are known to play an important role in memory, the particular mechanisms involved in VNS-enhanced cognition are unknown. In this study, we examined brain and behavior changes in VNS and sham rats performing a multiday novelty preference (NP) task. We found that VNS activated specific histone modifications and DNA methylation changes at important stress-response signaling and plasticity genes. Both cortical and hippocampal plasticity changes were predictive of NP test performance. Our results reveal important epigenetic alterations associated with VNS cognitive improvements, as well as new potential pharmacological targets for enhancing cortical and hippocampal plasticity.