{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T07:44:15Z","timestamp":1792395855917,"version":"4.4.0"},"reference-count":85,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T00:00:00Z","timestamp":1788048000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T00:00:00Z","timestamp":1788048000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Brain and Behavior"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>This review systematically elaborates multi\u2010system interactive mechanisms underlying comorbid chronic low back pain (CLBP) and major depressive disorder (MDD), synthesizes recent advances in diagnosis, treatment, and management, and proposes precision medicine directions to address clinical challenges, including missed diagnosis, treatment resistance, and poor prognosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Method<\/jats:title>\n                    <jats:p>We reviewed 86 studies published between 2015 and 2025 from the PubMed, Embase, and CNKI databases. We focused on basic research and clinical trials, integrating multi\u2010omics data to construct mechanistic frameworks and therapeutic evidence.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Result<\/jats:title>\n                    <jats:p>\n                      The comorbid pathogenesis of CLBP and MDD is driven by dysregulation of the \u201cneural\u2013immune\u2013endocrine\u2013gut\u2013brain axis\u201d network. Spinal dorsal horn N\u2010methyl\u2010D\u2010aspartate (NMDA) receptor NR2B phosphorylation amplifies pain signals 2\u2010 to 3\u2010fold, while anterior cingulate cortex (ACC)\u2013insula connectivity correlates positively with depression severity. Microglial toll\u2010like receptor 4\/nuclear factor\u2010\u03baB (TLR4\/NF\u2010\u03baB) activation increases cerebrospinal fluid interleukin\u20106 (IL\u20106) and tumor necrosis factor\u2010\u03b1 (TNF\u2010\u03b1) by 3.2\u2010 and 2.7\u2010fold, respectively. Hypothalamic\u2013pituitary\u2013adrenal (HPA) axis dysfunction causes a flattened cortisol rhythm, with glucocorticoid receptor gene (NR3C1) hypermethylation reducing glucocorticoid sensitivity by 45%. Gut dysbiosis decreases short\u2010chain fatty acids (SCFAs) by 30% and increases plasma lipopolysaccharide (LPS) by 2.3\u2010fold, accompanied by abnormal proliferation of pro\u2010inflammatory\n                      <jats:italic>E. coli<\/jats:italic>\n                      and\n                      <jats:italic>Desulfovibrio<\/jats:italic>\n                      as well as depletion of anti\u2010inflammatory\n                      <jats:italic>Prevotella<\/jats:italic>\n                      . Duloxetine reduces visual analog scale (VAS) pain scores by 40% and Hamilton Depression Rating Scale (HAM\u2010D) scores by 35% relative to placebo. Closed\u2010loop spinal cord stimulation (SCS) improves treatment response rates to 68% compared with open\u2010loop stimulation. Electroacupuncture at BL23\/LR3 alleviates clinical symptoms in 75% of patients relative to sham acupuncture. At the 12\u2010month follow\u2010up, duloxetine's pain relief efficacy slightly declined from 40% to 38%, a phenomenon speculated to be linked to serotonin transporter upregulation. At the 1\u2010year follow\u2010up, closed\u2010loop SCS efficacy decreases to 55%, which may be associated with secondary neural circuit re\u2010remodeling. At the 6\u2010month follow\u2010up, electroacupuncture treatment carries a 22% symptom recurrence rate, which researchers hypothesize arises from secondary gut microbiota re\u2010dysbiosis featuring reduced\n                      <jats:italic>Prevotella<\/jats:italic>\n                      abundance.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Pathological progression of concurrent CLBP and MDD relies on multi\u2010level remodeling of molecular, cellular, and systemic biological networks. Precision interventions targeting neural circuits, neuroinflammation, and the gut\u2013brain axis, combined with multidisciplinary clinical collaboration, represent core strategies to break through current diagnostic and therapeutic bottlenecks.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/brb3.71713","type":"journal-article","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T05:27:14Z","timestamp":1788154034000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Comorbidity Mechanism and Management of Chronic Low Back Pain and Major Depressive Disorder: From Neural Circuit Remodeling to Precision Medicine"],"prefix":"10.1002","volume":"16","author":[{"given":"Lin","family":"Faqu","sequence":"first","affiliation":[{"name":"Department of Acupuncture Ruian Hospital of Traditional Chinese Medicine Ruian Zhejiang Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Chenjuan","sequence":"additional","affiliation":[{"name":"Department of Acupuncture Ruian Hospital of Traditional Chinese Medicine Ruian Zhejiang Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Xiangyin","sequence":"additional","affiliation":[{"name":"Department of Acupuncture Ruian Hospital of Traditional Chinese Medicine Ruian Zhejiang Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Xin","sequence":"additional","affiliation":[{"name":"Department of Acupuncture, Massage and Rehabilitation The Second Affiliated Hospital of Hunan University of Traditional Chinese Medicine  Changsha Hunan Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,30]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1177\/20451253211034320"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2020.06.003"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.wneu.2017.06.093"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1177\/09645284211053821"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyg.2020.01825"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/brb3.71026"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainresbull.2022.01.017"},{"key":"e_1_2_12_9_1","volume-title":"Neuroanatomy of Neuroendocrine Systems","author":"Chang S.","year":"2022"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1177\/09645284231224305"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1142\/S0192415x20500548"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.otsr.2023.103474"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00018.2018"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2015.02.00"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/ner.13654"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41398\u2010019\u20100606\u20108"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1186\/s10194\u2010025\u201001967\u20108"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(18)30472\u20108"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12888\u2010015\u20100469\u20104"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2665\u20109913(23)00098\u2010X"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1097\/BRS.0b013e318241f1f3"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1342833"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.4103\/aer.AER8817"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bja.2019.07.026"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyt.2022.922733"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2022.30367"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctim.2025.103149"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.14968"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2025.1545997"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.72577"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2015.03.016"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.1177\/00912174211003760"},{"key":"e_1_2_12_33_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15767"},{"key":"e_1_2_12_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(21)00794\u20107"},{"key":"e_1_2_12_35_1","doi-asserted-by":"publisher","DOI":"10.1093\/pm\/pnaa318"},{"key":"e_1_2_12_36_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2020.22980"},{"key":"e_1_2_12_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2016.01.015"},{"key":"e_1_2_12_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinph.2019.11.002"},{"key":"e_1_2_12_39_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00406\u2010023\u201001693\u20103"},{"key":"e_1_2_12_40_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12264\u2010024\u201000951\u20105"},{"key":"e_1_2_12_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jad.2024.01.100"},{"key":"e_1_2_12_42_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12974\u2010019\u20101528\u2010y"},{"key":"e_1_2_12_43_1","doi-asserted-by":"publisher","DOI":"10.1002\/ar.24778"},{"key":"e_1_2_12_44_1","doi-asserted-by":"publisher","DOI":"10.1093\/psyrad\/kkae026"},{"key":"e_1_2_12_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jad.2024.01.098"},{"key":"e_1_2_12_46_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2471\u201016.2016"},{"key":"e_1_2_12_47_1","doi-asserted-by":"publisher","DOI":"10.1097\/RNJ.0000000000000099"},{"key":"e_1_2_12_48_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12035\u2010025\u201000123\u2010z"},{"key":"e_1_2_12_49_1","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyt.2017.00042"},{"key":"e_1_2_12_50_1","doi-asserted-by":"publisher","DOI":"10.1002\/hbm.26346"},{"key":"e_1_2_12_51_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells11162613"},{"key":"e_1_2_12_52_1","doi-asserted-by":"publisher","DOI":"10.3390\/brainsci11101298"},{"key":"e_1_2_12_53_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom5043112"},{"key":"e_1_2_12_54_1","doi-asserted-by":"publisher","DOI":"10.3390\/nu16172891"},{"key":"e_1_2_12_55_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12031\u2010021\u201001898\u20104"},{"key":"e_1_2_12_56_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40122\u2010023\u201000555\u20102"},{"key":"e_1_2_12_57_1","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.22992"},{"key":"e_1_2_12_58_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21134609"},{"key":"e_1_2_12_59_1","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2014.321"},{"key":"e_1_2_12_60_1","doi-asserted-by":"publisher","DOI":"10.12659\/AJCR.936600"},{"key":"e_1_2_12_61_1","doi-asserted-by":"publisher","DOI":"10.1002\/acr.22619"},{"key":"e_1_2_12_62_1","doi-asserted-by":"publisher","DOI":"10.3171\/2015.2.FOCUS14768"},{"key":"e_1_2_12_63_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2471\u201018.2018"},{"key":"e_1_2_12_64_1","doi-asserted-by":"publisher","DOI":"10.2174\/011570159x278075240314161"},{"key":"e_1_2_12_65_1","doi-asserted-by":"publisher","DOI":"10.1155\/2017\/9724371"},{"key":"e_1_2_12_66_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2016.06.006"},{"key":"e_1_2_12_67_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10143\u2010023\u201001998\u2010w"},{"key":"e_1_2_12_68_1","doi-asserted-by":"publisher","DOI":"10.1155\/2019\/1389296"},{"key":"e_1_2_12_69_1","doi-asserted-by":"publisher","DOI":"10.2147\/JPR.S315990"},{"key":"e_1_2_12_70_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2015.09.030"},{"key":"e_1_2_12_71_1","doi-asserted-by":"publisher","DOI":"10.2147\/JPR.S105558"},{"key":"e_1_2_12_72_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.acu.2021.100148"},{"key":"e_1_2_12_73_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.08.004"},{"key":"e_1_2_12_74_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22052648"},{"key":"e_1_2_12_75_1","doi-asserted-by":"publisher","DOI":"10.1142\/S0219635224500045"},{"key":"e_1_2_12_76_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12035\u2010024\u201004254\u20106"},{"key":"e_1_2_12_77_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25158324"},{"key":"e_1_2_12_78_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15268"},{"key":"e_1_2_12_79_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2024.148456"},{"key":"e_1_2_12_80_1","doi-asserted-by":"publisher","DOI":"10.2174\/1570159x19666210916164211"},{"key":"e_1_2_12_81_1","doi-asserted-by":"publisher","DOI":"10.1002\/brb3.3310"},{"key":"e_1_2_12_82_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00011\u2010023\u201001830\u20100"},{"key":"e_1_2_12_83_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.70302"},{"key":"e_1_2_12_84_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bja.2019.02.019"},{"key":"e_1_2_12_85_1","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyt.2018.00442"},{"key":"e_1_2_12_86_1","doi-asserted-by":"publisher","DOI":"10.1093\/fampra\/cmz056"}],"container-title":["Brain and Behavior"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/brb3.71713","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/brb3.71713","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/brb3.71713","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T07:21:11Z","timestamp":1792394471000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/brb3.71713"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,30]]},"references-count":85,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2026,9]]}},"alternative-id":["10.1002\/brb3.71713"],"URL":"https:\/\/doi.org\/10.1002\/brb3.71713","archive":["Portico"],"relation":{},"ISSN":["2162-3279","2162-3279"],"issn-type":[{"value":"2162-3279","type":"print"},{"value":"2162-3279","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,30]]},"assertion":[{"value":"2026-05-22","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-07","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-30","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e71713"}}