Advances in brain MRI research on the association between chronic low back pain and cognitive decline

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• Review •

LI Jinghu KONG Lingjun ZHANG Shuaipan ZHOU Xin ZHU Qingguang REN Jun JIN Ming MA Ying WANG Shoujian FANG Min

DOI:10.12015/issn.1674-8034.2025.12.025.

Abstract

[Abstract] Chronic low back pain (CLBP), one of the most disabling musculoskeletal conditions globally, presents not only with persistent pain and impaired mobility but also frequently involves cognitive impairments such as attention deficits, executive function decline, and working memory deficits. Multimodal magnetic resonance imaging studies provide crucial evidence elucidating the neural mechanisms of CLBP: functional MRI reveals abnormal activation in cognitive control regions including the prefrontal cortex, cingulate gyrus, and insula; resting-state analysis demonstrates functional connectivity imbalances in the default mode network, prefrontal-parietal control network, and salience network; diffusion tensor imaging identifies reduced integrity in frontal-parietal pathways and corpus callosum white matter fibers, correlated with cognitive assessment performance; and magnetic resonance spectroscopy indicates decreased N-acetylaspartate and disrupted glutamate/gamma-aminobutyric acid balance, reflecting impaired neuronal function and excitation-inhibition regulation. Current evidence supports that CLBP induces cognitive impairment through the "pain-emotion-cognition" loop and imbalances in three major brain networks. Current studies primarily exhibit the following limitations: most adopt cross-sectional designs, precluding the establishment of causality; lack of long-term follow-up data; and limited sample representativeness. Given these constraints, future research should: (1) Conduct longitudinal cohort and interventional studies to validate causal relationships between neural mechanisms and cognitive impairment; (2) Integrate multimodal MRI techniques with detailed cognitive-behavioral assessments to establish predictive models for CLBP-related cognitive impairment; (3) Explore the clinical translational value of imaging biomarkers to inform early identification and intervention strategies. Addressing these issues may offer novel approaches to improving cognitive outcomes in CLBP patients.This review systematically summarizes advances in neuroimaging research on cognitive impairment associated with chronic low back pain. It aims to provide theoretical references and research insights for scientists and clinicians engaged in chronic pain and cognitive neuroscience studies, thereby advancing the field from phenomenological description toward mechanism exploration and clinical intervention.

[Keywords] chronic low back pain；cognitive function；magnetic resonance imaging；functional magnetic resonance imaging；diffusion tensor imaging；magnetic resonance spectroscopy；default mode network；neural mechanisms

Contributor Information

LI Jinghu¹ KONG Lingjun¹ ZHANG Shuaipan¹ ZHOU Xin¹ ZHU Qingguang² REN Jun¹ JIN Ming¹ MA Ying¹ WANG Shoujian¹ FANG Min^{1,
2*}

¹ Department of Tuina, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China

² Tuina Research Institute, Shanghai Academy of Traditional Chinese Medicine, Shanghai 200437, China

Corresponding author: FANG M, E-mail: fm-tn0510@shutcm.edu.cn

Conflicts of interest None.

Publication Information

Received 2025-07-07

Accepted 2025-12-09

DOI: 10.12015/issn.1674-8034.2025.12.025

DOI:10.12015/issn.1674-8034.2025.12.025.

Text

References

[1]

NIJS J, JOHANSSON E. Long-term outcomes in chronic low back pain: costs, comorbidities, and clinical importance[J/OL]. Lancet Rheumatol, 2025, 7(9): e592-e593 [2025-07-07]. https://pubmed.ncbi.nlm.nih.gov/40449513/. DOI: 10.1016/S2665-9913(25)00104-3.

[2]

GBD 2021 US Burden of Disease Collaborators. The burden of diseases, injuries, and risk factors by state in the USA, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021[J/OL]. Lancet, 2024, 404(10469): 2314-2340. DOI: 10.1016/S0140-6736(24)01446-6.

[3]

MORENO-LIGERO M, SALAZAR A, FAILDE I, et al. Factors associated with pain-related functional interference in people with chronic low back pain enrolled in a physical exercise programme: the role of pain, sleep, and quality of life[J/OL]. J Rehabil Med, 2024, 56: jrm38820 [2025-07-07]. https://doi.org/10.2340/jrm.v56.38820. DOI: 10.2340/jrm.v56.38820.

[4]

CHEN J, WANG X, XU Z. The relationship between chronic pain and cognitive impairment in the elderly: a review of current evidence[J]. J Pain Res, 2023, 16(1): 2309-2319. DOI: 10.2147/JPR.S416253.

[5]

SOBOTT N, CROWTHER M E, VINCENT G E, et al. Chronic low back pain is associated with compromised cognitive function: a systematic review and meta-analysis[J/OL]. J Pain, 2025, 33: 105475 [2025-07-07]. https://doi.org/10.1016/j.jpain.2025.105475. DOI: 10.1016/j.jpain.2025.105475.

[6]

JIAO L, JING T, GUIYAN C, et al. The altered hippocampal functional connectivity and serum brain-derived neurotrophic factor level predict cognitive decline in patients with knee osteoarthritis[J/OL]. Cereb Cortex, 2023, 33(20): bhad305 [2025-07-07]. https://doi.org/10.1093/cercor/bhad305. DOI: 10.1093/cercor/bhad305.

[7]

WENHUI Z, LEI Z, XIANGYU C, et al. Elevated dementia risk, cognitive decline, and hippocampal atrophy in multisite chronic pain[J/OL]. Proc Natl Acad Sci U S A, 2023, 120(9): e2215192120 [2025-07-07]. https://doi.org/10.1073/pnas.2215192120. DOI: 10.1073/pnas.2215192120.

[8]

GUERREIRO S R, GUIMARÃES M R, SILVA J M, et al. Chronic pain causes tau-mediated hippocampal pathology and memory deficits[J]. Mol Psychiatry, 2022, 27(11): 4385-4393. DOI: 10.1038/s41380-022-01707-3.

[9]

SHIERS S, PRICE T J. Molecular, circuit, and anatomical changes in the prefrontal cortex in chronic pain[J]. Pain, 2020, 161(8): 1726-1729. DOI: 10.1097/j.pain.0000000000001897.

[10]

ZHAO L, ZHANG L, TANG Y, et al. Cognitive impairments in chronic pain: a brain aging framework[J]. Trends Cogn Sci, 2025, 29(6): 570-585. DOI: 10.1016/j.tics.2024.12.004.

[11]

CHEN X, CHEN N, LAI P, et al. Multimodal abnormalities of brain function in chronic low back pain: a systematic review and meta-analysis of neuroimaging studies[J/OL]. Front Neurosci, 2025, 19: 1535288 [2025-07-07]. https://doi.org/10.3389/fnins.2025.1535288. DOI: 10.3389/fnins.2025.1535288.

[12]

PEI Y, PENG J, ZHANG Y, et al. Aberrant functional connectivity and temporal variability of the dynamic pain connectome in patients with low back related leg pain[J/OL]. Sci Rep, 2022, 12(1): 6324 [2025-07-07]. https://doi.org/10.1038/s41598-022-10238-4. DOI: 10.1038/s41598-022-10238-4.

[13]

SIRUCEK L, DE SCHOENMACKER I, GORRELL L M, et al. The periaqueductal gray in chronic low back pain: dysregulated neurotransmitters and function[J]. Pain, 2025, 166(7): 1690-1705. DOI: 10.1097/j.pain.0000000000003617.

[14]

ALLEN-BRADY K, FYER A J, WEISSMAN M. The multi-generational familial aggregation of interstitial cystitis, other chronic nociplastic pain disorders, depression, and panic disorder[J]. Psychol Med, 2023, 53(16): 7847-7856. https://pubmed.ncbi.nlm.nih.gov/37458197/. DOI: 10.1017/S0033291723001885.

[15]

ZIPP F, BITTNER S, SCHAFER D P. Cytokines as emerging regulators of central nervous system synapses[J]. Immunity, 2023, 56(5): 914-925. DOI: 10.1016/j.immuni.2023.04.011.

[16]

MAO C P, YANG H J, ZHANG Q J, et al. Altered effective connectivity within the cingulo-frontal-parietal cognitive attention networks in chronic low back pain: a dynamic causal modeling study[J]. Brain Imaging Behav, 2022, 16(4): 1516-1527. DOI: 10.1007/s11682-021-00623-4.

[17]

MAO C P, ZHANG Q L, BAO F X, et al. Decreased activation of cingulo-frontal-parietal cognitive/attention network during an attention-demanding task in patients with chronic low back pain[J]. Neuroradiology, 2014, 56(10): 903-912. DOI: 10.1007/s00234-014-1391-6.

[18]

LIU H, WAN X. Alterations in static and dynamic functional network connectivity in chronic low back pain: a resting-state network functional connectivity and machine learning study[J]. Neuroreport, 2025, 36(7): 364-377. DOI: 10.1097/WNR.0000000000002158.

[19]

GU S Y, YAO X X, WANG S, et al. Aberrant alterations of static and dynamic functional connectivity in chronic low back pain[J]. Neuroscience, 2025, 579: 179-186. DOI: 10.1016/j.neuroscience.2025.06.011.

[20]

MAO C P, WILSON G, CAO J, et al. Abnormal anatomical and functional connectivity of the thalamo-sensorimotor circuit in chronic low back pain: resting-state functional magnetic resonance imaging and diffusion tensor imaging study[J]. Neuroscience. 2022, 487: 143-154. DOI: 10.1016/j.neuroscience.2022.02.001.

[21]

BAUMBACH P, MEIßNER W, REICHENBACH J R, et al. Functional connectivity and neurotransmitter impairments of the salience brain network in chronic low back pain patients: a combined resting-state functional magnetic resonance imaging and 1H-MRS study[J]. Pain, 2022, 163(12): 2337-2347. DOI: 10.1097/j.pain.0000000000002626.

[22]

QI K L, LI J, YUAN Y M, et al. Progress of research on chronic pain associated with multidimensional frailty in older adults[J]. Chinese Journal of Disease Control, 2023, 27(6): 711-716, 721. DOI: 10.16462/j.cnki.zhjbkz.2023.06.016.

[23]

KAPLAN M C, KELLEHER E, IRANI A, et al. Deciphering nociplastic pain: clinical features, risk factors and potential mechanisms[J]. Nat Rev Neurol, 2024, 20(6): 347-363. DOI: 10.1038/s41582-024-00966-8.

[24]

[25]

ALCON C, KRIEGER C, NEAL K. The relationship between pain catastrophizing, kinesiophobia, central sensitization, and cognitive function in patients with chronic low back pain[J/OL]. Clin J Pain, 2025, 41(7): e1293 [2025-07-07]. https://doi.org/10.1097/AJP.0000000000001293. DOI: 10.1097/AJP.0000000000001293.

[26]

ZU Y, ZHANG Z, HAO Z, et al. Changes in brain structure and function during early aging in patients with chronic low back pain[J/OL]. Front Aging Neurosci, 2024, 16: 1356507 [2025-07-07]. https://doi.org/10.3389/fnagi.2024.1356507. DOI: 10.3389/fnagi.2024.1356507.

[27]

FAN N, CHEN J, ZHAO B, et al. Neural correlates of central pain sensitization in chronic low back pain: a resting-state fMRI study[J]. Neuroradiology. 2023, 65(12): 1767-1776. DOI: 10.1007/s00234-023-03237-3.

[28]

ZHANG B, JUNG M, TU Y, et al. Identifying brain regions associated with the neuropathology of chronic low back pain: a resting-state amplitude of low-frequency fluctuation study[J/OL]. Br J Anaesth, 2019, 123(2): e303-e311 [2025-07-07]. https://doi.org/10.1016/j.bja.2019.02.021. DOI: 10.1016/j.bja.2019.02.021.

[29]

YU S, LI W, SHEN W, et al. Impaired mesocorticolimbic connectivity underlies increased pain sensitivity in chronic low back pain[J/OL]. Neuroimage, 2020, 218: 116969 [2025-07-07]. https://doi.org/10.1016/j.neuroimage.2020.116969. DOI: 10.1016/j.neuroimage.2020.116969.

[30]

LAMOTH C J, STINS J F, PONT M, et al. Effects of attention on the control of locomotion in individuals with chronic low back pain[J/OL]. J Neuroeng Rehabil, 2008, 5: 13 [2025-07-07]. https://doi.org/10.1186/1743-0003-5-13. DOI: 10.1186/1743-0003-5-13.

[31]

MAO C, ZHANG B, GUO M, et al. Functional connectivity of the periaqueductal grey subdivisions is disrupted in chronic low back pain[J/OL]. Brain Imaging Behav, 2025 [2025-07-07]. https://doi.org/10.1007/s11682-025-01047-0. DOI: 10.1007/s11682-025-01047-0.

[32]

BUSH G, LUU P, POSNER I M. Cognitive and emotional influences in anterior cingulate cortex[J]. Trends Cogn Sci, 2000, 4(6): 215-222. DOI: 10.1016/S1364-6613(00)01483-2.

[33]

SEMINOWICZ D A, WIDEMAN T H, NASO L, et al. Effective treatment of chronic low back pain in humans reverses abnormal brain anatomy and function[J]. J Neurosci, 2011, 31(20): 7540-7550. DOI: 10.1523/JNEUROSCI.5280-10.2011.

[34]

PING C M, LI Q Z, XIU F B, et al. Decreased activation of cingulo-frontal-parietal cognitive/attention network during an attention-demanding task in patients with chronic low back pain[J]. Neuroradiology, 2014, 56(10): 903-912. DOI: 10.1007/s00234-014-1391-6.

[35]

FRISTON K J. Functional and effective connectivity: a review[J]. Brain Connect, 2011, 1(1): 13-36. DOI: 10.1089/brain.2011.0008.

[36]

PING C M, JUAN H Y, JUAN Q Z, et al. Altered effective connectivity within the cingulo-frontal-parietal cognitive attention networks in chronic low back pain: a dynamic causal modeling study[J]. Brain Imaging Behav, 2022, 16(4): 1-12. DOI: 10.1007/s11682-021-00623-4.

[37]

IVO R, NICKLAS A, DARGEL J, et al. Brain structural and psychometric alterations in chronic low back pain[J]. Eur Spine J, 2013, 22(9): 1958-1964. DOI: 10.1007/s00586-013-2692-x.

[38]

JIANG J, DU W, CUI Y N, et al. An fMRI study of cerebral gray matter volume and structural network in patients with lower back pain[J]. Chin J Magn Reson Imaging, 2021, 12(9): 454-460. DOI: 10.12015/issn.1674-8034.2021.09.010.

[39]

NG S K, URQUHART D M, FITZGERALD P B, et al. The relationship between structural and functional brain changes and altered emotion and cognition in chronic low back pain: a systematic review of MRI and fMRI studies[J]. Clin J Pain, 2018, 34(3): 237-261. DOI: 10.1097/AJP.0000000000000534.

[40]

MEDRANO-ESCALADA Y, PLAZA-MANZANO G, FERNÁNDEZ-DE-LAS-PEÑAS C, et al. Structural, functional and neurochemical cortical brain changes associated with chronic low back pain[J]. Tomography, 2022, 8(5): 2153-2163. DOI: 10.3390/tomography8050180.

[41]

GU S Y, SHI F C, WANG S, et al. Altered volume of the amygdala subregions in patients with chronic low back pain[J]. Front Neurol, 2024, 15: 1351335 [2025-07-07]. https://doi.org/10.3389/fneur.2024.1351335. DOI: 10.3389/fneur.2024.1351335.

[42]

ITO A, YANG S, SHINTO E, et al. Interhemispheric and corticothalamic white-matter dysfunction underlies affective morbidity and impaired pain modulation in chronic pain[J]. Anesth Analg, 2025, 140(2): 465-475. DOI: 10.1213/ANE.0000000000006992.

[43]

SACCA V, CHAI-ZHANG T C, HODGES S, et al. Morphological changes of the limbic system associated with acute and chronic low-back pain: a UK Biobank imaging study[J]. Eur J Pain, 2024, 28(4): 608-619. DOI: 10.1002/ejp.2206.

[44]

JI Y, LIANG X, PEI Y, et al. Disrupted topological organization of brain connectome in patients with chronic low back related leg pain and clinical correlations[J/OL]. Sci Rep, 2025, 15(1): 7515 [2025-07-07]. https://doi.org/10.1038/s41598-025-91570-3. DOI: 10.1038/s41598-025-91570-3.

[45]

SACCA V, MALEKI N, REDDY S, et al. Assessing the modulatory effects of tDCS and acupuncture on cerebral blood flow in chronic low back pain using arterial spin labeling perfusion imaging[J/OL]. Brain Sci, 2025, 15(3): 261 [2025-07-07]. https://doi.org/10.3390/brainsci15030261. DOI: 10.3390/brainsci15030261.

[46]

FRANCESCO C, PIERO C, FRANCESCO G, et al. Osteopathy modulates brain–heart interaction in chronic pain patients: an ASL study[J/OL]. Sci Rep, 2021, 11(1): 4556 [2025-07-07]. https://doi.org/10.1038/s41598-021-83893-8. DOI: 10.1038/s41598-021-83893-8.

[47]

LEE J, MAWLA I, KIM J, et al. Machine learning-based prediction of clinical pain using multimodal neuroimaging and autonomic metrics[J]. Pain, 2019, 160(3): 550-560. DOI: 10.1097/j.pain.0000000000001417.

[48]

LAURA S, IARA S D, MARY L G, et al. The periaqueductal gray in chronic low back pain: dysregulated neurotransmitters and function[J]. Pain, 2025, 166(7): 1690-1705. DOI: 10.1097/j.pain.0000000000003617.

[49]

JEUNGCHAN L, OVIDIU C, ANGEL T, et al. Brain metabolite concentration in pain processing regions is linked with multidimensional morbidity in fibromyalgia: a voxel-wise 3D MR spectroscopic imaging study[J]. J Pain, 2021, 22(5): 579-589. DOI: 10.1016/j.jpain.2021.03.009.

[50]

WEERASEKERA A, KNIGHT P C, ALSHELH Z, et al. Thalamic neurometabolite alterations in chronic low back pain: a common phenomenon across musculoskeletal pain conditions?[J]. Pain, 2024, 165(1): 126-134. DOI: 10.1097/j.pain.0000000000003002.

[51]

XU H, CHEN Y, TAO Y, et al. Modulation effect of acupuncture treatment on chronic neck and shoulder pain in female patients: evidence from periaqueductal gray based functional connectivity[J]. CNS Neurosci Ther, 2022, 28(5): 714-723. DOI: 10.1111/cns.13789.

[52]

ARCHIBALD J, MACMILLAN E L, ENZLER A, et al. Excitatory and inhibitory responses in the brain to experimental pain: a systematic review of MR spectroscopy studies[J/OL]. Neuroimage, 2020, 215: 116794 [2025-07-07]. https://doi.org/10.1016/j.neuroimage.2020.116794. DOI: 10.1016/j.neuroimage.2020.116794.

[53]

[54]

SADEGHI S, SCHMIDT S N L, MIER D, et al. Effective connectivity of the human mirror neuron system during social cognition[J]. Soc Cogn Affect Neurosci, 2022, 17(8): 732-743. DOI: 10.1093/scan/nsab138.

[55]

ROUCH I, DOREY J M, STRIPPOLI M F, et al. Does cognitive functioning predict chronic pain in older adult? Results from the CoLaus|PsyCoLaus longitudinal study[J]. J Pain, 2021, 22(8): 905-913. DOI: 10.1016/j.jpain.2021.01.007.

[56]

COLLÉE M, RAJKUMAR R, FARRHER E, et al. Predicting performance in attention by measuring key metabolites in the PCC with 7T MRS[J/OL]. Sci Rep, 2024, 14(1): 17099 [2025-07-07]. https://doi.org/10.1038/s41598-024-67866-1. DOI: 10.1038/s41598-024-67866-1.

[57]

YEHA J, HYEONJIN K, DASOM L, et al. Dysfunctional energy metabolisms in fibromyalgia compared with healthy subjects[J/OL]. Mol Pain, 2021, 17: 17448069211012833 [2025-07-07]. https://doi.org/10.1177/17448069211012833. DOI: 10.1177/17448069211012833.

[58]

ZHANG Y N, FENG C C, DONG X, et al. Progress of cerebral energy metabolism imbalance in chronic pain[J]. Chinese Journal of Pain Medicine, 2023, 29(6): 443-447. DOI: 10.3969/j.issn.1006-9852.2023.06.007.

[59]

SHIGEMURA T, OSONE F, HARA A, et al. Alterations in metabolites in the anterior cingulate cortex and thalamus and their associations with pain and empathy in patients with chronic mild pain: a preliminary study[J]. J Neural Transm (Vienna), 2024, 131(9): 1079-1094. DOI: 10.1007/s00702-024-02791-1.

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