Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Neuromelanin-sensitive MRI for mechanistic research and biomarker development in psychiatry

Abstract

Neuromelanin-sensitive MRI is a burgeoning non-invasive neuroimaging method with an increasing number of applications in psychiatric research. This MRI modality is sensitive to the concentration of neuromelanin, which is synthesized from intracellular catecholamines and accumulates in catecholaminergic nuclei including the dopaminergic substantia nigra and the noradrenergic locus coeruleus. Emerging data suggest the utility of neuromelanin-sensitive MRI as a proxy measure for variability in catecholamine metabolism and function, even in the absence of catecholaminergic cell loss. Given the importance of catecholamine function to several psychiatric disorders and their treatments, neuromelanin-sensitive MRI is ideally positioned as an informative and easy-to-acquire catecholaminergic index. In this review paper, we examine basic aspects of neuromelanin and neuromelanin-sensitive MRI and focus on its psychiatric applications in the contexts of mechanistic research and biomarker development. We discuss ongoing debates and state-of-the-art research into the mechanisms of the neuromelanin-sensitive MRI contrast, standardized protocols and optimized analytic approaches, and application of cutting-edge methods such as machine learning and artificial intelligence to enhance the feasibility and predictive power of neuromelanin-sensitive-MRI-based tools. We finally lay out important future directions to allow neuromelanin-sensitive-MRI to fulfill its potential as a key component of the research, and ultimately clinical, toolbox in psychiatry.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Anatomy of catecholaminergic nuclei, neuromelanin synthesis, and neuromelanin-sensitive MRI.
Fig. 2: Clinical applications of SN-VTA NM-MRI.
Fig. 3: Measurement of LC NM-MRI contrast and its clinical and behavioral correlates.
Fig. 4: A lab-to-clinic pipeline for NM-MRI-based biomarkers.

Similar content being viewed by others

References

  1. Dayan P. Twenty-five lessons from computational neuromodulation. Neuron. 2012;76:240–56. https://doi.org/10.1016/j.neuron.2012.09.027.

    Article  CAS  PubMed  Google Scholar 

  2. Arnsten AF. Catecholamine modulation of prefrontal cortical cognitive function. Trends Cogn Sci. 1998;2:436–47. https://doi.org/10.1016/s1364-6613(98)01240-6.

    Article  CAS  PubMed  Google Scholar 

  3. Grace AA. Dysregulation of the dopamine system in the pathophysiology of schizophrenia and depression. Nat Rev Neurosci. 2016;17:524–32. https://doi.org/10.1038/nrn.2016.57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Di Giovanni G, Svob Strac D, Sole M, Unzeta M, Tipton KF, Mück-Šeler D, et al. Monoaminergic and histaminergic strategies and treatments in brain diseases. Front Neurosci. 2016;10:541 https://doi.org/10.3389/fnins.2016.00541.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Weinstein JJ, Chohan MO, Slifstein M, Kegeles LS, Moore H, Abi-Dargham A. Pathway-specific dopamine abnormalities in schizophrenia. Biol Psychiatry. 2017;81:31–42.

    Article  CAS  PubMed  Google Scholar 

  6. McCutcheon RA, Abi-Dargham A, Howes OD. Schizophrenia, dopamine and the striatum: from biology to symptoms. Trends Neurosci. 2019;42:205–20. https://doi.org/10.1016/j.tins.2018.12.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Koob GF, Volkow ND. Neurobiology of addiction: a neurocircuitry analysis. Lancet Psychiatry. 2016;3:760–73. https://doi.org/10.1016/S2215-0366(16)00104-8.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Volkow ND, Boyle M. Neuroscience of addiction: relevance to prevention and treatment. Am J Psychiatry. 2018;175:729–40. https://doi.org/10.1176/appi.ajp.2018.17101174.

    Article  PubMed  Google Scholar 

  9. Trujillo P, Aumann MA, Claassen DO Neuromelanin-sensitive MRI as a promising biomarker of catecholamine function. Brain. 2024;147:337–51.

    Article  PubMed  Google Scholar 

  10. Cassidy CM, Zucca FA, Girgis RR, Baker SC, Weinstein JJ, Sharp ME, et al. Neuromelanin-sensitive MRI as a noninvasive proxy measure of dopamine function in the human brain. Proc Natl Acad Sci USA. 2019;116:5108–17. https://doi.org/10.1073/pnas.1807983116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Wengler K, Baker SC, Velikovskaya A, Fogelson A, Girgis RR, Reyes-Madrigal F, et al. Generalizability and out-of-sample predictive ability of associations between neuromelanin-sensitive magnetic resonance imaging and psychosis in antipsychotic-free individuals. JAMA Psychiatry. 2024;81:198–208.

    Article  PubMed  Google Scholar 

  12. Sulzer D, Cassidy C, Horga G, Kang UJ, Fahn S, Casella L, et al. Neuromelanin detection by magnetic resonance imaging (MRI) and its promise as a biomarker for Parkinson’s disease. NPJ Parkinson's Dis. 2018;4:11.

    Article  Google Scholar 

  13. Liang CL, Nelson O, Yazdani U, Pasbakhsh P, German DC. Inverse relationship between the contents of neuromelanin pigment and the vesicular monoamine transporter-2: human midbrain dopamine neurons. J Comp Neurol. 2004;473:97–106. https://doi.org/10.1002/cne.20098.

    Article  CAS  PubMed  Google Scholar 

  14. Zecca L, Stroppolo A, Gatti A, Tampellini D, Toscani M, Gallorini M, et al. The role of iron and copper molecules in the neuronal vulnerability of locus coeruleus and substantia nigra during aging. Proc Natl Acad Sci USA. 2004;101:9843–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Zucca FA, Segura-Aguilar J, Ferrari E, Muñoz P, Paris I, Sulzer D, et al. Interactions of iron, dopamine and neuromelanin pathways in brain aging and Parkinson’s disease. Prog Neurobiol. 2017;155:96–119.

    Article  CAS  PubMed  Google Scholar 

  16. Sun Y, Pham AN, Hare DJ, Waite TD. Kinetic modeling of pH-dependent oxidation of dopamine by iron and its relevance to Parkinson's disease. Front Neurosci. 2018;12:417568.

    Article  Google Scholar 

  17. Monzani E, Nicolis S, Dell'Acqua S, Capucciati A, Bacchella C, Zucca FA, et al. Dopamine, oxidative stress and protein–quinone modifications in Parkinson's and other neurodegenerative diseases. Angew Chem Int Ed. 2019;58:6512–27.

    Article  CAS  Google Scholar 

  18. Ito S, Napolitano A, Sarna T, Wakamatsu K. Iron and copper ions accelerate and modify dopamine oxidation to eumelanin: implications for neuromelanin genesis. J Neural Transm. 2023;130:29–42.

    Article  CAS  PubMed  Google Scholar 

  19. Zecca L, Tampellini D, Gerlach M, Riederer P, Fariello R, Sulzer D. Substantia nigra neuromelanin: structure, synthesis, and molecular behaviour. Mol Pathol. 2001;54:414.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Zecca L, Zucca FA, Wilms H, Sulzer D. Neuromelanin of the substantia nigra: a neuronal black hole with protective and toxic characteristics. Trends Neurosci. 2003;26:578–80. https://doi.org/10.1016/j.tins.2003.08.009.

    Article  CAS  PubMed  Google Scholar 

  21. Sulzer D, Bogulavsky J, Larsen KE, Behr G, Karatekin E, Kleinman MH, et al. Neuromelanin biosynthesis is driven by excess cytosolic catecholamines not accumulated by synaptic vesicles. Proc Natl Acad Sci USA. 2000;97:11869–74. https://doi.org/10.1073/pnas.97.22.11869.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Segura A, Sulzer D, Zucca FA, Zecca L. Overexpression of vesicular monoamine transporter-2 may block neurotoxic metabolites from cytosolic dopamine: a potential neuroprotective therapy for Parkinson's disease. Clin Pharmacol Transl Med. 2019;3:143–8.

  23. Zecca L, Shima T, Stroppolo A, Goj C, Battiston G, Gerbasi R, et al. Interaction of neuromelanin and iron in substantia nigra and other areas of human brain. Neuroscience. 1996;73:407–15.

    Article  CAS  PubMed  Google Scholar 

  24. Sasaki M, Shibata E, Tohyama K, Takahashi J, Otsuka K, Tsuchiya K, et al. Neuromelanin magnetic resonance imaging of locus ceruleus and substantia nigra in Parkinson's disease. Neuroreport. 2006;17:1215–8.

    Article  PubMed  Google Scholar 

  25. Watanabe T. Neuromelanin? MRI of catecholaminergic neurons. Brain. 2024;147:e24–e6.

    Article  PubMed  Google Scholar 

  26. Trujillo P, Aumann MA, Claassen DO. Reply: Neuromelanin? MRI of catecholaminergic neurons. Brain. 2024;147:e27–e8.

    Article  PubMed  Google Scholar 

  27. Wolff SD, Balaban RS. Magnetization transfer contrast (MTC) and tissue water proton relaxation in vivo. Magn Reson Med. 1989;10:135–44.

    Article  CAS  PubMed  Google Scholar 

  28. Henkelman R, Stanisz G, Graham S. Magnetization transfer in MRI: a review. NMR in biomedicine: an international journal devoted to the development and application of magnetic resonance. Vivo. 2001;14:57–64.

    CAS  Google Scholar 

  29. van der Pluijm M, Cassidy C, Zandstra M, Wallert E, de Bruin K, Booij J, et al. Reliability and reproducibility of neuromelanin‐sensitive imaging of the substantia nigra: a comparison of three different sequences. J Magn Reson Imaging. 2020.

  30. Wengler K, He X, Abi-Dargham A, Horga G. Reproducibility assessment of neuromelanin-sensitive magnetic resonance imaging protocols for region-of-interest and voxelwise analyses. NeuroImage. 2020;208:116457.

    Article  CAS  PubMed  Google Scholar 

  31. Langley J, Huddleston DE, Liu CJ, Hu X. Reproducibility of locus coeruleus and substantia nigra imaging with neuromelanin sensitive MRI. Magn Reson Mater Phys Biol Med. 2017;30:121–5.

    Article  CAS  Google Scholar 

  32. Oshima S, Fushimi Y, Okada T, Nakajima S, Yokota Y, Shima A, et al. Neuromelanin‐sensitive magnetic resonance imaging using DANTE pulse. Mov Disord. 2021;36:874–82.

    Article  CAS  PubMed  Google Scholar 

  33. Ji S, Choi E-J, Sohn B, Baik K, Shin N-Y, Moon W-J, et al. Sandwich spatial saturation for neuromelanin-sensitive MRI: development and multi-center trial. NeuroImage. 2022;264:119706.

    Article  CAS  PubMed  Google Scholar 

  34. Trujillo P, Petersen KJ, Cronin MJ, Lin Y-C, Kang H, Donahue MJ, et al. Quantitative magnetization transfer imaging of the human locus coeruleus. NeuroImage. 2019;200:191–8.

    Article  PubMed  Google Scholar 

  35. Trujillo P, Summers PE, Smith AK, Smith SA, Mainardi LT, Cerutti S, et al. Pool size ratio of the substantia nigra in Parkinson’s disease derived from two different quantitative magnetization transfer approaches. Neuroradiology. 2017;59:1251–63.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Trujillo P, Smith AK, Summers PE, Mainardi LM, Cerutti S, Smith SA, et al., editors. High-resolution quantitative imaging of the substantia nigra. 2015 37th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC). IEEE; 2015.

  37. Salzman G, Kim J, Horga G, Wengler K. Standardized data acquisition for neuromelanin-sensitive magnetic resonance imaging of the substantia Nigra. J Vis Exp. 2021.

  38. Chen X, Huddleston DE, Langley J, Ahn S, Barnum CJ, Factor SA, et al. Simultaneous imaging of locus coeruleus and substantia nigra with a quantitative neuromelanin MRI approach. Magn Reson Imaging. 2014;32:1301–6.

    Article  PubMed  Google Scholar 

  39. Oshima S, Fushimi Y, Miyake KK, Nakajima S, Sakata A, Okuchi S, et al. Denoising approach with deep learning-based reconstruction for neuromelanin-sensitive MRI: image quality and diagnostic performance. Jpn J Radiol. 2023;41:1216–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Watanabe T, Wang X, Tan Z, Frahm J. Magnetic resonance imaging of brain cell water. Sci Rep. 2019;9:5084.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Watanabe T, Tan Z, Wang X, Martinez-Hernandez A, Frahm J. Magnetic resonance imaging of noradrenergic neurons. Brain Struct Funct. 2019;224:1609–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Keren NI, Taheri S, Vazey EM, Morgan PS, Granholm A-CE, Aston-Jones GS, et al. Histologic validation of locus coeruleus MRI contrast in post-mortem tissue. Neuroimage. 2015;113:235–45.

    Article  PubMed  Google Scholar 

  43. Trujillo P, Summers PE, Ferrari E, Zucca FA, Sturini M, Mainardi LT, et al. Contrast mechanisms associated with neuromelanin‐MRI. Magn Reson Med. 2017;78:1790–800.

    Article  CAS  PubMed  Google Scholar 

  44. Kitao S, Matsusue E, Fujii S, Miyoshi F, Kaminou T, Kato S, et al. Correlation between pathology and neuromelanin MR imaging in Parkinson’s disease and dementia with Lewy bodies. Neuroradiology. 2013;55:947–53.

    Article  PubMed  Google Scholar 

  45. Carballo-Carbajal I, Laguna A, Romero-Giménez J, Cuadros T, Bové J, Martinez-Vicente M, et al. Brain tyrosinase overexpression implicates age-dependent neuromelanin production in Parkinson’s disease pathogenesis. Nat Commun. 2019;10:973.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Compte J, Tible M, Cuadros T, Romero-Jimenez J, Laguna A, Aubry J-F, et al. Non-ablative disease-modifying effects of magnetic resonance-guided focused ultrasound in neuromelanin-producing Parkinsonian rodents. bioRxiv. 2023. https://doi.org/10.1101/2023.08.08.552410.

  47. Mazei-Robison MS, Koo JW, Friedman AK, Lansink CS, Robison AJ, Vinish M, et al. Role for mTOR signaling and neuronal activity in morphine-induced adaptations in ventral tegmental area dopamine neurons. Neuron. 2011;72:977–90. https://doi.org/10.1016/j.neuron.2011.10.012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Ohtsuka C, Sasaki M, Konno K, Koide M, Kato K, Takahashi J, et al. Changes in substantia nigra and locus coeruleus in patients with early-stage Parkinson's disease using neuromelanin-sensitive MR imaging. Neurosci Lett. 2013;541:93–8.

    Article  CAS  PubMed  Google Scholar 

  49. Gaurav R, Valabrègue R, Yahia-Chérif L, Mangone G, Narayanan S, Arnulf I, et al. NigraNet: An automatic framework to assess nigral neuromelanin content in early Parkinson’s disease using convolutional neural network. NeuroImage: Clin. 2022;36:103250.

    Article  PubMed  Google Scholar 

  50. Dünnwald M, Betts MJ, Sciarra A, Düzel E, Oeltze-Jafra S, editors. Automated segmentation of the locus coeruleus from neuromelanin-sensitive 3T MRI using deep convolutional neural networks. Bildverarbeitung für die Medizin 2020: Algorithmen–Systeme–Anwendungen Proceedings des Workshops vom 15 bis 17 März 2020 in Berlin. Springer; 2020.

  51. Kang J, Kim H, Kim E, Kim E, Lee H, Shin N-Y, et al. Convolutional neural network-based automatic segmentation of substantia nigra on nigrosome and neuromelanin sensitive MR images. Investig Magn Reson Imaging. 2021;25:156–63.

    Article  Google Scholar 

  52. Grimm J, Mueller A, Hefti F, Rosenthal A. Molecular basis for catecholaminergic neuron diversity. Proc Natl Acad Sci USA. 2004;101:13891–6.

  53. Liss B, Roeper J. Individual dopamine midbrain neurons: functional diversity and flexibility in health and disease. Brain Res Rev. 2008;58:314–21.

    Article  CAS  PubMed  Google Scholar 

  54. Eklund A, Nichols TE, Knutsson H. Cluster failure: Why fMRI inferences for spatial extent have inflated false-positive rates. Proc Natl Acad Sci USA. 2016;113:7900–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Clewett DV, Lee TH, Greening S, Ponzio A, Margalit E, Mather M. Neuromelanin marks the spot: identifying a locus coeruleus biomarker of cognitive reserve in healthy aging. Neurobiol Aging. 2016;37:117–26. https://doi.org/10.1016/j.neurobiolaging.2015.09.019.

    Article  CAS  PubMed  Google Scholar 

  56. Mather M, Joo Yoo H, Clewett DV, Lee TH, Greening SG, Ponzio A, et al. Higher locus coeruleus MRI contrast is associated with lower parasympathetic influence over heart rate variability. Neuroimage. 2017;150:329–35. https://doi.org/10.1016/j.neuroimage.2017.02.025.

    Article  PubMed  Google Scholar 

  57. Sasaki M, Shibata E, Ohtsuka K, Endoh J, Kudo K, Narumi S, et al. Visual discrimination among patients with depression and schizophrenia and healthy individuals using semiquantitative color-coded fast spin-echo T1-weighted magnetic resonance imaging. Neuroradiology. 2010;52:83–9. https://doi.org/10.1007/s00234-009-0595-7.

    Article  PubMed  Google Scholar 

  58. Shibata E, Sasaki M, Tohyama K, Otsuka K, Endoh J, Terayama Y, et al. Use of neuromelanin-sensitive MRI to distinguish schizophrenic and depressive patients and healthy individuals based on signal alterations in the substantia nigra and locus ceruleus. Biol Psychiatry. 2008;64:401–6. https://doi.org/10.1016/j.biopsych.2008.03.021.

    Article  CAS  PubMed  Google Scholar 

  59. Dahl MJ, Mather M, Duzel S, Bodammer NC, Lindenberger U, Kuhn S, et al. Rostral locus coeruleus integrity is associated with better memory performance in older adults. Nat Hum Behav. 2019;3:1203–14. https://doi.org/10.1038/s41562-019-0715-2.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Sibahi A, Gandhi R, Al-Haddad R, Therriault J, Pascoal T, Chamoun M, et al. Characterization of an automated method to segment the human locus coeruleus. Hum Brain Mapp. 2023;44:3913–25. https://doi.org/10.1002/hbm.26324.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Gallant SN, Kennedy BL, Bachman SL, Huang R, Cho C, Lee TH, et al. Behavioral and fMRI evidence that arousal enhances bottom-up selectivity in young but not older adults. Neurobiol Aging. 2022;120:149–66. https://doi.org/10.1016/j.neurobiolaging.2022.08.006.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Dahl MJ, Mather M, Werkle-Bergner M, Kennedy BL, Guzman S, Hurth K, et al. Locus coeruleus integrity is related to tau burden and memory loss in autosomal-dominant Alzheimer's disease. Neurobiol Aging. 2022;112:39–54. https://doi.org/10.1016/j.neurobiolaging.2021.11.006.

    Article  CAS  PubMed  Google Scholar 

  63. Hwang KS, Langley J, Tripathi R, Hu XP, Huddleston DE. In vivo detection of substantia nigra and locus coeruleus volume loss in Parkinson's disease using neuromelanin-sensitive MRI: Replication in two cohorts. PLoS One. 2023;18:e0282684 https://doi.org/10.1371/journal.pone.0282684.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Al Haddad R, Chamoun M, Tardif CL, Guimond S, Horga G, Rosa-Neto P, et al. Normative values of neuromelanin-sensitive MRI signal in older adults obtained using a turbo spin echo sequence. J Magn Reson Imaging. 2023;58:294–300. https://doi.org/10.1002/jmri.28530.

    Article  PubMed  Google Scholar 

  65. Calarco N, Cassidy CM, Selby B, Hawco C, Voineskos AN, Diniz BS, et al. Associations between locus coeruleus integrity and diagnosis, age, and cognitive performance in older adults with and without late-life depression: an exploratory study. Neuroimage Clin. 2022;36:103182 https://doi.org/10.1016/j.nicl.2022.103182.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Cassidy CM, Therriault J, Pascoal TA, Cheung V, Savard M, Tuominen L, et al. Association of locus coeruleus integrity with Braak stage and neuropsychiatric symptom severity in Alzheimer's disease. Neuropsychopharmacology. 2022;47:1128–36. https://doi.org/10.1038/s41386-022-01293-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. McCall A, Forouhandehpour R, Celebi S, Richard-Malenfant C, Hamati R, Guimond S, et al. Evidence for locus coeruleus-norepinephrine system abnormality in military PTSD revealed by neuromelanin-sensitive MRI. Biol Psychiatry. 2024;96:268–77. https://doi.org/10.1016/j.biopsych.2024.01.013.

  68. Dunnwald M, Ernst P, Duzel E, Tonnies K, Betts MJ, Oeltze-Jafra S. Fully automated deep learning-based localization and segmentation of the locus coeruleus in aging and Parkinson's disease using neuromelanin-sensitive MRI. Int J Comput Assist Radiol Surg. 2021;16:2129–35. https://doi.org/10.1007/s11548-021-02528-5.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Haxby JV. Multivariate pattern analysis of fMRI: the early beginnings. Neuroimage. 2012;62:852–5.

    Article  PubMed  Google Scholar 

  70. Wengler K, Cassidy C, van der Pluijm M, Weinstein JJ, Abi-Dargham A, van de Giessen E, et al. Cross-scanner harmonization of neuromelanin-sensitive MRI for multisite studies. J Magn Reson Imaging. 2021. https://doi.org/10.1002/jmri.27679.

  71. Zecca L, Fariello R, Riederer P, Sulzer D, Gatti A, Tampellini D. The absolute concentration of nigral neuromelanin, assayed by a new sensitive method, increases throughout the life and is dramatically decreased in Parkinson's disease. FEBS Lett. 2002;510:216–20.

    Article  CAS  PubMed  Google Scholar 

  72. Sommerauer M, Fedorova TD, Hansen AK, Knudsen K, Otto M, Jeppesen J, et al. Evaluation of the noradrenergic system in Parkinson’s disease: an 11C-MeNER PET and neuromelanin MRI study. Brain. 2017;141:496–504.

    Article  Google Scholar 

  73. Chen H-Y, Parent JH, Ciampa CJ, Dahl MJ, Hämmerer D, Maass A, et al. Interactive effects of locus coeruleus structure and catecholamine synthesis capacity on cognitive function. Front Aging neurosci. 2023;15.

  74. Langley J, Huddleston DE, Chen X, Sedlacik J, Zachariah N, Hu X. A multicontrast approach for comprehensive imaging of substantia nigra. Neuroimage. 2015;112:7–13. https://doi.org/10.1016/j.neuroimage.2015.02.045.

    Article  PubMed  Google Scholar 

  75. Larsen B, Olafsson V, Calabro F, Laymon C, Tervo-Clemmens B, Campbell E, et al. Maturation of the human striatal dopamine system revealed by PET and quantitative MRI. Nat Commun. 2020;11:846 https://doi.org/10.1038/s41467-020-14693-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Oldehinkel M, Llera A, Faber M, Huertas I, Buitelaar JK, Bloem BR, et al. Mapping dopaminergic projections in the human brain with resting-state fMRI. Elife. 2022;11. Epub 20220203. https://doi.org/10.7554/eLife.71846.

  77. Pessiglione M, Seymour B, Flandin G, Dolan RJ, Frith CD. Dopamine-dependent prediction errors underpin reward-seeking behaviour in humans. Nature. 2006;442:1042–5. https://doi.org/10.1038/nature05051.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Horga G, Wengler K, Cassidy CM. Neuromelanin-sensitive magnetic resonance imaging as a proxy marker for catecholamine function in psychiatry. JAMA Psychiatry. 2021;78:788–9. https://doi.org/10.1001/jamapsychiatry.2021.0927.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Nestler EJ. Is there a common molecular pathway for addiction? Nat Neurosci. 2005;8:1445–9. https://doi.org/10.1038/nn1578.

    Article  CAS  PubMed  Google Scholar 

  80. Kawaguchi H, Shimada H, Kodaka F, Suzuki M, Shinotoh H, Hirano S, et al. Principal component analysis of multimodal neuromelanin MRI and dopamine transporter PET data provides a specific metric for the nigral dopaminergic neuronal density. PLoS One. 2016;11:e0151191 https://doi.org/10.1371/journal.pone.0151191.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Okuzumi A, Hatano T, Kamagata K, Hori M, Mori A, Oji Y, et al. Neuromelanin or DaT-SPECT: which is the better marker for discriminating advanced Parkinson's disease? Eur J Neurol. 2019;26:1408–16. https://doi.org/10.1111/ene.14009.

    Article  CAS  PubMed  Google Scholar 

  82. Schwarz ST, Rittman T, Gontu V, Morgan PS, Bajaj N, Auer DP. T1‐weighted MRI shows stage‐dependent substantia nigra signal loss in Parkinson's disease. Mov Disord. 2011;26:1633–8.

    Article  PubMed  Google Scholar 

  83. Matsuura K, Maeda M, Yata K, Ichiba Y, Yamaguchi T, Kanamaru K, et al. Neuromelanin magnetic resonance imaging in Parkinson's disease and multiple system atrophy. Eur Neurol. 2013;70:70–7.

    Article  CAS  PubMed  Google Scholar 

  84. Bae YJ, Kim J-M, Sohn C-H, Choi J-H, Choi BS, Song YS, et al. Imaging the substantia nigra in Parkinson disease and other Parkinsonian syndromes. Radiology. 2021;300:260–78.

    Article  PubMed  Google Scholar 

  85. Isaias IU, Trujillo P, Summers P, Marotta G, Mainardi L, Pezzoli G, et al. Neuromelanin imaging and dopaminergic loss in Parkinson's disease. Front Aging Neurosci. 2016;8:196.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Cho SJ, Bae YJ, Kim JM, Kim D, Baik SH, Sunwoo L, et al. Diagnostic performance of neuromelanin-sensitive magnetic resonance imaging for patients with Parkinson's disease and factor analysis for its heterogeneity: a systematic review and meta-analysis. Eur Radiol. 2021;31:1268–80. https://doi.org/10.1007/s00330-020-07240-7.

    Article  PubMed  Google Scholar 

  87. Wang J, Huang Z, Li Y, Ye F, Wang C, Zhang Y, et al. Neuromelanin-sensitive MRI of the substantia nigra: an imaging biomarker to differentiate essential tremor from tremor-dominant Parkinson's disease. Parkinsonism Relat Disord. 2019;58:3–8. https://doi.org/10.1016/j.parkreldis.2018.07.007.

    Article  PubMed  Google Scholar 

  88. Sung YH, Noh Y, Kim EY. Early‐stage Parkinson's disease: Abnormal nigrosome 1 and 2 revealed by a voxelwise analysis of neuromelanin‐sensitive MRI. Hum Brain Mapp. 2021;42:2823–32.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Ben Bashat D, Thaler A, Lerman Shacham H, Even-Sapir E, Hutchison M, Evans KC, et al. Neuromelanin and T2*-MRI for the assessment of genetically at-risk, prodromal, and symptomatic Parkinson’s disease. npj Parkinson's Dis. 2022;8:139.

    Article  Google Scholar 

  90. He N, Ghassaban K, Huang P, Jokar M, Wang Y, Cheng Z, et al. Imaging iron and neuromelanin simultaneously using a single 3D gradient echo magnetization transfer sequence: Combining neuromelanin, iron and the nigrosome-1 sign as complementary imaging biomarkers in early stage Parkinson's disease. Neuroimage. 2021;230:117810.

    Article  CAS  PubMed  Google Scholar 

  91. Xing Y, Sapuan AH, Martín‐Bastida A, Naidu S, Tench C, Evans J, et al. Neuromelanin‐MRI to quantify and track nigral depigmentation in Parkinson's disease: a multicenter longitudinal study using template‐based standardized analysis. Mov Disord. 2022;37:1028–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Gaurav R, Yahia‐Cherif L, Pyatigorskaya N, Mangone G, Biondetti E, Valabrègue R, et al. Longitudinal changes in neuromelanin MRI signal in Parkinson's disease: a progression marker. Mov Disord. 2021;36:1592–602.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Wang J, Li Y, Huang Z, Wan W, Zhang Y, Wang C, et al. Neuromelanin‐sensitive magnetic resonance imaging features of the substantia nigra and locus coeruleus in de novo Parkinson's disease and its phenotypes. Eur J Neurol. 2018;25:949–e73.

    Article  CAS  PubMed  Google Scholar 

  94. Biondetti E, Gaurav R, Yahia-Cherif L, Mangone G, Pyatigorskaya N, Valabrègue R, et al. Spatiotemporal changes in substantia nigra neuromelanin content in Parkinson’s disease. Brain. 2020;143:2757–70.

    Article  PubMed  Google Scholar 

  95. Furukawa K, Shima A, Kambe D, Nishida A, Wada I, Sakamaki H, et al. Motor progression and nigrostriatal neurodegeneration in Parkinson disease. Ann Neurol. 2022;92:110–21.

    Article  CAS  PubMed  Google Scholar 

  96. Kuya K, Ogawa T, Shinohara Y, Ishibashi M, Fujii S, Mukuda N, et al. Evaluation of Parkinson’s disease by neuromelanin-sensitive magnetic resonance imaging and 123I-FP-CIT SPECT. Acta Radiol. 2018;59:593–8.

    Article  PubMed  Google Scholar 

  97. Wang S, Wu T, Cai Y, Yu Y, Chen X, Wang L. Neuromelanin magnetic resonance imaging of substantia nigra and locus coeruleus in Parkinson’s disease with freezing of gait. Frontiers in Aging. Neuroscience. 2023;15:1060935.

    CAS  Google Scholar 

  98. Su D, Gan Y, Zhang Z, Cui Y, Zhang Z, Liu Z, et al. Multimodal imaging of substantia nigra in Parkinson's disease with levodopa‐induced dyskinesia. Mov Disord. 2023;38:616–25.

    Article  CAS  PubMed  Google Scholar 

  99. Yan S, Lu J, Li Y, Zhu H, Tian T, Qin Y, et al. Large-scale functional network connectivity mediates the association between nigral neuromelanin hypopigmentation and motor impairment in Parkinson’s disease. Brain Struct Funct. 2024:1–10.

  100. Lakhani DA, Zhou X, Tao S, Patel V, Wen S, Okromelidze L, et al. Diagnostic utility of 7T neuromelanin imaging of the substantia nigra in Parkinson’s disease. npj Parkinson's Dis. 2024;10:13.

    Article  CAS  Google Scholar 

  101. Tan S, Zhou C, Wen J, Duanmu X, Guo T, Wu H, et al. Presence but not the timing of onset of REM sleep behavior disorder distinguishes evolution patterns in Parkinson's disease. Neurobiol Dis. 2023;180:106084.

    Article  PubMed  Google Scholar 

  102. Nobileau A, Gaurav R, Chougar L, Faucher A, Valabrègue R, Mangone G, et al. Neuromelanin‐sensitive magnetic resonance imaging changes in the locus coeruleus/subcoeruleus complex in patients with typical and atypical parkinsonism. Mov Disord. 2023;38:479–84.

    Article  CAS  PubMed  Google Scholar 

  103. Gaurav R, Pyatigorskaya N, Biondetti E, Valabrègue R, Yahia‐Cherif L, Mangone G, et al. Deep learning‐based neuromelanin MRI changes of isolated REM sleep behavior disorder. Mov Disord. 2022;37:1064–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Matzaras R, Shi K, Artemiadis A, Zis P, Hadjigeorgiou G, Rominger A, et al. Brain neuroimaging of rapid eye movement sleep behavior disorder in Parkinson’s disease: a systematic review. J Parkinson's Dis. 2022;12:69–83.

    Article  Google Scholar 

  105. Mangone G, Houot M, Gaurav R, Boluda S, Pyatigorskaya N, Chalancon A, et al. Relationship between substantia nigra neuromelanin imaging and dual alpha-synuclein labeling of labial minor in salivary glands in isolated rapid eye movement sleep behavior disorder and Parkinson’s disease. Genes. 2022;13:1715.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Krupička R, Mareček S, Malá C, Lang M, Klempíř O, Duspivová T, et al. Automatic substantia nigra segmentation in neuromelanin-sensitive MRI by deep neural network in patients with prodromal and manifest synucleinopathy. Physiol Res. 2019;68:S453–S8.

    Article  PubMed  Google Scholar 

  107. Knudsen K, Fedorova TD, Hansen AK, Sommerauer M, Otto M, Svendsen KB, et al. In-vivo staging of pathology in REM sleep behaviour disorder: a multimodality imaging case-control study. Lancet Neurol. 2018;17:618–28.

    Article  PubMed  Google Scholar 

  108. Ehrminger M, Latimier A, Pyatigorskaya N, Garcia-Lorenzo D, Leu-Semenescu S, Vidailhet M, et al. The coeruleus/subcoeruleus complex in idiopathic rapid eye movement sleep behaviour disorder. Brain. 2016;139:1180–8.

    Article  PubMed  Google Scholar 

  109. Pyatigorskaya N, Gaurav R, Arnaldi D, Leu-Semenescu S, Yahia-Cherif L, Valabregue R, et al. Magnetic resonance imaging biomarkers to assess substantia nigra damage in idiopathic rapid eye movement sleep behavior disorder. Sleep. 2017;40:zsx149.

    Article  Google Scholar 

  110. García-Lorenzo D, Longo-Dos Santos C, Ewenczyk C, Leu-Semenescu S, Gallea C, Quattrocchi G, et al. The coeruleus/subcoeruleus complex in rapid eye movement sleep behaviour disorders in Parkinson’s disease. Brain. 2013;136:2120–9.

    Article  PubMed  PubMed Central  Google Scholar 

  111. Iranzo A, Valldeoriola F, Lomeña F, Molinuevo JL, Serradell M, Salamero M, et al. Serial dopamine transporter imaging of nigrostriatal function in patients with idiopathic rapid-eye-movement sleep behaviour disorder: a prospective study. Lancet Neurol. 2011;10:797–805.

    Article  CAS  PubMed  Google Scholar 

  112. de Laat B, Hoye J, Stanley G, Hespeler M, Ligi J, Mohan V, et al. Intense exercise increases dopamine transporter and neuromelanin concentrations in the substantia nigra in Parkinson’s disease. npj Parkinson's Dis. 2024;10:34.

    Article  Google Scholar 

  113. O’Callaghan C, Hezemans FH, Ye R, Rua C, Jones PS, Murley AG, et al. Locus coeruleus integrity and the effect of atomoxetine on response inhibition in Parkinson’s disease. Brain 2021;144:2513–26.

    Article  PubMed  PubMed Central  Google Scholar 

  114. Prasuhn J, Prasuhn M, Fellbrich A, Strautz R, Lemmer F, Dreischmeier S, et al. Association of locus coeruleus and substantia nigra pathology with cognitive and motor functions in patients with Parkinson disease. Neurology. 2021;97:e1007–e16.

    Article  CAS  PubMed  Google Scholar 

  115. Madelung CF, Meder D, Fuglsang SA, Marques MM, Boer VO, Madsen KH, et al. Locus coeruleus shows a spatial pattern of structural disintegration in Parkinson's disease. Mov Disord. 2022;37:479–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Ryman SG, Poston KL. MRI biomarkers of motor and non-motor symptoms in Parkinson's disease. Parkinsonism Relat Disord. 2020;73:85–93.

    Article  PubMed  Google Scholar 

  117. Liu Q, Wang P, Liu C, Xue F, Wang Q, Chen Y, et al. An investigation of neuromelanin distribution in substantia nigra and locus coeruleus in patients with Parkinson’s disease using neuromelanin-sensitive MRI. BMC Neurol. 2023;23:301.

    Article  PubMed  PubMed Central  Google Scholar 

  118. Li Y, Wang C, Wang J, Zhou Y, Ye F, Zhang Y, et al. Mild cognitive impairment in de novo Parkinson's disease: a neuromelanin MRI study in locus coeruleus. Mov Disord. 2019;34:884–92.

    Article  PubMed  Google Scholar 

  119. Laurencin C, Lancelot S, Brosse S, Mérida I, Redouté J, Greusard E, et al. Noradrenergic alterations in Parkinson's disease: a combined 11 C-yohimbine PET/neuromelanin MRI study. Brain. 2023.

  120. Wolters AF, Heijmans M, Priovoulos N, Jacobs HI, Postma AA, Temel Y, et al. Neuromelanin related ultra-high field signal intensity of the locus coeruleus differs between Parkinson’s disease and controls. NeuroImage: Clin. 2023;39:103479.

    Article  PubMed  Google Scholar 

  121. Huddleston DE, Chen X, Hwang K, Langley J, Tripathi R, Tucker K, et al. Neuromelanin-sensitive MRI correlates of cognitive and motor function in Parkinson's disease with freezing of gait. Front Dementia. 2023;2. https://doi.org/10.3389/frdem.2023.1215505.

  122. David M, Malhotra PA. New approaches for the quantification and targeting of noradrenergic dysfunction in Alzheimer's disease. Ann Clin Transl Neurol.2022;9:582–96.

    Article  PubMed  PubMed Central  Google Scholar 

  123. Andrés‐Benito P, Fernández‐Dueñas V, Carmona M, Escobar L, Torrejón‐Escribano B, Asó E, et al. Locus coeruleus at asymptomatic early and middle Braak stages of neurofibrillary tangle pathology. Neuropathol Appl Neurobiol. 2017;43:373–92.

    Article  PubMed  Google Scholar 

  124. Beardmore R, Durkin M, Zayee‐Mellick F, Lau LC, Nicoll JA, Holmes C, et al. Changes in the locus coeruleus during the course of Alzheimer's disease and their relationship to cortical pathology. Neuropathol Appl Neurobiol. 2024;50:e12965.

    Article  CAS  PubMed  Google Scholar 

  125. Beardmore R, Hou R, Darekar A, Holmes C, Boche D. The locus coeruleus in aging and Alzheimer’s disease: a postmortem and brain imaging review. J Alzheimer's Dis. 2021;83:5–22.

    Article  CAS  Google Scholar 

  126. Jacobs HI, Becker JA, Kwong K, Engels-Domínguez N, Prokopiou PC, Papp KV, et al. In vivo and neuropathology data support locus coeruleus integrity as indicator of Alzheimer’s disease pathology and cognitive decline. Sci Transl Med. 2021;13:eabj2511.

    Article  PubMed  PubMed Central  Google Scholar 

  127. Takahashi J, Shibata T, Sasaki M, Kudo M, Yanezawa H, Obara S, et al. Detection of changes in the locus coeruleus in patients with mild cognitive impairment and Alzheimer's disease: High‐resolution fast spin‐echo T 1‐weighted imaging. Geriatr Gerontol Int. 2015;15:334–40.

    Article  PubMed  Google Scholar 

  128. Betts MJ, Cardenas-Blanco A, Kanowski M, Spottke A, Teipel SJ, Kilimann I, et al. Locus coeruleus MRI contrast is reduced in Alzheimer's disease dementia and correlates with CSF Aβ levels. Alzheimer's & dementia: diagnosis. Assess Dis Monit. 2019;11:281–5.

    Google Scholar 

  129. Olivieri P, Lagarde J, Lehericy S, Valabrègue R, Michel A, Macé P, et al. Early alteration of the locus coeruleus in phenotypic variants of Alzheimer’s disease. Ann Clin Transl Neurol. 2019;6:1345–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Hou R, Beardmore R, Holmes C, Osmond C, Darekar A. A case-control study of the locus coeruleus degeneration in Alzheimer's disease. Eur Neuropsychopharmacol. 2021;43:153–9.

    Article  CAS  PubMed  Google Scholar 

  131. Liu R, Guo Z, Li M, Liu S, Zhi Y, Jiang Z, et al. Lower fractional dimension in Alzheimer's disease correlates with reduced locus coeruleus signal intensity. Magn Reson Imaging. 2024;106:24–30.

    Article  CAS  PubMed  Google Scholar 

  132. Elman JA, Puckett OK, Beck A, Fennema‐Notestine C, Cross LK, Dale AM, et al. MRI‐assessed locus coeruleus integrity is heritable and associated with multiple cognitive domains, mild cognitive impairment, and daytime dysfunction. Alzheimer's Dement. 2021;17:1017–25.

    Article  Google Scholar 

  133. Dai M, Guo Z, Chen J, Liu H, Li J, Zhu M, et al. Altered functional connectivity of the locus coeruleus in Alzheimer's disease patients with depression symptoms. Exp Gerontol. 2023;179:112252.

    Article  PubMed  Google Scholar 

  134. Serra L, D'Amelio M, Di Domenico C, Dipasquale O, Marra C, Mercuri NB, et al. In vivo mapping of brainstem nuclei functional connectivity disruption in Alzheimer's disease. Neurobiol Aging. 2018;72:72–82.

    Article  PubMed  Google Scholar 

  135. Bogerts B, Häntsch J, Herzer M. A morphometric study of the dopamine-containing cell groups in the mesencephalon of normals, Parkinson patients, and schizophrenics. Biol Psychiatry. 1983;18:951–69.

    CAS  PubMed  Google Scholar 

  136. McCutcheon R, Beck K, Jauhar S, Howes OD. Defining the locus of dopaminergic dysfunction in Schizophrenia: a meta-analysis and test of the mesolimbic hypothesis. Schizophr Bull. 2018;44:1301–11. https://doi.org/10.1093/schbul/sbx180.

    Article  PubMed  Google Scholar 

  137. Ueno F, Iwata Y, Nakajima S, Caravaggio F, Rubio JM, Horga G, et al. Neuromelanin accumulation in patients with schizophrenia: a systematic review and meta-analysis. Neurosci Biobehav Rev. 2022;132:1205–13. https://doi.org/10.1016/j.neubiorev.2021.10.028.

    Article  CAS  PubMed  Google Scholar 

  138. Wieland L, Fromm S, Hetzer S, Schlagenhauf F, Kaminski J. Neuromelanin-sensitive magnetic resonance imaging in schizophrenia: a meta-analysis of case-control studies. Front Psychiatry. 2021;12:770282 https://doi.org/10.3389/fpsyt.2021.770282.

    Article  PubMed  PubMed Central  Google Scholar 

  139. Choi S, Kim M, Kim T, Choi EJ, Lee J, Moon SY, et al. Fronto-striato-thalamic circuit connectivity and neuromelanin in schizophrenia: an fMRI and neuromelanin-MRI study. Schizophrenia. 2023;9:81 https://doi.org/10.1038/s41537-023-00410-8.

    Article  PubMed  PubMed Central  Google Scholar 

  140. van der Pluijm M, Wengler K, Reijers PN, Cassidy CM, Tjong Tjin Joe K, de Peuter OR, et al. Neuromelanin-sensitive MRI as candidate marker for treatment resistance in first-episode schizophrenia. Am J Psychiatry. 2024:appiajp20220780. Epub 20240313. https://doi.org/10.1176/appi.ajp.20220780.

  141. Watanabe Y, Tanaka H, Tsukabe A, Kunitomi Y, Nishizawa M, Hashimoto R, et al. Neuromelanin magnetic resonance imaging reveals increased dopaminergic neuron activity in the substantia nigra of patients with schizophrenia. PLoS One. 2014;9:e104619 https://doi.org/10.1371/journal.pone.0104619.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Chen S, Seeman P, Liu F. Antipsychotic drug binding in the substantia nigra: an examination of high metoclopramide binding in the brains of normal, Alzheimer's disease, Huntington's disease, and Multiple Sclerosis patients, and its relation to tardive dyskinesia. Synapse. 2011;65:119–24. https://doi.org/10.1002/syn.20825.

    Article  CAS  PubMed  Google Scholar 

  143. Elhwuegi AS. Central monoamines and their role in major depression. Prog Neuropsychopharmacol Biol Psychiatry. 2004;28:435–51. https://doi.org/10.1016/j.pnpbp.2003.11.018.

    Article  CAS  PubMed  Google Scholar 

  144. Moriguchi S, Yamada M, Takano H, Nagashima T, Takahata K, Yokokawa K, et al. Norepinephrine transporter in major depressive disorder: a PET study. Am J Psychiatry. 2017;174:36–41. https://doi.org/10.1176/appi.ajp.2016.15101334.

    Article  PubMed  Google Scholar 

  145. Shibata E, Sasaki M, Tohyama K, Otsuka K, Sakai A. Reduced signal of locus ceruleus in depression in quantitative neuromelanin magnetic resonance imaging. Neuroreport. 2007;18:415–8. https://doi.org/10.1097/WNR.0b013e328058674a.

    Article  PubMed  Google Scholar 

  146. Guinea-Izquierdo A, Gimenez M, Martinez-Zalacain I, Del Cerro I, Canal-Noguer P, Blasco G, et al. Lower locus coeruleus MRI intensity in patients with late-life major depression. PeerJ 2021;9:e10828 https://doi.org/10.7717/peerj.10828.

    Article  PubMed  PubMed Central  Google Scholar 

  147. Pizzagalli DA, Berretta S, Wooten D, Goer F, Pilobello KT, Kumar P, et al. Assessment of striatal dopamine transporter binding in individuals with major depressive disorder: in vivo positron emission tomography and postmortem evidence. JAMA. Psychiatry 2019;76:854–61. https://doi.org/10.1001/jamapsychiatry.2019.0801.

    Article  PubMed  PubMed Central  Google Scholar 

  148. Kuai X, Shao D, Wang S, Wu PY, Wu Y, Wang X, et al. Neuromelanin-sensitive MRI of the substantia nigra distinguishes bipolar from unipolar depression. Cereb Cortex. 2024;34. https://doi.org/10.1093/cercor/bhad423.

  149. Morris LS, Mehta M, Ahn C, Corniquel M, Verma G, Delman B, et al. Ventral tegmental area integrity measured with high-resolution 7-Tesla MRI relates to motivation across depression and anxiety diagnoses. Neuroimage. 2022;264:119704 https://doi.org/10.1016/j.neuroimage.2022.119704.

    Article  PubMed  Google Scholar 

  150. Morris LS, Tan A, Smith DA, Grehl M, Han-Huang K, Naidich TP, et al. Sub-millimeter variation in human locus coeruleus is associated with dimensional measures of psychopathology: an in vivo ultra-high field 7-Tesla MRI study. Neuroimage Clin. 2020;25:102148 https://doi.org/10.1016/j.nicl.2019.102148.

    Article  PubMed  PubMed Central  Google Scholar 

  151. Jacobs HI, Priovoulos N, Poser BA, Pagen LH, Ivanov D, Verhey FR, et al. Dynamic behavior of the locus coeruleus during arousal-related memory processing in a multi-modal 7T fMRI paradigm. Elife. 2020;9. Epub 20200624. https://doi.org/10.7554/eLife.52059.

  152. Hammerer D, Callaghan MF, Hopkins A, Kosciessa J, Betts M, Cardenas-Blanco A, et al. Locus coeruleus integrity in old age is selectively related to memories linked with salient negative events. Proc Natl Acad Sci USA 2018;115:2228–33. https://doi.org/10.1073/pnas.1712268115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Clewett DV, Huang R, Velasco R, Lee TH, Mather M. Locus coeruleus activity strengthens prioritized memories under arousal. J Neurosci. 2018;38:1558–74. https://doi.org/10.1523/JNEUROSCI.2097-17.2017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Naegeli C, Zeffiro T, Piccirelli M, Jaillard A, Weilenmann A, Hassanpour K, et al. Locus coeruleus activity mediates hyperresponsiveness in posttraumatic stress disorder. Biol Psychiatry. 2018;83:254–62. https://doi.org/10.1016/j.biopsych.2017.08.021.

    Article  PubMed  Google Scholar 

  155. Bremner JD, Innis RB, Ng CK, Staib LH, Salomon RM, Bronen RA, et al. Positron emission tomography measurement of cerebral metabolic correlates of yohimbine administration in combat-related posttraumatic stress disorder. Arch Gen Psychiatry 1997;54:246–54. https://doi.org/10.1001/archpsyc.1997.01830150070011.

    Article  CAS  PubMed  Google Scholar 

  156. Morey RA, Dunsmoor JE, Haswell CC, Brown VM, Vora A, Weiner J, et al., Workgroup VAM-AM, LaBar KS. Fear learning circuitry is biased toward generalization of fear associations in posttraumatic stress disorder. Transl Psychiatry. 2015;5:e700. Epub 20151215. https://doi.org/10.1038/tp.2015.196.

  157. Grueschow M, Stenz N, Thorn H, Ehlert U, Breckwoldt J, Brodmann Maeder M, et al. Real-world stress resilience is associated with the responsivity of the locus coeruleus. Nat Commun 2021;12:2275 https://doi.org/10.1038/s41467-021-22509-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Morris LS, McCall JG, Charney DS, Murrough JW. The role of the locus coeruleus in the generation of pathological anxiety. Brain Neurosci Adv. 2020;4:2398212820930321 https://doi.org/10.1177/2398212820930321.

    Article  PubMed  PubMed Central  Google Scholar 

  159. Bachman SL, Nashiro K, Yoo H, Wang D, Thayer JF, Mather M. Associations between locus coeruleus MRI contrast and physiological responses to acute stress in younger and older adults. Brain Res. 2022;1796:148070 https://doi.org/10.1016/j.brainres.2022.148070.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Poe GR, Foote S, Eschenko O, Johansen JP, Bouret S, Aston-Jones G, et al. Locus coeruleus: a new look at the blue spot. Nat Rev Neurosci. 2020;21:644–59. https://doi.org/10.1038/s41583-020-0360-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Raskind MA, Peskind ER, Chow B, Harris C, Davis-Karim A, Holmes HA, et al. Trial of prazosin for post-traumatic stress disorder in military veterans. N Engl J Med. 2018;378:507–17. https://doi.org/10.1056/NEJMoa1507598.

    Article  CAS  PubMed  Google Scholar 

  162. Reist C, Streja E, Tang CC, Shapiro B, Mintz J, Hollifield M. Prazosin for treatment of post-traumatic stress disorder: a systematic review and meta-analysis. CNS Spectr. 2021;26:338–44. https://doi.org/10.1017/S1092852920001121.

    Article  PubMed  Google Scholar 

  163. Raskind MA, Millard SP, Petrie EC, Peterson K, Williams T, Hoff DJ, et al. Higher pretreatment blood pressure is associated with greater posttraumatic stress disorder symptom reduction in soldiers treated with prazosin. Biol Psychiatry. 2016;80:736–42. https://doi.org/10.1016/j.biopsych.2016.03.2108.

    Article  CAS  PubMed  Google Scholar 

  164. Shiner B, Leonard CE, Gui J, Cornelius SL, Schnurr PP, Hoyt JE, et al. Comparing medications for DSM-5 PTSD in routine VA practice. J Clin Psychiatry. 2020;81. Epub 20201013. https://doi.org/10.4088/JCP.20m13244.

  165. Rae Olmsted KL, Bartoszek M, Mulvaney S, McLean B, Turabi A, Young R, et al. Effect of stellate ganglion block treatment on posttraumatic stress disorder symptoms: a randomized clinical trial. JAMA Psychiatry. 2020;77:130–8. https://doi.org/10.1001/jamapsychiatry.2019.3474.

    Article  PubMed  Google Scholar 

  166. Smits JA, Rosenfield D, Davis ML, Julian K, Handelsman PR, Otto MW, et al. Yohimbine enhancement of exposure therapy for social anxiety disorder: a randomized controlled trial. Biol Psychiatry. 2014;75:840–6. https://doi.org/10.1016/j.biopsych.2013.10.008.

    Article  CAS  PubMed  Google Scholar 

  167. Cassidy CM, Carpenter KM, Konova AB, Cheung V, Grassetti A, Zecca L, et al. Evidence for dopamine abnormalities in the substantia nigra in cocaine addiction revealed by neuromelanin-sensitive MRI. Am J Psychiatry 2020;177:1038–47. https://doi.org/10.1176/appi.ajp.2020.20010090.

    Article  PubMed  PubMed Central  Google Scholar 

  168. Narendran R, Jedema HP, Lopresti BJ, Mason NS, Himes ML, Bradberry CW. Decreased vesicular monoamine transporter type 2 availability in the striatum following chronic cocaine self-administration in nonhuman primates. Biol Psychiatry. 2015;77:488–92. https://doi.org/10.1016/j.biopsych.2014.06.012.

    Article  CAS  PubMed  Google Scholar 

  169. Wang W, Zhornitsky S, Zhang S, Li CR. Noradrenergic correlates of chronic cocaine craving: neuromelanin and functional brain imaging. Neuropsychopharmacology. 2021;46:851–9. https://doi.org/10.1038/s41386-020-00937-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Aston-Jones G, Kalivas PW. Brain norepinephrine rediscovered in addiction research. Biol Psychiatry. 2008;63:1005–6. https://doi.org/10.1016/j.biopsych.2008.03.016.

    Article  PubMed  PubMed Central  Google Scholar 

  171. Jarcho JM, Wyngaarden JB, Johnston CR, Quarmley M, Smith DV, Cassidy CM. Substance abuse in emerging adults: the role of neuromelanin and ventral striatal response to social and monetary rewards. Brain Sci. 2022;12:Epub 20220304 https://doi.org/10.3390/brainsci12030352.

    Article  Google Scholar 

  172. Perlman G, Wengler K, Moeller SJ, Kotov R, Klein D, Weinstein J, et al. Neuromelanin-sensitive MRI signal is associated with lifetime substance use in young women. Am J Psychiatry. 2024. (in press).

  173. Raio CM, Biernacki K, Kapoor A, Wengler K, Bonagura D, Xue J, et al. Suboptimal foraging decisions and involvement of the ventral tegmental area in human opioid addiction. bioRxiv. https://doi.org/10.1101/2022.03.24.485654.

  174. Pagliaccio D, Wengler K, Durham K, Fontaine M, Rueppel M, Becker H, et al. Probing midbrain dopamine function in pediatric obsessive-compulsive disorder via neuromelanin-sensitive magnetic resonance imaging. Mol Psychiatry. 2023:1-8. Epub 20230517. https://doi.org/10.1038/s41380-023-02105-z.

  175. Theofilas P, Ehrenberg AJ, Dunlop S, Di Lorenzo Alho AT, Nguy A, Leite REP, et al. Locus coeruleus volume and cell population changes during Alzheimer's disease progression: a stereological study in human postmortem brains with potential implication for early-stage biomarker discovery. Alzheimers Dement. 2017;13:236–46. https://doi.org/10.1016/j.jalz.2016.06.2362.

    Article  PubMed  Google Scholar 

  176. Liu KY, Acosta-Cabronero J, Cardenas-Blanco A, Loane C, Berry AJ, Betts MJ, et al. In vivo visualization of age-related differences in the locus coeruleus. Neurobiol Aging. 2019;74:101–11. https://doi.org/10.1016/j.neurobiolaging.2018.10.014.

    Article  PubMed  PubMed Central  Google Scholar 

  177. Liu KY, Kievit RA, Tsvetanov KA, Betts MJ, Duzel E, Rowe JB, et al. Noradrenergic-dependent functions are associated with age-related locus coeruleus signal intensity differences. Nat Commun 2020;11:1712 https://doi.org/10.1038/s41467-020-15410-w.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Dahl MJ, Bachman SL, Dutt S, Duzel S, Bodammer NC, Lindenberger U, et al. The integrity of dopaminergic and noradrenergic brain regions is associated with different aspects of late-life memory performance. Nat Aging. 2023;3:1128–43. https://doi.org/10.1038/s43587-023-00469-z.

    Article  PubMed  PubMed Central  Google Scholar 

  179. Elman JA, Puckett OK, Beck A, Fennema-Notestine C, Cross LK, Dale AM, et al. MRI-assessed locus coeruleus integrity is heritable and associated with multiple cognitive domains, mild cognitive impairment, and daytime dysfunction. Alzheimers Dement. 2021;17:1017–25. https://doi.org/10.1002/alz.12261.

    Article  PubMed  Google Scholar 

  180. Bell TR, Elman JA, Beck A, Fennema-Notestine C, Gustavson DE, Hagler DJ, et al. Rostral-middle locus coeruleus integrity and subjective cognitive decline in early old age. J Int Neuropsychol Soc. 2023;29:763–74. https://doi.org/10.1017/S1355617722000881.

    Article  PubMed  Google Scholar 

  181. Ciampa CJ, Parent JH, Harrison TM, Fain RM, Betts MJ, Maass A, et al. Associations among locus coeruleus catecholamines, tau pathology, and memory in aging. Neuropsychopharmacology. 2022;47:1106–13. https://doi.org/10.1038/s41386-022-01269-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Giorgi FS, Lombardo F, Galgani A, Hlavata H, Della Latta D, Martini N, et al. Locus Coeruleus magnetic resonance imaging in cognitively intact elderly subjects. Brain Imaging Behav. 2022;16:1077–87. https://doi.org/10.1007/s11682-021-00562-0.

    Article  PubMed  Google Scholar 

  183. Xing Y, Sapuan A, Dineen RA, Auer DP. Life span pigmentation changes of the substantia nigra detected by neuromelanin-sensitive MRI. Mov Disord 2018;33:1792–9. https://doi.org/10.1002/mds.27502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Di Lorenzo Alho AT, Suemoto CK, Polichiso L, Tampellini E, de Oliveira KC, Molina M, et al. Three-dimensional and stereological characterization of the human substantia nigra during aging. Brain Struct Funct. 2016;221:3393–403. https://doi.org/10.1007/s00429-015-1108-6.

    Article  PubMed  Google Scholar 

  185. Abi-Dargham A, Horga G. The search for imaging biomarkers in psychiatric disorders. Nat Med. 2016;22:1248–55. https://doi.org/10.1038/nm.4190.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

CC was supported by NSERC grant RGPIN-1502. GH was supported by NIMH grants R01 MH117323 and R01 MH114965.

Author information

Authors and Affiliations

Authors

Contributions

KW, PT, CMC, GH: Conceptualization, literature review, writing of original and revised drafts. All authors contributed to drafting and approved the final version of the manuscript.

Corresponding author

Correspondence to Guillermo Horga.

Ethics declarations

Competing interests

KW, CMC, and GH are inventors on filed patents for the analysis and use of neuromelanin-sensitive MRI in central nervous system disorders licensed to Terran Biosciences, with no royalties received. GH and PT reported investigator-initiated sponsored research agreements with Terran Biosciences outside the submitted work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wengler, K., Trujillo, P., Cassidy, C.M. et al. Neuromelanin-sensitive MRI for mechanistic research and biomarker development in psychiatry. Neuropsychopharmacol. (2024). https://doi.org/10.1038/s41386-024-01934-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41386-024-01934-y

Search

Quick links