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Subcortical biophysical abnormalities in patients with mood disorders

Abstract

Cortical–subcortical circuits have been implicated in the pathophysiology of mood disorders. Structural and biochemical abnormalities have been identified in patients diagnosed with mood disorders using magnetic resonance imaging-related approaches. In this study, we used magnetization transfer (MT), an innovative magnetic resonance approach, to study biophysical changes in both gray and white matter regions in cortical–subcortical circuits implicated in emotional regulation and behavior. Our study samples comprised 28 patients clinically diagnosed with major depressive disorder (MDD) and 31 non-depressed subjects of comparable age and gender. MT ratio (MTR), representing the biophysical integrity of macromolecular proteins within key components of cortical–subcortical circuits—the caudate, thalamic, striatal, orbitofrontal, anterior cingulate and dorsolateral regions—was the primary outcome measure. In our study, the MTR in the head of the right caudate nucleus was significantly lower in the MDD group when compared with the comparison group. MTR values showed an inverse relationship with age in both groups, with more widespread relationships observed in the MDD group. These data indicate that focal biophysical abnormalities in the caudate nucleus may be central to the pathophysiology of depression and critical to the cortical–subcortical abnormalities that underlie mood disorders. Depression may also accentuate age-related changes in the biophysical properties of cortical and subcortical regions. These observations have broad implications for the neuronal circuitry underlying mood disorders across the lifespan.

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References

  1. Kessler RC, Berglund P, Demler O, Jin R, Koretz D, Merikangas KR et al. The epidemiology of major depressive disorder results from the National Comorbidity Survey Replication (NCS-R). JAMA 2003; 289: 3095–3105.

    PubMed  Google Scholar 

  2. Wittchen HU . The burden of mood disorders. Science 2012; 338: 15.

    Article  CAS  PubMed  Google Scholar 

  3. Saveanu RV, Nemeroff CB . Etiology of depression: genetic and environmental factors. Psychiatr Clin N Am 2012; 35: 51–71.

    Article  Google Scholar 

  4. Belmaker RH, Agam G . Major depressive disorder. N Engl J Med 2008; 358: 55–68.

    Article  CAS  PubMed  Google Scholar 

  5. Hasler G, Northoff G . Discovering imaging endophenotypes for major depression. Mol Psychiatry 2011; 16: 604–619.

    Article  CAS  PubMed  Google Scholar 

  6. Nestler EJ . Epigenetics: stress makes its molecular mark. Nature 2012; 490: 171–172.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Duman RS, Aghajanian GK . Synaptic dysfunction in depression: potential therapeutic targets. Science 2012; 338: 68–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Berton O, Hahn CG, Thase ME . Are we getting closer to valid translational models for major depression? Science 2012; 338: 75–79.

    Article  CAS  PubMed  Google Scholar 

  9. Cummings JL . The neuroanatomy of depression. J Clin Psychiatry 1993; 54 (Suppl): 14–20.

    PubMed  Google Scholar 

  10. Alexopoulos GS . Frontostriatal and limbic dysfunction in late-life depression. Am J Geriatr Psychiatry 2002; 10: 687–695.

    Article  PubMed  Google Scholar 

  11. Chow TW, Cummings JL . Frontal–subcortical circuitsMiller BL In: JC (ed.), The Human Frontal Lobes. The Guilford Press: New York, NY, USA pp 3–26 1999.

    Google Scholar 

  12. Kumar A, Newberg A, Alavi A, Berlin J, Smith R, Reivich M . Regional cerebral glucose metabolism in late-life depression and Alzheimer disease: a preliminary positron emission tomography study. Proc Natl Acad Sci USA 1993; 90: 7019–7023.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kumar A, Jin Z, Bilker W, Udupa J, Gottlieb G . Late-onset minor and major depression: early evidence for common neuroanatomical substrates detected by using MRI. Proc Natl Acad Sci USA 1998; 95: 7654–7658.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Vythilingam M, Charles HC, Tupler LA, Blitchington T, Kelly L, Krishnan KR . Focal and lateralized subcortical abnormalities in unipolar major depressive disorder: an automated multivoxel proton magnetic resonance spectroscopy study. Biol Psychiatry 2003; 54: 744–750.

    Article  PubMed  Google Scholar 

  15. Sheline YI, Price JL, Yan Z, Mintun MA . Resting-state functional MRI in depression unmasks increased connectivity between networks via the dorsal nexus. Proc Natl Acad Sci USA 2010; 107: 11020–11025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Alexopoulos GS, Murphy CF, Gunning-Dixon FM, Glatt CE, Latoussakis V, Kelly RE Jr et al. Serotonin transporter polymorphisms, microstructural white matter abnormalities and remission of geriatric depression. J Affect Disord 2009; 119: 132–141.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Eng J, Ceckler TL, Balaban RS . Quantitative 1H magnetization transfer imaging in vivo. Magn Reson Med 1991; 17: 304–314.

    Article  CAS  PubMed  Google Scholar 

  18. Balaban RS, Ceckler TL . Magnetization transfer contrast in magnetic resonance imaging. Magn Reson Q 1992; 8: 116–137.

    CAS  PubMed  Google Scholar 

  19. Grossman RI . Magnetization transfer in multiple sclerosis. Ann Neurol 1994; 36 (Suppl 1): S97–S99.

    Article  PubMed  Google Scholar 

  20. Henkelman RM, Stanisz GJ, Graham SJ . Magnetization transfer in MRI: a review. NMR Biomed 2001; 14: 57–64.

    Article  CAS  PubMed  Google Scholar 

  21. Van Waesberghe JHTM, Kamphorst W, De Groot CJ, van Walderveen MA, Castelijns JA, Ravid R et al. Axonal loss in multiple sclerosis lesions: magnetic resonance imaging insights into substrates of disability. Ann Neurol 1999; 46: 747–754.

    Article  Google Scholar 

  22. Schmierer K, Tozer DJ, Scaravilli F, Altmann DR, Barker GJ, Tofts PS et al. Quantitative magnetization transfer imaging in postmortem multiple sclerosis brain. J Magn Reson Imag 2007; 26: 41–51.

    Article  Google Scholar 

  23. Bagary MS, Symms MR, Barker GJ, Mutsatsa SH, Joyce EM, Ron MA et al. Gray and white matter brain abnormalities in first-episode schizophrenia inferred from magnetization transfer imaging. Arch Gen Psychiatry 2003; 60: 779–788.

    Article  PubMed  Google Scholar 

  24. Khaleeli Z, Altmann DR, Cercignani M, Ciccarelli O, Miller DH, Thompson AJ . Magnetization transfer ratio in gray matter: a potential surrogate marker for progression in early primary progressive multiple sclerosis. Arch Neurol 2008; 65: 1454–1459.

    Article  PubMed  Google Scholar 

  25. Steens SC, Bosma GP, Steup-Beekman GM, le Cessie S, Huizinga TW, van Buchem MA . Association between microscopic brain damage as indicated by magnetization transfer imaging and anticardiolipin antibodies in neuropsychiatric lupus. Arthritis Res Ther 2006; 8: R38.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Bruno SD, Barker GJ, Cercignani M, Symms M, Ron MA . A study of bipolar disorder using magnetization transfer imaging and voxel-based morphometry. Brain 2004; 127: 2433–2440.

    Article  CAS  PubMed  Google Scholar 

  27. Hanyu H, Asano T, Sakurai H, Takasaki M, Shindo H, Abe K . Magnetisation transfer measurements of the subcortical grey and white matter in Parkinson’s disease with and without dementia and in progressive supranuclear palsy. Neuroradiology 2001; 43: 542–546.

    Article  CAS  PubMed  Google Scholar 

  28. Hanyu H, Asano T, Sakurai H, Takasaki M, Shindo H, Abe K . Magnetization transfer measurements of the hippocampus in the early diagnosis of Alzheimer’s disease. J Neurol Sci 2001; 188: 79–84.

    Article  CAS  PubMed  Google Scholar 

  29. Hanyu H, Shimizu S, Tanaka Y, Kanetaka H, Iwamoto T, Abe K . Differences in magnetization transfer ratios of the hippocampus between dementia with Lewy bodies and Alzheimer’s disease. Neurosci Lett 2005; 380: 166–169.

    Article  CAS  PubMed  Google Scholar 

  30. Hickman SJ, Toosy AT, Jones SJ, Altmann DR, Miszkiel KA, MacManus DG et al. Serial magnetization transfer imaging in acute optic neuritis. Brain 2004; 127: 692–700.

    Article  CAS  PubMed  Google Scholar 

  31. Gunning-Dixon FM, Hoptman MJ, Lim KO, Murphy CF, Klimstra S, Latoussakis V et al. Macromolecular white matter abnormalities in geriatric depression: a magnetization transfer imaging study. Am J Geriatr Psychiatry 2008; 16: 255–262.

    Article  PubMed  Google Scholar 

  32. Kumar A, Gupta RC, Albert Thomas M, Alger J, Wyckoff N, Hwang S . Biophysical changes in normal-appearing white matter and subcortical nuclei in late-life major depression detected using magnetization transfer. Psychiatry Res 2004; 130: 131–140.

    Article  PubMed  Google Scholar 

  33. Zhang T-J, Wu QZ, Huang XQ, Sun XL, Zou K, Lui S et al. Magnetization transfer imaging reveals the brain deficit in patients with treatment-refractory depression. J Affect Disord 2009; 117: 157–161.

    Article  PubMed  Google Scholar 

  34. Alexander GE, DeLong MR, Strick PL . Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci 1986; 9: 357–381.

    Article  CAS  PubMed  Google Scholar 

  35. Selemon LD, Goldman-Rakic PS . Longitudinal topography and interdigitation of corticostriatal projections in the rhesus monkey. J Neurosci 1985; 5: 776–794.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 4th edn. APA: Washington, DC, USA, 1994.

  37. Hamilton M . A rating scale for depression. J Neurol Neurosurg Psychiatry 1960; 23: 56–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Folstein MF, Folstein SE, McHugh PR . ‘Mini-mental state’. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12: 189–198.

    Article  CAS  PubMed  Google Scholar 

  39. Radloff LS . The CES-D scale. Appl Psychol Meas 1977; 1: 385–401.

    Article  Google Scholar 

  40. Wolf PA, D’Agostino RB, Belanger AJ, Kannel WB . Probability of stroke: a risk profile from the Framingham Study. Stroke 1991; 22: 312–318.

    Article  CAS  PubMed  Google Scholar 

  41. Smith SA, Farrell JA, Jones CK, Reich DS, Calabresi PA, van Zijl PC . Pulsed magnetization transfer imaging with body coil transmission at 3 Tesla: feasibility and application. Magn Reson Med 2006; 56: 866–875.

    Article  PubMed  Google Scholar 

  42. Chau W, McIntosh AR . The Talairach coordinate of a point in the MNI space: how to interpret it. NeuroImage 2005; 25: 408–416.

    Article  PubMed  Google Scholar 

  43. Jenkinson M, Beckmann CF, Behrens TE, Woolrich MW, Smith SM . FSL. NeuroImage 2012; 62: 782–790.

    Article  PubMed  Google Scholar 

  44. Benjamini Y, Hochberg Y . Controlling the FDR: a practical and powerful approach to multiple testing. J R Stat Soc Ser B 1995; 57: 289–300.

    Google Scholar 

  45. Bhaumik DK, Roy A, Lazar NA, Kapur K, Aryal S, Sweeney JA et al. Hypothesis testing, power and sample size determination for between group comparisons in fMRI experiments. Statist Methodol 2009; 6: 133–149.

    Article  Google Scholar 

  46. Kumar A, Gupta R, Thomas A, Ajilore O, Hellemann G . Focal subcortical biophysical abnormalities in patients diagnosed with type 2 diabetes and depression. Arch Gen Psychiatry 2009; 66: 324–330.

    Article  PubMed  Google Scholar 

  47. Ajilore O, Haroon E, Kumaran S, Darwin C, Binesh N, Mintz J et al. Measurement of brain metabolites in patients with type 2 diabetes and major depression using proton magnetic resonance spectroscopy. Neuropsychopharmacology 2007; 32: 1224–1231.

    Article  CAS  PubMed  Google Scholar 

  48. Gabbay V, Hess DA, Liu S, Babb JS, Klein RG, Gonen O et al. Lateralized caudate metabolic abnormalities in adolescent major depressive disorder: a proton MR spectroscopy study. Am J Psychiatry 2007; 164: 1881–1889.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Butters MA, Aizenstein HJ, Hayashi KM, Meltzer CC, Seaman J, Reynolds CF III et al. Three-dimensional surface mapping of the caudate nucleus in late-life depression. Am J Geriatr Psychiatry 2009; 17: 4–12.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Pizzagalli DA, Holmes AJ, Dillon DG, Goetz EL, Birk JL, Bogdan R et al. Reduced caudate and nucleus accumbens response to rewards in unmedicated individuals with major depressive disorder. Am J Psychiatry 2009; 166: 702–710.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Kim MJ, Hamilton JP, Gotlib IH . Reduced caudate gray matter volume in women with major depressive disorder. Psychiatry Res 2008; 164: 114–122.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Krishnan KR, McDonald WM, Escalona PR, Doraiswamy PM, Na C, Husain MM et al. Magnetic resonance imaging of the caudate nuclei in depression. Preliminary observations. Arch Gen Psychiatry 1992; 49: 553–557.

    Article  CAS  PubMed  Google Scholar 

  53. Joseph R . Caudate Nucleus. Neuropsychiatry, Neuropsychology, Clinical Neuroscience. Academic Press: New York, NY, USA, 2000.

    Google Scholar 

  54. Kumral E, Evyapan D, Balkir K . Acute caudate vascular lesions. Stroke 1999; 30: 100–108.

    Article  CAS  PubMed  Google Scholar 

  55. Starkstein SE, Robinson RG, Berthier ML, Parikh RM, Price TR . Differential mood changes following basal ganglia vs thalamic lesions. Arch Neurol 1988; 45: 725–730.

    Article  CAS  PubMed  Google Scholar 

  56. Villablanca JR . Why do we have a caudate nucleus? Acta Neurobiol Exp (Wars) 2010; 70: 95–105.

    Google Scholar 

  57. Khundakar A, Morris C, Oakley A, Thomas AJ . Morphometric analysis of neuronal and glial cell pathology in the caudate nucleus in late-life depression. Am J Geriatr Psychiatry 2011; 19: 132–141.

    Article  PubMed  Google Scholar 

  58. Westlye LT, Walhovd KB, Dale AM, Bjørnerud A, Due-Tønnessen P, Engvig A et al. Life-span changes of the human brain white matter: diffusion tensor imaging (DTI) and volumetry. Cereb Cortex 2010; 20: 2055–2068.

    Article  PubMed  Google Scholar 

  59. Moseley M . Diffusion tensor imaging and aging—a review. NMR Biomed 2002; 15: 553–560.

    Article  PubMed  Google Scholar 

  60. Rovaris M, Iannucci G, Cercignani M, Sormani MP, De Stefano N, Gerevini S et al. Age-related changes in conventional, magnetization transfer, and diffusion-tensor MR imaging findings: study with whole-brain tissue histogram analysis. Radiology 2003; 227: 731–738.

    Article  PubMed  Google Scholar 

  61. Silver NC, Barker GJ, MacManus DG, Tofts PS, Miller DH . Magnetisation transfer ratio of normal brain white matter: a normative database spanning four decades of life. J Neurol Neurosurg Psychiatry 1997; 62: 223–228.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Charlton RA, Schiavone F, Barrick TR, Morris RG, Markus HS . Diffusion tensor imaging detects age related white matter change over a 2 year follow-up which is associated with working memory decline. J Neurol Neurosurg Psychiatry 2010; 81: 13–19.

    Article  CAS  PubMed  Google Scholar 

  63. Foong J, Symms MR, Barker GJ, Maier M, Woermann FG, Miller DH et al. Neuropathological abnormalities in schizophrenia: evidence from magnetization transfer imaging. Brain 2001; 124: 882–892.

    Article  CAS  PubMed  Google Scholar 

  64. Audoin B, Davies G, Rashid W, Fisniku L, Thompson AJ, Miller DH . Voxel-based analysis of grey matter magnetization transfer ratio maps in early relapsing remitting multiple sclerosis. Multiple Sclerosis 2007; 13: 483–489.

    Article  CAS  PubMed  Google Scholar 

  65. Haroon E, Raison CL, Miller AH . Psychoneuroimmunology meets neuropsychopharmacology: translational implications of the impact of inflammation on behavior. Neuropsychopharmacology 2012; 37: 137–162.

    Article  CAS  PubMed  Google Scholar 

  66. Raison CL, Capuron L, Miller AH . Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol 2006; 27: 24–31.

    Article  CAS  PubMed  Google Scholar 

  67. Alexopoulos GS, Meyers BS, Young RC, Campbell S, Silbersweig D, Charlson M . ‘Vascular depression’ hypothesis. Arch Gen Psychiatry 1997; 54: 915–922.

    Article  CAS  PubMed  Google Scholar 

  68. Krishnan KR, Hays JC, Blazer DG . MRI-defined vascular depression. Am J Psychiatry 1997; 154: 497–501.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by National Institute of Mental Health Grants 5R01MH063764-09, 5R01MH073989-05, 5K23MH081175-04 and 1K01AG040192-01A1. We thank Emma Rhodes, MA, Luan Phan, MD, Dulal Bhaumik, PhD for their helpful comments and manuscript preparation. We also thank Peter van Zijl, PhD and Joseph S Gillen for the MT sequence, which was developed by the support of the NCRR resource Grant P41 RR015241.

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Kumar, A., Yang, S., Ajilore, O. et al. Subcortical biophysical abnormalities in patients with mood disorders. Mol Psychiatry 19, 710–716 (2014). https://doi.org/10.1038/mp.2013.84

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