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Volume increase in the dentate gyrus after electroconvulsive therapy in depressed patients as measured with 7T


Electroconvulsive therapy (ECT) is the most effective treatment for depression, yet its working mechanism remains unclear. In the animal analog of ECT, neurogenesis in the dentate gyrus (DG) of the hippocampus is observed. In humans, volume increase of the hippocampus has been reported, but accurately measuring the volume of subfields is limited with common MRI protocols. If the volume increase of the hippocampus in humans is attributable to neurogenesis, it is expected to be exclusively present in the DG, whereas other processes (angiogenesis, synaptogenesis) also affect other subfields. Therefore, we acquired an optimized MRI scan at 7-tesla field strength allowing sensitive investigation of hippocampal subfields. A further increase in sensitivity of the within-subjects measurements is gained by automatic placement of the field of view. Patients receive two MRI scans: at baseline and after ten bilateral ECT sessions (corresponding to a 5-week interval). Matched controls are also scanned twice, with a similar 5-week interval. A total of 31 participants (23 patients, 8 controls) completed the study. A large and significant increase in DG volume was observed after ECT (M = 75.44 mm3, std error = 9.65, p < 0.001), while other hippocampal subfields were unaffected. We note that possible type II errors may be present due to the small sample size. In controls no changes in volume were found. Furthermore, an increase in DG volume was related to a decrease in depression scores, and baseline DG volume predicted clinical response. These findings suggest that the volume change of the DG is related to the antidepressant properties of ECT, and may reflect neurogenesis.

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  1. 1.

    UK ECT Review Group. Efficacy and safety of electroconvulsive therapy in depressive disorders: a systematic review and meta-analysis. Lancet. 2003;361:799–808.

  2. 2.

    Pagnin D, de Queiroz V, Pini S, Cassano GB. Efficacy of ECT in depression: a meta-analytic review. J ECT. 2004;20:13–20.

  3. 3.

    Dierckx B, Heijnen WT, van den Broek WW, Birkenhäger TK. Efficacy of electroconvulsive therapy in bipolar versus unipolar major depression: a meta-analysis. Bipolar Disord. 2012;14:146–50.

  4. 4.

    Kellner CH, Kaicher DC, Banerjee H, Knapp RG, Shapiro RJ, Briggs MC, et al. Depression severity in electroconvulsive therapy (ECT) versus pharmacotherapy trials. J ECT. 2015;31:31–33.

  5. 5.

    Husain MM, Rush AJ, Fink M, Knapp R, Petrides G, Rummans T, et al. Speed of response and remission in major depressive disorder with acute electroconvulsive therapy (ECT): a Consortium for Research in ECT (CORE) report. J Clin Psychiatry. 2004;65:485–91.

  6. 6.

    Tor P-C, Bautovich A, Wang M-J, Martin D, Harvey SB, Loo C. A systematic review and meta-analysis of brief versus ultrabrief right unilateral electroconvulsive therapy for depression. J Clin Psychiatry. 2015;76:e1092–8.

  7. 7.

    Inta D, Lima-Ojeda JM, Lau T, Tang W, Dormann C, Sprengel R, et al. Electroconvulsive therapy induces neurogenesis in frontal rat brain areas. PLoS One. 2013;8:e69869.

  8. 8.

    Nakamura K, Ito M, Liu Y, Seki T, Suzuki T, Arai H. Effects of single and repeated electroconvulsive stimulation on hippocampal cell proliferation and spontaneous behaviors in the rat. Brain Res. 2013;1491:88–97.

  9. 9.

    Perera TD, Coplan JD, Lisanby SH, Lipira CM, Arif M, Carpio C, et al. Antidepressant-induced neurogenesis in the hippocampus of adult nonhuman primates. J Neurosci. 2007;27:4894–901.

  10. 10.

    Kyeremanteng C, MacKay JC, James JS, Kent P, Cayer C, Anisman H, et al. Effects of electroconvulsive seizures on depression-related behavior, memory and neurochemical changes in Wistar and Wistar–Kyoto rats. Prog Neuropsychopharmacol Biol Psychiatry. 2014;54:170–8.

  11. 11.

    Rotheneichner P, Lange S, O’Sullivan A, Marschallinger J, Zaunmair P, Geretsegger C, et al. Hippocampal neurogenesis and antidepressive therapy: shocking relations. Neural Plast. 2014;2014:1–14.

  12. 12.

    Ito M, Seki T, Liu J, Nakamura K, Namba T, Matsubara Y, et al. Effects of repeated electroconvulsive seizure on cell proliferation in the rat hippocampus. Synapse. 2010;64:814–21.

  13. 13.

    Parent JM. Adult neurogenesis in the intact and epileptic dentate gyrus. Prog Brain Res. 2007;163:529–17.

  14. 14.

    Olesen MV, Wörtwein G, Folke J, Pakkenberg B. Electroconvulsive stimulation results in long-term survival of newly generated hippocampal neurons in rats. Hippocampus. 2017;27:52–60.

  15. 15.

    Hellsten J, West MJ, Arvidsson A, Ekstrand J, Jansson L, Wennström M, et al. Electroconvulsive seizures induce angiogenesis in adult rat hippocampus. Biol Psychiatry. 2005;58:871–8.

  16. 16.

    Wennström M, Hellsten J, Ekdahl CT, Tingström A. Electroconvulsive seizures induce proliferation of NG2-expressing glial cells in adult rat hippocampus. Biol Psychiatry. 2003;54:1015–24.

  17. 17.

    Vaidya VA, Siuciak JA, Du F, Duman RS. Hippocampal mossy fiber sprouting induced by chronic electroconvulsive seizures. Neuroscience. 1999;89:157–66.

  18. 18.

    Madsen TM, Treschow A, Bengzon J, Bolwig TG, Lindvall O, Tingström A. Increased neurogenesis in a model of electroconvulsive therapy. Biol Psychiatry. 2000;47:1043–9.

  19. 19.

    Ming G, Song H. Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron. 2011;70:687–702.

  20. 20.

    Rusznák Z, Henskens W, Schofield E, Kim WS, Fu Y. Adult neurogenesis and gliogenesis: possible mechanisms for neurorestoration. Exp Neurobiol. 2016;25:103.

  21. 21.

    Hickmott PW, Ethell IM. Dendritic plasticity in the adult neocortex. Neurosci. 2006;12:16–28.

  22. 22.

    Plate KH. Mechanisms of angiogenesis in the brain. J Neuropathol Exp Neurol. 1999;58:313–20.

  23. 23.

    Nordanskog P, Dahlstrand U, Larsson MR, Larsson E-M, Knutsson L, Johanson A. Increase in hippocampal volume after electroconvulsive therapy in patients with depression. J ECT. 2010;26:62–67.

  24. 24.

    Tendolkar I, van Beek M, van Oostrom I, Mulder M, Janzing J, Voshaar RO, et al. Electroconvulsive therapy increases hippocampal and amygdala volume in therapy refractory depression: a longitudinal pilot study. Psychiatry Res Neuroimaging. 2013;214:197–203.

  25. 25.

    Ota M, Noda T, Sato N, Okazaki M, Ishikawa M, Hattori K, et al. Effect of electroconvulsive therapy on gray matter volume in major depressive disorder. J Affect Disord. 2015;186:186–91.

  26. 26.

    Abbott CC, Jones T, Lemke NT, Gallegos P, McClintock SM, Mayer AR, et al. Hippocampal structural and functional changes associated with electroconvulsive therapy response. Transl Psychiatry. 2014;4:e483–e483.

  27. 27.

    Bouckaert F, Dols A, Emsell L, De Winter F-L, Vansteelandt K, Claes L, et al. Relationship between hippocampal volume, serum BDNF and depression severity following electroconvulsive therapy in late-life depression. Neuropsychopharmacology. 2016;41:2741–8.

  28. 28.

    Sartorius A, Demirakca T, Böhringer A, Clemm von Hohenberg C, Aksay SS, Bumb JM, et al. Electroconvulsive therapy increases temporal gray matter volume and cortical thickness. Eur Neuropsychopharmacol. 2016;26:506–17.

  29. 29.

    Redlich R, Opel N, Grotegerd D, Dohm K, Zaremba D, Bürger C, et al. Prediction of individual response to electroconvulsive therapy via machine learning on structural magnetic resonance imaging data. JAMA Psychiatry. 2016;73:557.

  30. 30.

    Cao B, Luo Q, Fu Y, Du L, Qiu T, Yang X, et al. Predicting individual responses to the electroconvulsive therapy with hippocampal subfield volumes in major depression disorder. Sci Rep. 2018;8:5434.

  31. 31.

    Nordanskog P, Larsson MR, Larsson E-M, Johanson A. Hippocampal volume in relation to clinical and cognitive outcome after electroconvulsive therapy in depression. Acta Psychiatr Scand. 2014;129:303–11.

  32. 32.

    Oltedal L, Narr KL, Abbott C, Anand A, Argyelan M, Bartsch H, et al. Volume of the human hippocampus and clinical response following electroconvulsive therapy. Biol Psychiatry. 2018.

  33. 33.

    Takamiya A, Chung JK, Liang K, Graff-Guerrero A, Mimura M, Kishimoto T. Effect of electroconvulsive therapy on hippocampal and amygdala volumes: systematic review and meta-analysis. Br J Psychiatry. 2018;212:19–26.

  34. 34.

    Gbyl K, Videbech P. Electroconvulsive therapy increases brain volume in major depression: a systematic review and meta-analysis. Acta Psychiatr Scand. 2018.

  35. 35.

    Wilkinson ST, Sanacora G, Bloch MH. Hippocampal volume changes following electroconvulsive therapy: a systematic review and meta-analysis. Biol Psychiatry Cogn Neurosci Neuroimaging. 2017;2:327–35.

  36. 36.

    Oltedal L, Bartsch H, Sørhaug OJE, Kessler U, Abbott C, Dols A, et al. The Global ECT-MRI Research Collaboration (GEMRIC): establishing a multi-site investigation of the neural mechanisms underlying response to electroconvulsive therapy. NeuroImage Clin. 2017;14:422–32.

  37. 37.

    Sorrells SF, Paredes MF, Cebrian-Silla A, Sandoval K, Qi D, Kelley KW, et al. Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults. Nature. 2018;555:377–81.

  38. 38.

    Boldrini M, Fulmore CA, Tartt AN, Simeon LR, Pavlova I, Poposka V, et al. Human hippocampal neurogenesis persists throughout aging. Cell Stem Cell. 2018;22:589–99.e5.

  39. 39.

    Wisse LEM, Biessels GJ, Geerlings MI. A critical appraisal of the hippocampal subfield segmentation package in FreeSurfer. Front Aging Neurosci. 2014.

  40. 40.

    Wisse LEM, Kuijf HJ, Honingh AM, Wang H, Pluta JB, Das SR, et al. Automated hippocampal subfield segmentation at 7T MRI. AJNR Am J Neuroradiol. 2016;37:1050–7.

  41. 41.

    Giuliano A, Donatelli G, Cosottini M, Tosetti M, Retico A, Fantacci ME. Hippocampal subfields at ultra high field MRI: an overview of segmentation and measurement methods. Hippocampus. 2017;27:481–94.

  42. 42.

    Yushkevich PA, Wang H, Pluta J, Das SR, Craige C, Avants BB, et al. Nearly automatic segmentation of hippocampal subfields in in vivo focal T2-weighted MRI. Neuroimage. 2010;53:1208–24.

  43. 43.

    van der Kolk AG, Hendrikse J, Zwanenburg JJM, Visser F, Luijten PR. Clinical applications of 7T MRI in the brain. Eur J Radiol. 2013;82:708–18.

  44. 44.

    Diagnostic and statistical manual of mental disorders, fourth edition, text revision (DSM-IV-TR). 2000.

  45. 45.

    van den Broek WW, Birkenhäger TK, de Boer D, Burggraaf JP, van Gemert B, Groenland THN, et al. Richtlijn elektroconvulsietherapie. Boom uitgevers Amsterdam: Amsterdam, 2010.

  46. 46.

    Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry Psychiatry. 1998;59(Suppl 2):22–33. quiz 34-57

  47. 47.

    van Vliet IM, de Beurs E. The MINI-International Neuropsychiatric Interview. A brief structured diagnostic psychiatric interview for DSM-IV & ICD-10 psychiatric disorders. Tijdschr Psychiatr. 2007;49:393–7.

  48. 48.

    Abrams R. Electroconvulsive therapy. 4th ed. New York, NY: Oxford University Press; 2002.

  49. 49.

    Yushkevich PA, Pluta JB, Wang H, Xie L, Ding S-L, Gertje EC, et al. Automated volumetry and regional thickness analysis of hippocampal subfields and medial temporal cortical structures in mild cognitive impairment. Hum Brain Mapp. 2015;36:258–87.

  50. 50.

    Smith SM, Jenkinson M, Woolrich MW, Beckmann CF, Behrens TEJ, Johansen-Berg H, et al. Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage. 2004;23(Suppl 1):S208–19.

  51. 51.

    Tustison NJ, Cook PA, Klein A, Song G, Das SR, Duda JT, et al. Large-scale evaluation of ANTs and FreeSurfer cortical thickness measurements. Neuroimage. 2014;99:166–79.

  52. 52.

    Avants BB, Epstein CL, Grossman M, Gee JC. Symmetric diffeomorphic image registration with cross-correlation: evaluating automated labeling of elderly and neurodegenerative brain. Med Image Anal. 2008;12:26–41.

  53. 53.

    Wang H, Suh JW, Das SR, Pluta JB, Craige C, Yushkevich PA. Multi-atlas segmentation with joint label fusion. IEEE Trans Pattern Anal Mach Intell. 2013;35:611–23.

  54. 54.

    Wang H, Das SR, Suh JW, Altinay M, Pluta J, Craige C, et al. A learning-based wrapper method to correct systematic errors in automatic image segmentation: consistently improved performance in hippocampus, cortex and brain segmentation. Neuroimage. 2011;55:968–85.

  55. 55.

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

  56. 56.

    Moran PW, Lambert MJ. (1983). A review of current assessment tools for monitoring changes in depression. In: Lambert MJ, Christensen ER, DeJulio SS (eds). The assessment of psychotherapy outcome. Wiley: New York, pp 304-355.

  57. 57.

    Kuznetsova A, Brockhoff PB, Christensen RHB. lmerTest Package: tests in linear mixed effects models. J Stat Softw. 2017.

  58. 58.

    R Core Team (2013) R: a language and environment for statistical computing.

  59. 59.

    Bates D, Mächler M, Bolker B, Walker S. Fitting linear mixed-effects models using lme4. J Stat Softw. 2015.

  60. 60.

    Kuznetsova A, Brockhoff PB, Christensen RHB. lmerTest Package: tests in linear mixed effects models. J Stat Softw. 2017.

  61. 61.

    Bakdash JZ, Marusich LR. Repeated measures correlation. Front Psychol. 2017.

  62. 62.

    Zhao C, Warner-Schmidt JS, Duman R, Gage FH. Electroconvulsive seizure promotes spine maturation in newborn dentate granule cells in adult rat. Dev Neurobiol. 2012;72:937–42.

  63. 63.

    Gombos Z, Spiller A, Cottrell GA, Racine RJ, McIntyre Burnham W. Mossy fiber sprouting induced by repeated electroconvulsive shock seizures. Brain Res. 1999;844:28–33.

  64. 64.

    Lamont SR, Paulls A, Stewart CA. Repeated electroconvulsive stimulation, but not antidepressant drugs, induces mossy fibre sprouting in the rat hippocampus. Brain Res. 2001;893:53–8.

  65. 65.

    Chen F, Madsen TM, Wegener G, Nyengaard JR. Repeated electroconvulsive seizures increase the total number of synapses in adult male rat hippocampus. Eur Neuropsychopharmacol. 2009;19:329–38.

  66. 66.

    Smitha JSM, Roopa R, Khaleel N, Kutty BM, Andrade C. Images in electroconvulsive therapy. J ECT. 2014;30:191–2.

  67. 67.

    Ekstrand J, Hellsten J, Wennström M, Tingström A. Differential inhibition of neurogenesis and angiogenesis by corticosterone in rats stimulated with electroconvulsive seizures. Prog Neuro-Psychopharmacol Biol Psychiatry. 2008;32:1466–72.

  68. 68.

    Girgenti MJ, Collier E, Sathyanesan M, Su XW, Newton SS. Characterization of electroconvulsive seizure-induced TIMP-1 and MMP-9 in hippocampal vasculature. Int J Neuropsychopharmacol. 2011;14:535–44.

  69. 69.

    Newton SS, Girgenti MJ, Collier EF, Duman RS. Electroconvulsive seizure increases adult hippocampal angiogenesis in rats. Eur J Neurosci. 2006;24:819–28.

  70. 70.

    Palmer TD, Willhoite AR, Gage FH. Vascular niche for adult hippocampal neurogenesis. J Comp Neurol. 2000;425:479–94.

  71. 71.

    Kaae SS, Chen F, Wegener G, Madsen TM, Nyengaard JR. Quantitative hippocampal structural changes following electroconvulsive seizure treatment in a rat model of depression. Synapse. 2012;66:667–76.

  72. 72.

    Wennström M, Hellsten J, Ekstrand J, Lindgren H, Tingström A. Corticosterone-induced inhibition of gliogenesis in rat hippocampus is counteracted by electroconvulsive seizures. Biol Psychiatry. 2006;59:178–86.

  73. 73.

    Lieberwirth C, Pan Y, Liu Y, Zhang Z, Wang Z. Hippocampal adult neurogenesis: Its regulation and potential role in spatial learning and memory. Brain Res. 2016;1644:127–40.

  74. 74.

    Akers KG, Martinez-Canabal A, Restivo L, Yiu AP, De Cristofaro A, Hsiang H-L, et al. Hippocampal neurogenesis regulates forgetting during adulthood and infancy. Science. 2014;344:598–602.

  75. 75.

    Weisz VI, Argibay PF. Neurogenesis interferes with the retrieval of remote memories: forgetting in neurocomputational terms. Cognition. 2012;125:13–25.

  76. 76.

    Frankland PW, Köhler S, Josselyn SA. Hippocampal neurogenesis and forgetting. Trends Neurosci. 2013;36:497–503.

  77. 77.

    Toda T, Parylak SL, Linker SB, Gage FH. The role of adult hippocampal neurogenesis in brain health and disease. Mol Psychiatry. 2018.

  78. 78.

    Vasavada MM, Leaver AM, Njau S, Joshi SH, Ercoli L, Hellemann G, et al. Short- and long-term cognitive outcomes in patients with major depression treated with electroconvulsive therapy. J ECT. 2017;33:278–85.

  79. 79.

    Semkovska M, McLoughlin DM. Objective cognitive performance associated with electroconvulsive therapy for depression: a systematic review and meta-analysis. Biol Psychiatry. 2010;68:568–77.

  80. 80.

    Nuninga JO, Claessens TFI, Somers M, Mandl R, Nieuwdorp W, Boks MP, et al. Immediate and long-term effects of bilateral electroconvulsive therapy on cognitive functioning in patients with a depressive disorder. J Affect Disord. 2018;238:659–65.

  81. 81.

    Sackeim HA. Autobiographical memory and electroconvulsive therapy. J ECT. 2014;30:177–86.

  82. 82.

    Small SA, Schobel SA, Buxton RB, Witter MP, Barnes CA. A pathophysiological framework of hippocampal dysfunction in ageing and disease. Nat Rev Neurosci. 2011;12:585–601.

  83. 83.

    Koolschijn PCMP, van Haren NEM, Lensvelt-Mulders GJLM, Hulshoff Pol HE, Kahn RS. Brain volume abnormalities in major depressive disorder: a meta-analysis of magnetic resonance imaging studies. Hum Brain Mapp. 2009;30:3719–35.

  84. 84.

    Malberg JE, Eisch AJ, Nestler EJ, Duman RS. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci. 2000;20:9104–10.

  85. 85.

    Santarelli L. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science. 2003;301:805–9.

  86. 86.

    Eisch AJ, Petrik D. Depression and hippocampal neurogenesis: a road to remission? Science. 2012;338:72–75.

  87. 87.

    Eliwa H, Belzung C, Surget A. Adult hippocampal neurogenesis: is it the alpha and omega of antidepressant action? Biochem Pharmacol. 2017;141:86–99.

  88. 88.

    David DJ, Samuels BA, Rainer Q, Wang J-W, Marsteller D, Mendez I, et al. Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression. Neuron. 2009;62:479–93.

  89. 89.

    Tanti A, Belzung C. Neurogenesis along the septo-temporal axis of the hippocampus: are depression and the action of antidepressants region-specific? Neuroscience. 2013;252:234–52.

  90. 90.

    Serafini G, Hayley S, Pompili M, Dwivedi Y, Brahmachari G, Girardi P, et al. Hippocampal neurogenesis, neurotrophic factors and depression: possible therapeutic targets? CNS Neurol Disord Drug Targets. 2014;13:1708–21.

  91. 91.

    Perera TD, Dwork AJ, Keegan KA, Thirumangalakudi L, Lipira CM, Joyce N, et al. Necessity of hippocampal neurogenesis for the therapeutic action of antidepressants in adult nonhuman primates. PLoS One. 2011;6:e17600.

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The authors thank the Netherlands Organization for Scientific Research (NWO) for providing the financial support (Aspasia grant) for this study.

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Correspondence to Jasper O. Nuninga.

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