The impact of electroconvulsive therapy on brain grey matter volume: What does it mean?
Harold A. Sackeïm
Abstract
The Global ECT-MRI Research Collaboration (GEMRIC) has produced startling findings [1Ousdal O.T. Argyelan M. Narr K.L. Abbott C. Wade B. Vandenbulcke M. et al.Brain changes induced by electroconvulsive therapy are broadly distributed.Biol Psychiatr. 2020; 87: 451-461Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar, 2Mulders P.C.R. Llera A. Beckmann C.F. Vandenbulcke M. Stek M. Sienaert P. et al.Structural changes induced by electroconvulsive therapy are associated with clinical outcome. Brain Stimulation: basic, Translational, and Clinical Research in Neuromodulation.. 2020; 13: 696-704Google Scholar, 3Argyelan M. Oltedal L. Deng Z.D. Wade B. Bikson M. Joanlanne A. et al.Electric field causes volumetric changes in the human brain.Elife. 2019; 8Crossref PubMed Scopus (21) Google Scholar]. Over the last several years it has become evident that electroconvulsive therapy (ECT) results in increased hippocampal and amygdala volume [[4]Gbyl K. Videbech P. Electroconvulsive therapy increases brain volume in major depression: a systematic review and meta-analysis.Acta Psychiatr Scand. 2018; 138: 180-195Crossref PubMed Scopus (50) Google Scholar,[5]Wilkinson S.T. Sanacora G. Bloch M.H. Hippocampal volume changes following electroconvulsive therapy: a systematic review and meta-analysis.Biol Psychiatr Cogn Neurosci Neuroimag. 2017; 2: 327-335Scopus (44) Google Scholar], with considerable speculation that structural or functional changes in these regions are linked to therapeutic or adverse cognitive effects [[6]Joshi S.H. Espinoza R.T. Pirnia T. Shi J. Wang Y. Ayers B. et al.Structural plasticity of the Hippocampus and amygdala induced by electroconvulsive therapy in major depression.Biol Psychiatr. 2016; 79: 282-292Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar,[7]Abbott C.C. Jones T. Lemke N.T. Gallegos P. McClintock S.M. Mayer A.R. et al.Hippocampal structural and functional changes associated with electroconvulsive therapy response.Transl Psychiatry. 2014; 4: e483Crossref PubMed Scopus (114) Google Scholar]. However, with a large sample treated at multiple sites in Europe and the US, GEMRIC observed that 79 of 84 grey matter regions increased in volume shortly following a course of ECT [[1]Ousdal O.T. Argyelan M. Narr K.L. Abbott C. Wade B. Vandenbulcke M. et al.Brain changes induced by electroconvulsive therapy are broadly distributed.Biol Psychiatr. 2020; 87: 451-461Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar]. These regions included the hippocampus and amygdala, but were far more widely distributed than had been anticipated. Univariate analyses indicated that changes in some regions were associated with electrode placement (bifrontotemporal, BL vs. right unilateral ECT, RUL), as well as the number of ECT treatments, but there were no associations with clinical outcome. In contrast, Mulders et al. [[2]Mulders P.C.R. Llera A. Beckmann C.F. Vandenbulcke M. Stek M. Sienaert P. et al.Structural changes induced by electroconvulsive therapy are associated with clinical outcome. Brain Stimulation: basic, Translational, and Clinical Research in Neuromodulation.. 2020; 13: 696-704Google Scholar], using a subset of the same data, applied multivariate methods to identify discriminant spatial patterns that distinguished ECT responders and nonresponders. Patterns involving specific lateral and midline cortical and striatal structures contributed to the discrimination, with increases in some regions associated with response, while other regional increases were linked to nonresponse. Notably, the hippocampus and amygdala did not contribute to the discrimination of the clinical outcome groups. In part as a validation, Mulders et al. [[2]Mulders P.C.R. Llera A. Beckmann C.F. Vandenbulcke M. Stek M. Sienaert P. et al.Structural changes induced by electroconvulsive therapy are associated with clinical outcome. Brain Stimulation: basic, Translational, and Clinical Research in Neuromodulation.. 2020; 13: 696-704Google Scholar] applied the same analytic method to isolate a discriminant spatial pattern that distinguished BL and RUL ECT. In this case, volumetric increases in left medial temporal lobe structures distinguished the interventions, as might be expected given their differences in current density patterns [[8]Lee W.H. Lisanby S.H. Laine A.F. Peterchev A.V. Comparison of electric field strength and spatial distribution of electroconvulsive therapy and magnetic seizure therapy in a realistic human head model.Eur Psychiatr. 2016; 36: 55-64Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar,[9]Bai S. Galvez V. Dokos S. Martin D. Bikson M. Loo C. Computational models of Bitemporal, Bifrontal and Right Unilateral ECT predict differential stimulation of brain regions associated with efficacy and cognitive side effects.Eur Psychiatr. 2017; 41: 21-29Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar], with RUL ECT having less impact on these structures. Indeed, another GEMRIC report suggests that the extent of structural change following ECT is related to the local electrical field strength during stimulus delivery [[3]Argyelan M. Oltedal L. Deng Z.D. Wade B. Bikson M. Joanlanne A. et al.Electric field causes volumetric changes in the human brain.Elife. 2019; 8Crossref PubMed Scopus (21) Google Scholar]. The most secure finding in the GEMRIC reports is that there are wide spread volumetric increases in both cortical and subcortical grey matter regions within a week or two of completing an acute course of ECT. Ousdal et al. [[1]Ousdal O.T. Argyelan M. Narr K.L. Abbott C. Wade B. Vandenbulcke M. et al.Brain changes induced by electroconvulsive therapy are broadly distributed.Biol Psychiatr. 2020; 87: 451-461Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar] examined longitudinal MRI data from 328 patients in a major depressive episode treated with ECT at 14 sites, with comparable scanning procedures in 95 healthy controls. Volumes were computed in 84 grey matter regions of interest (ROIs), as well as total volume in subcortical grey matter (16 regions), cortical grey matter (66 regions), white matter, and ventricles (left and right lateral, third and fourth ventricles). At repeat imaging, healthy controls did not show significant volumetric change in any ROI. In contrast, at retesting, the patient group showed significantly increased volumes in all ROIs other than cerebellar grey matter and the white matter composite index. In addition, the patient group had decreased ventricular volume, which covaried (inversely) with the increase in subcortical grey matter volume. Presuming no major methodological artifacts, this work demonstrates that widespread grey matter volumetric change occurs during or shortly following ECT. The validity of these observations was reinforced by the fact that Ousdal et al. [[1]Ousdal O.T. Argyelan M. Narr K.L. Abbott C. Wade B. Vandenbulcke M. et al.Brain changes induced by electroconvulsive therapy are broadly distributed.Biol Psychiatr. 2020; 87: 451-461Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar] replicated the widely observed volumetric increases in the hippocampus and amygdala. They noted, however, that medial temporal lobe regions displayed the greatest effect sizes for volumetric change and, thus, were readily detected in previous studies that had considerably smaller samples. With the large sample size in the GEMRIC study, and perhaps improved image processing, all grey matter regions had significant volumetric increase, excluding the cerebellum and brain stem. The validity of these results was also supported by relations with the number of ECT treatments. Longer courses of ECT were associated with greater increases in total cortical and total subcortical volume, and a greater decrease in ventricular volume. Establishing the time course of these structural changes is fundamental to interpreting their significance. Clearly, a transient effect has different implications than persistent change. The available evidence indicates that both increased hippocampal volume and cortical thickness reverse when assessed 6–12 months postECT [10Bouckaert 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: 2741-2748Crossref PubMed Scopus (54) Google Scholar, 11Nordanskog P. Larsson M.R. Larsson E.M. Johanson A. Hippocampal volume in relation to clinical and cognitive outcome after electroconvulsive therapy in depression.Acta Psychiatr Scand. 2014; 129: 303-311Crossref PubMed Scopus (66) Google Scholar, 12Gbyl K. Rostrup E. Raghava J.M. Carlsen J.F. Schmidt L.S. Lindberg U. et al.Cortical thickness following electroconvulsive therapy in patients with depression: a longitudinal MRI study.Acta Psychiatr Scand. 2019; 140: 205-216Crossref PubMed Scopus (9) Google Scholar]. It will be important to learn whether the reversibility is complete across the volumetric changes reported in the GEMRIC sample, and to obtain finer timing for the emergence and resolution of these structural alterations. ECT, like monoaminergic antidepressant medications, results in increased neurogenesis in hippocampal structures, particularly the dentate gyrus and the subventricular zone. Indeed, there is evidence in both rodents [[13]Madsen T.M. Treschow A. Bengzon J. Bolwig T.G. Lindvall O. Tingstrom A. Increased neurogenesis in a model of electroconvulsive therapy.Biol Psychiatr. 2000; 47: 1043-1049Abstract Full Text Full Text PDF PubMed Scopus (613) Google Scholar] and primates [[14]Perera T.D. Coplan J.D. Lisanby S.H. Lipira C.M. Arif M. Carpio C. et al.Antidepressant-induced neurogenesis in the hippocampus of adult nonhuman primates.J Neurosci. 2007; 27: 4894-4901Crossref PubMed Scopus (346) Google Scholar] that electroconvulsive shock (ECS), the animal model of ECT, results in especially rapid and pronounced proliferation and differentiation of neuronal progenitors in hippocampal subunits. This enhancement of neurogenesis is not seen with classes of psychotropic medication other than antidepressants [[15]Malberg J.E. Eisch A.J. Nestler E.J. Duman R.S. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus.J Neurosci : Off J Soc Neurosci. 2000; 20: 9104-9110Crossref PubMed Google Scholar], and there is evidence that interfering with this neurotrophic process may block antidepressant effects in animal models. For example, targeted irradiation of the hippocampus that impedes the proliferation of stem cells appears to interfere with the antidepressant effects of fluoxetine in rodent [[16]Santarelli L. Saxe M. Gross C. Surget A. Battaglia F. Dulawa S. et al.Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants.Science. 2003; 301: 805-809Crossref PubMed Scopus (3382) Google Scholar] and primate [[17]Perera T.D. Dwork A.J. Keegan K.A. Thirumangalakudi L. Lipira C.M. Joyce N. et al.Necessity of hippocampal neurogenesis for the therapeutic action of antidepressants in adult nonhuman primates.PLoS One. 2011; 6e17600Crossref PubMed Scopus (179) Google Scholar] models of depression. Furthermore, ECS lost its typical antidepressant properties in a pharmacogenetic rodent model that suppresses hippocampal neurogenesis [[18]Schloesser R.J. Orvoen S. Jimenez D.V. Hardy N.F. Maynard K.R. Sukumar M. et al.Antidepressant-like effects of electroconvulsive seizures require adult neurogenesis in a neuroendocrine model of depression.Brain Stimul. 2015; 8: 862-867Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar]. This evidence, as well as findings linking major depression with hippocampal volume loss [19Shelline Y.I. Sanghavi M. Mintun M.A. Gado M.H. Depression duration but not age predicts hippocampal volume loss in medically healthy women with recurrent major depression.J Neurosci. 1999; 19: 5034-5043Crossref PubMed Google Scholar, 20Shelline Y.I. Wang P.W. Gado M.H. Csernansky J.G. Vannier M. Hippocampal atrophy in recurrent major depression.Proc Natl Acad Sci USA. 1996; 93: 3908-3913Crossref PubMed Scopus (1608) Google Scholar, 21McKinnon M.C. Yucel K. Nazarov A. MacQueen G.M. A meta-analysis examining clinical predictors of hippocampal volume in patients with major depressive disorder.J Psychiatr Neurosci : JPN. 2009; 34: 41-54PubMed Google Scholar], has created considerable interest in the possibility that promotion of neurogenesis is key to the therapeutic effects of ECT [22Inta D. Lima-Ojeda J.M. Lau T. Tang W. Dormann C. Sprengel R. et al.Electroconvulsive therapy induces neurogenesis in frontal rat brain areas.PLoS One. 2013; 8e69869Crossref PubMed Scopus (56) Google Scholar, 23Pirnia T. Joshi S.H. Leaver A.M. 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In not the that are the for the widespread volumetric Indeed, given the of effects of ECT, it may be that volumetric changes are by multiple and extent show regional the mediating it is important to the extent to which stimulation and patterns of contribute to the extent and spatial distribution of volumetric change. with patterns of should be examined both in of the and in seizure expression and In other in with the for the volumetric it is important to establish the of the ECT process that and the volumetric change. in which patients were to different electrode and electrical that both the efficacy of this treatment and the and of adverse cognitive effects are on the current and of the electrical the of density H.A. Prudic J. Devanand D.P. Kiersky J.E. Fitzsimons L. Moody B.J. et al.Effects of stimulus intensity and electrode placement on the efficacy and cognitive effects of electroconvulsive therapy.N Engl J Med. 1993; 328: 839-846Crossref PubMed Scopus (755) Google H.A. P. M. B. 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Joanlanne A. et al.Electric field causes volumetric changes in the human brain.Elife. 2019; 8Crossref PubMed Scopus (21) Google Scholar] examined the relations the electric volumetric and therapeutic in patients treated with RUL ECT. previous work on the electrical field has applied models to or a few structural MRI scans when the different spatial produced by in electrode or stimulus [[8]Lee W.H. Lisanby S.H. Laine A.F. Peterchev A.V. Comparison of electric field strength and spatial distribution of electroconvulsive therapy and magnetic seizure therapy in a realistic human head model.Eur Psychiatr. 2016; 36: 55-64Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar,[9]Bai S. Galvez V. Dokos S. Martin D. Bikson M. Loo C. 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