Hostname: page-component-78c5997874-fbnjt Total loading time: 0 Render date: 2024-11-14T19:19:29.808Z Has data issue: false hasContentIssue false
  • English
  • Français

Neural correlates of improved executive function following erythropoietin treatment in mood disorders

Published online by Cambridge University Press:  21 March 2016

K. W. Miskowiak ,
M. Vinberg ,
L. Glerup ,
O. B. Paulson ,
G. M. Knudsen ,
H. Ehrenreich ,
C. J. Harmer ,
L. V. Kessing ,
H. R. Siebner  and
J. Macoveanu
K. W. Miskowiak*
Affiliation:
Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark Danish Research Centre for Magnetic Resonance (DRCMR), Centre for Functional and Diagnostic Imaging and Research, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark
M. Vinberg
Affiliation:
Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
L. Glerup
Affiliation:
Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
O. B. Paulson
Affiliation:
Danish Research Centre for Magnetic Resonance (DRCMR), Centre for Functional and Diagnostic Imaging and Research, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark Center for Integrated Molecular Brain Imaging, Rigshospitalet, Copenhagen, Denmark Neurobiology Research Unit, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
G. M. Knudsen
Affiliation:
Center for Integrated Molecular Brain Imaging, Rigshospitalet, Copenhagen, Denmark Neurobiology Research Unit, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
H. Ehrenreich
Affiliation:
Division of Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany
C. J. Harmer
Affiliation:
Department of Psychiatry, University of Oxford, Oxford, UK
L. V. Kessing
Affiliation:
Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
H. R. Siebner
Affiliation:
Danish Research Centre for Magnetic Resonance (DRCMR), Centre for Functional and Diagnostic Imaging and Research, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark Center for Integrated Molecular Brain Imaging, Rigshospitalet, Copenhagen, Denmark Department of Neurology, Copenhagen University Hospital Bispebjerg, Copenhagen, Denmark
J. Macoveanu
Affiliation:
Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark Danish Research Centre for Magnetic Resonance (DRCMR), Centre for Functional and Diagnostic Imaging and Research, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark Center for Integrated Molecular Brain Imaging, Rigshospitalet, Copenhagen, Denmark
*
*Address for correspondence: Dr K. W. Miskowiak, Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, DK-2100, Copenhagen, Denmark. (Email: [email protected])
Get access Rights & Permissions [Opens in a new window]

Abstract

Background

Cognitive dysfunction in depression and bipolar disorder (BD) is insufficiently targeted by available treatments. Erythropoietin (EPO) increases neuroplasticity and may improve cognition in mood disorders, but the neuronal mechanisms of these effects are unknown. This functional magnetic resonance imaging (fMRI) study investigated the effects of EPO on neural circuitry activity during working memory (WM) performance.

Method

Patients with treatment-resistant major depression, who were moderately depressed, or with BD in partial remission, were randomized to eight weekly infusions of EPO (40 000 IU) (N = 30) or saline (N = 26) in a double-blind, parallel-group design. Patients underwent fMRI, mood ratings and blood tests at baseline and week 14. During fMRI patients performed an n-back WM task.

Results

EPO improved WM accuracy compared with saline (p = 0.045). Whole-brain analyses revealed that EPO increased WM load-related activity in the right superior frontal gyrus (SFG) compared with saline (p = 0.01). There was also enhanced WM load-related deactivation of the left hippocampus in EPO-treated compared to saline-treated patients (p = 0.03). Across the entire sample, baseline to follow-up changes in WM performance correlated positively with changes in WM-related SFG activity and negatively with hippocampal response (r = 0.28–0.30, p < 0.05). The effects of EPO were not associated with changes in mood or red blood cells (p ⩾0.08).

Conclusions

The present findings associate changes in WM-load related activity in the right SFG and left hippocampus with improved executive function in EPO-treated patients. Clinical trial registration: clinicaltrials.gov: NCT00916552.

Keywords

Bipolar disordercognitiondorsolateral prefrontal cortexerythropoietinEPOexecutive functionfMRItreatment-resistant depression
Type
Original Articles
Information
Psychological Medicine , Volume 46 , Issue 8 , June 2016 , pp. 1679 - 1691
Copyright
Copyright © Cambridge University Press 2016 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Bora, E, Harrison, BJ, Yucel, M, Pantelis, C (2013). Cognitive impairment in euthymic major depressive disorder: a meta-analysis. Psychological Medicine 43, 2017–2026.Google Scholar
Bourne, C, Aydemir, O, Balanza-Martinez, V, Bora, E, Brissos, S, Cavanagh, JT, Clark, L, Cubukcuoglu, Z, Dias, VV, Dittmann, S, Ferrier, IN, Fleck, DE, Frangou, S, Gallagher, P, Jones, L, Kieseppa, T, Martinez-Aran, A, Melle, I, Moore, PB, Mur, M, Pfennig, A, Raust, A, Senturk, V, Simonsen, C, Smith, DJ, Bio, DS, Soeiro-de-Souza, MG, Stoddart, SD, Sundet, K, Szoke, A, Thompson, JM, Torrent, C, Zalla, T, Craddock, N, Andreassen, OA, Leboyer, M, Vieta, E, Bauer, M, Worhunsky, PD, Tzagarakis, C, Rogers, RD, Geddes, JR, Goodwin, GM (2013). Neuropsychological testing of cognitive impairment in euthymic bipolar disorder: an individual patient data meta-analysis. Acta Psychiatrica Scandinavica 128, 149–162.Google Scholar
Brines, ML, Ghezzi, P, Keenan, S, Agnello, D, de Lanerolle, NC, Cerami, C, Itri, LM, Cerami, A (2000). Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proceedings of the National Academy of Sciences USA 97, 10526–10531.Google Scholar
Callicott, JH, Mattay, VS, Bertolino, A, Finn, K, Coppola, R, Frank, JA, Goldberg, TE, Weinberger, DR (1999). Physiological characteristics of capacity constraints in working memory as revealed by functional MRI. Cerebral Cortex 9, 20–26.Google Scholar
Carlson, PJ, Singh, JB, Zarate, CA Jr., Drevets, WC, Manji, HK (2006). Neural circuitry and neuroplasticity in mood disorders: insights for novel therapeutic targets. NeuroRx 3, 22–41.CrossRefGoogle ScholarPubMed
Demant, KM, Almer, GM, Vinberg, M, Kessing, LV, Miskowiak, KW (2013). Effects of cognitive remediation on cognitive dysfunction in partially or fully remitted patients with bipolar disorder: study protocol for a randomized controlled trial. Trials 14, 378.CrossRefGoogle ScholarPubMed
Demant, KM, Vinberg, M, Kessing, LV, Miskowiak, KW (2015). Effects of cognitive remediation on cognitive dysfunction in partially or fully remitted individuals with bipolar disorder: results of a randomised controlled trial. PLoS ONE 10, e0127955.Google Scholar
Depp, CA, Mausbach, BT, Harmell, AL, Savla, GN, Bowie, CR, Harvey, PD, Patterson, TL (2012). Meta-analysis of the association between cognitive abilities and everyday functioning in bipolar disorder. Bipolar Disorder 14, 217–226.Google Scholar
Dias, VV, Balanza-Martinez, V, Soeiro-de-Souza, MG, Moreno, RA, Figueira, ML, Machado-Vieira, R, Vieta, E (2012). Pharmacological approaches in bipolar disorder and the impact on cognition: a critical overview. Acta Psychiatrica Scandinavica 126, 315–331.Google Scholar
Ehrenreich, H, Degner, D, Meller, J, Brines, M, Béhé, M, Hasselblatt, M, Woldt, H, Falkai, P, Knerlich, F, Jacob, S, von Ahsen, N, Maier, W, Brück, W, Rüther, E, Cerami, A, Becker, W, Sirén, AL (2004). Erythropoietin: a candidate compound for neuroprotection in schizophrenia. Molecular Psychiatry 9, 42–54.Google Scholar
Ehrenreich, H, Fischer, B, Norra, C, Schellenberger, F, Stender, N, Stiefel, M, Siren, AL, Paulus, W, Nave, KA, Gold, R, Bartels, C (2007 a). Exploring recombinant human erythropoietin in chronic progressive multiple sclerosis. Brain 130, 2577–2588.CrossRefGoogle ScholarPubMed
Ehrenreich, H, Hinze-Selch, D, Stawicki, S, Aust, C, Knolle-Veentjer, S, Wilms, S, Heinz, G, Erdag, S, Jahn, H, Degner, D, Ritzen, M, Mohr, A, Wagner, M, Schneider, U, Bohn, M, Huber, M, Czernik, A, Pollmacher, T, Maier, W, Siren, AL, Klosterkotter, J, Falkai, P, Ruther, E, Aldenhoff, JB, Krampe, H (2007 b). Improvement of cognitive functions in chronic schizophrenic patients by recombinant human erythropoietin. Molecular Psychiatry 12, 206–220.Google Scholar
Fernandez-Corcuera, P, Salvador, R, Monte, GC, Salvador, SS, Goikolea, JM, Amann, B, Moro, N, Sans-Sansa, B, Ortiz-Gil, J, Vieta, E, Maristany, T, McKenna, PJ, Pomarol-Clotet, E (2013). Bipolar depressed patients show both failure to activate and failure to de-activate during performance of a working memory task. Journal of Affective Disorder 148, 170–178.CrossRefGoogle ScholarPubMed
Filippi, M, Riccitelli, G, Mattioli, F, Capra, R, Stampatori, C, Pagani, E, Valsasina, P, Copetti, M, Falini, A, Comi, G, Rocca, MA (2012). Multiple sclerosis: effects of cognitive rehabilitation on structural and functional MR imaging measures–-an explorative study. Radiology 262, 932–940.Google Scholar
Garrett, A, Kelly, R, Gomez, R, Keller, J, Schatzberg, AF, Reiss, AL (2011). Aberrant brain activation during a working memory task in psychotic major depression. American Journal of Psychiatry 168, 173–182.CrossRefGoogle ScholarPubMed
Ge, XH, Zhu, GJ, Geng, DQ, Zhang, ZJ, Liu, CF (2012). Erythropoietin attenuates 6-hydroxydopamine-induced apoptosis via glycogen synthase kinase 3beta-mediated mitochondrial translocation of Bax in PC12 cells. Neurological Sciences 33, 1249–1256.Google Scholar
Gonzalez-Castillo, J, Roopchansingh, V, Bandettini, PA, Bodurka, J (2011). Physiological noise effects on the flip angle selection in BOLD fMRI. Neuroimage 54, 2764–2778.Google Scholar
Grier, JB (1971). Nonparametric indices for sensitivity and bias: computing formulas. Psychological Bulletin 75, 424–429.Google Scholar
Harvey, PO, Fossati, P, Pochon, JB, Levy, R, Lebastard, G, Lehericy, S, Allilaire, JF, Dubois, B (2005). Cognitive control and brain resources in major depression: an fMRI study using the n-back task. Neuroimage 26, 860–869.CrossRefGoogle ScholarPubMed
Jaeger, J, Berns, S, Uzelac, S, Davis-Conway, S (2006). Neurocognitive deficits and disability in major depressive disorder. Psychiatry Research 145, 39–48.Google Scholar
Kastner, A, Grube, S, El-Kordi, A, Stepniak, B, Friedrichs, H, Sargin, D, Schwitulla, J, Begemann, M, Giegling, I, Miskowiak, KW, Sperling, S, Hannke, K, Ramin, A, Heinrich, R, Gefeller, O, Nave, KA, Rujescu, D, Ehrenreich, H (2012). Common variants of the genes encoding erythropoietin and its receptor modulate cognitive performance in schizophrenia. Molecular Medicine 18, 1029–1040.Google Scholar
Maldjian, JA, Laurienti, PJ, Kraft, RA, Burdette, JH (2003). An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets. Neuroimage 19, 1233–1239.Google Scholar
Marsden, WN (2013). Synaptic plasticity in depression: molecular, cellular and functional correlates. Progress in Neuropsychopharmacology and Biological Psychiatry 43, 168–184.Google Scholar
Matsuo, K, Glahn, DC, Peluso, MA, Hatch, JP, Monkul, ES, Najt, P, Sanches, M, Zamarripa, F, Li, J, Lancaster, JL, Fox, PT, Gao, JH, Soares, JC (2007). Prefrontal hyperactivation during working memory task in untreated individuals with major depressive disorder. Molecular Psychiatry 12, 158–166.Google Scholar
McDonald, JH (2014). Handbook of Biological Statistics. Sparky House Publishing: Baltimore, Maryland.Google Scholar
Meusel, LA, Hall, GB, Fougere, P, McKinnon, MC, MacQueen, GM (2013). Neural correlates of cognitive remediation in patients with mood disorders. Psychiatry Research 214, 142–152.Google Scholar
Miskowiak, K, Inkster, B, O'Sullivan, U, Selvaraj, S, Goodwin, GM, Harmer, CJ (2008). Differential effects of erythropoietin on neural and cognitive measures of executive function 3 and 7 days post-administration. Experimental Brain Research 184, 313–321.CrossRefGoogle ScholarPubMed
Miskowiak, K, O'Sullivan, U, Harmer, CJ (2007). Erythropoietin enhances hippocampal response during memory retrieval in humans. Journal of Neuroscience 27, 2788–2792.Google Scholar
Miskowiak, KW, Ehrenreich, H, Christensen, EM, Kessing, LV, Vinberg, M (2014 a). Recombinant human erythropoietin to target cognitive dysfunction in bipolar disorder: a double-blind, randomized, placebo-controlled phase 2 trial. Journal of Clinical Psychiatry 75, 1347–1355.Google Scholar
Miskowiak, KW, Favaron, E, Hafizi, S, Inkster, B, Goodwin, GM, Cowen, PJ, Harmer, CJ (2009). Effects of erythropoietin on emotional processing biases in patients with major depression: an exploratory fMRI study. Psychopharmacology (Berlin) 207, 133–142.Google Scholar
Miskowiak, KW, Glerup, L, Vestbo, C, Harmer, CJ, Reinecke, A, Macoveanu, J, Siebner, HR, Kessing, LV, Vinberg, M (2014 b). Different neural and cognitive response to emotional faces in healthy monozygotic twins at risk of depression. Psychological Medicine 45, 1447–1458.Google Scholar
Miskowiak, KW, Vinberg, M, Christensen, EM, Bukh, JD, Harmer, CJ, Ehrenreich, H, Kessing, LV (2014 c). Recombinant human erythropoietin for treating treatment-resistant depression: a double-blind, randomized, placebo-controlled phase 2 trial. Neuropsychopharmacology 39, 1399–1408.Google Scholar
Miskowiak, KW, Vinberg, M, Harmer, CJ, Ehrenreich, H, Kessing, LV (2012). Erythropoietin: a candidate treatment for mood symptoms and memory dysfunction in depression. Psychopharmacology (Berlin) 219, 687–698.CrossRefGoogle ScholarPubMed
Miskowiak, KW, Vinberg, M, Harmer, CJ, Ehrenreich, H, Knudsen, GM, Macoveanu, J, Hansen, AR, Paulson, OB, Siebner, HR, Kessing, LV (2010). Effects of erythropoietin on depressive symptoms and neurocognitive deficits in depression and bipolar disorder. Trials 11, 97.Google Scholar
Miskowiak, KW, Vinberg, M, Macoveanu, J, Ehrenreich, H, Koster, N, Inkster, B, Paulson, OB, Kessing, LV, Skimminge, A, Siebner, HR (2015). Effects of Erythropoietin on Hippocampal Volume and Memory in Mood Disorders. Biological Psychiatry 78, 270–277.Google Scholar
Nathan, PJ, Phan, KL, Harmer, CJ, Mehta, MA, Bullmore, ET (2014). Increasing pharmacological knowledge about human neurological and psychiatric disorders through functional neuroimaging and its application in drug discovery. Current Opinion in Pharmacology 14, 54–61.Google Scholar
Pomarol-Clotet, E, Alonso-Lana, S, Moro, N, Sarro, S, Bonnin, MC, Goikolea, JM, Fernandez-Corcuera, P, Amann, BL, Romaguera, A, Vieta, E, Blanch, J, McKenna, PJ, Salvador, R (2015). Brain functional changes across the different phases of Bipolar disorder . British Journal of Psychiatry 206, 136–144.Google Scholar
Porter, RJ, Bowie, CR, Jordan, J, Malhi, GS (2013). Cognitive remediation as a treatment for major depression: a rationale, review of evidence and recommendations for future research. Australian and New Zealand Journal of Psychiatry 47, 1165–1175.Google Scholar
Raichle, ME, MacLeod, AM, Snyder, AZ, Powers, WJ, Gusnard, DA, Shulman, GL (2001). A default mode of brain function. Proceedings of the National Academy of Sciences 98, 676–682.Google Scholar
Ramsay, IS, MacDonald, AW III (2015). Brain correlates of cognitive remediation in Schizophrenia: activation likelihood analysis shows preliminary evidence of neural target engagement. Schizophrenia Bulletin 41, 1276–1284.Google Scholar
Sheline, YI, Barch, DM, Price, JL, Rundle, MM, Vaishnavi, SN, Snyder, AZ, Mintun, MA, Wang, S, Coalson, RS, Raichle, ME (2009). The default mode network and self-referential processes in depression. Proceedings of the National Academy of Sciences USA 106, 1942–1947.CrossRefGoogle ScholarPubMed
Siegle, GJ, Thompson, W, Carter, CS, Steinhauer, SR, Thase, ME (2007). Increased amygdala and decreased dorsolateral prefrontal BOLD responses in unipolar depression: related and independent features. Biological Psychiatry 61, 198–209.Google Scholar
Siren, AL, Fasshauer, T, Bartels, C, Ehrenreich, H (2009). Therapeutic potential of erythropoietin and its structural or functional variants in the nervous system. Neurotherapeutics 6, 108–127.Google Scholar
Subramaniam, K, Luks, TL, Garrett, C, Chung, C, Fisher, M, Nagarajan, S, Vinogradov, S (2014). Intensive cognitive training in schizophrenia enhances working memory and associated prefrontal cortical efficiency in a manner that drives long-term functional gains. Neuroimage 99, 281–292.Google Scholar
Talairach, J, Tournoux, P (1988). Co-planar Stereotaxic Atlas of the Human Brain. Thieme: New York.Google Scholar
Townsend, J, Bookheimer, SY, Foland-Ross, LC, Sugar, CA, Altshuler, LL (2010). fMRI abnormalities in dorsolateral prefrontal cortex during a working memory task in manic, euthymic and depressed bipolar subjects. Psychiatry Research 182, 22–29.Google Scholar
Wager, TD, Smith, EE (2003). Neuroimaging studies of working memory: a meta-analysis. Cognive, Affective and Behavioral Neuroscience 3, 255–274.Google Scholar
Wang, R, Foniok, T, Wamsteeker, JI, Qiao, M, Tomanek, B, Vivanco, RA, Tuor, UI (2006). Transient blood pressure changes affect the functional magnetic resonance imaging detection of cerebral activation. Neuroimage 31, 1–11.CrossRefGoogle ScholarPubMed
Woolrich, MW, Behrens, TE, Beckmann, CF, Jenkinson, M, Smith, SM (2004). Multilevel linear modelling for FMRI group analysis using Bayesian inference. Neuroimage 21, 1732–1747.Google Scholar
Worsley, KJ (2001). In Functional MRI: An Introduction to Methods (ed. Jezzars, P. M., Matthews, P. and Smith, S. M.) pp. 251–270. Oxford University Press: Oxford.Google Scholar
Zandbelt, BB, Gladwin, TE, Raemaekers, M, van, BM, Neggers, SF, Kahn, RS, Ramsey, NF, Vink, M (2008). Within-subject variation in BOLD-fMRI signal changes across repeated measurements: quantification and implications for sample size. Neuroimage 42, 196–206.Google Scholar
Supplementary material: Image

Miskowiak supplementary material

Miskowiak supplementary material 1

Download Miskowiak supplementary material(Image)
Image 122.9 KB
Supplementary material: Image

Miskowiak supplementary material

Miskowiak supplementary material 2

Download Miskowiak supplementary material(Image)
Image 82.9 KB
Supplementary material: File

Miskowiak supplementary material

Miskowiak supplementary material 3

Download Miskowiak supplementary material(File)
File 11.5 KB