Skip to main content
Log in

Overlapping expression of serotonin transporters and neurokinin-1 receptors in posttraumatic stress disorder: a multi-tracer PET study

  • Original Article
  • Published:
Molecular Psychiatry Submit manuscript

Abstract

The brain serotonergic system is colocalized and interacts with the neuropeptidergic substance P/neurokinin-1 (SP/NK1) system. Both these neurochemical systems have independently been implicated in stress and anxiety, but interactions between them might be crucial for human anxiety conditions. Here, we examined the serotonin and substance P/neurokinin-1 (SP/NK1) systems individually as well as their overlapping expression in 16 patients with posttraumatic stress disorder (PTSD) and 16 healthy controls. Participants were imaged with the highly selective radiotracers [11C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile (DASB) and [11C]GR205171 assessing serotonin transporter (SERT) and NK1 receptor availability, respectively. Voxel-wise analyses in the amygdala, our a priori-defined region of interest, revealed increased number of NK1 receptors, but not SERT in the PTSD group. Symptom severity, as indexed by the Clinician-administered PTSD Scale, was negatively related to SERT availability in the amygdala, and NK1 receptor levels moderated this relationship. Exploratory, voxel-wise whole-brain analyses revealed increased SERT availability in the precentral gyrus and posterior cingulate cortex of PTSD patients. Patients, relative to controls, displayed lower degree of overlapping expression between SERT and NK1 receptors in the putamen, thalamus, insula and lateral orbitofrontal gyrus, lower overlap being associated with higher PTSD symptom severity. Expression overlap also explained more of the symptomatology than did either system individually, underscoring the importance of taking interactions between the neurochemical systems into account. Thus, our results suggest that aberrant serotonergic-SP/NK1 couplings contribute to the pathophysiology of PTSD and, consequently, that normalization of these couplings may be therapeutically important.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 4th (edn). Text Revision American Psychiatric Publishing, Inc.: Washington, DC, USA, 2000.

  2. Kessler RC, Petukhova M, Sampson NA, Zaslavsky AM, Wittchen H-U . Twelve-month and lifetime prevalence and lifetime morbid risk of anxiety and mood disorders in the United States. Int J Methods Psychiatr Res 2012; 21: 169–184.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Perkonigg A, Pfister H, Stein MB, Höfler M, Lieb R, Maercker A et al. Longitudinal course of posttraumatic stress disorder and posttraumatic stress disorder symptoms in a community sample of adolescents and young Adults. AJP 2005; 162: 1320–1327.

    Article  Google Scholar 

  4. Pietrzak RH, Goldstein RB, Southwick SM, Grant BF . Psychiatric comorbidity of full and partial posttraumatic stress disorder among older adults in the United States: results from wave 2 of the national epidemiologic survey on alcohol and related conditions. Am J Geriatr Psychiatry 2012; 20: 380–390.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Bailey CR, Cordell E, Sobin SM, Neumeister A . Recent progress in understanding the pathophysiology of post-traumatic stress disorder. CNS Drugs 2013; 27: 221–232.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Pitman RK, Rasmusson AM, Koenen KC, Shin LM, Orr SP, Gilbertson MW et al. Biological studies of post-traumatic stress disorder. Nat Rev Neurosci 2012; 13: 769–787.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Neumeister A, Normandin MD, Pietrzak RH, Piomelli D, Zheng MQ, Gujarro-Anton A et al. Elevated brain cannabinoid CB1 receptor availability in post-traumatic stress disorder: a positron emission tomography study. Mol Psychiatry 2013; 18: 1034–1040.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Pole N . The psychophysiology of posttraumatic stress disorder: a meta-analysis. Psychol Bull 2007; 133: 725–746.

    Article  PubMed  Google Scholar 

  9. Peri T, Ben-Shakhar G, Orr SP, Shalev AY . Psychophysiologic assessment of aversive conditioning in posttraumatic stress disorder. Biol Psychiatry 2000; 47: 512–519.

    Article  CAS  PubMed  Google Scholar 

  10. Sartory G, Cwik J, Knuppertz H, Schürholt B, Lebens M, Seitz RJ et al. In search of the trauma memory: a meta-analysis of functional neuroimaging studies of symptom provocation in posttraumatic stress disorder (PTSD). PLoS One 2013; 8: e58150.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Sehlmeyer C, Schöning S, Zwitserlood P, Pfleiderer B, Kircher T, Arolt V et al. Human fear conditioning and extinction in neuroimaging: a systematic review. PLoS One 2009; 4: e5865.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Rhodes RA, Murthy NV, Dresner MA, Selvaraj S, Stavrakakis N, Babar S et al. Human 5-HT transporter availability predicts amygdala reactivity in vivo. J Neurosci 2007; 27: 9233–9237.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Fisher PM, Meltzer CC, Ziolko SK, Price JC, Hariri AR . Capacity for 5-HT1A–mediated autoregulation predicts amygdala reactivity. Nat Neurosci 2006; 9: 1362–1363.

    Article  CAS  PubMed  Google Scholar 

  14. Åhs F, Frick A, Furmark T, Fredrikson M . Human serotonin transporter availability predicts fear conditioning. Int J Psychophysiol 2015; doi:10.1016/j.ijpsycho.2014.12.002; e-pub ahead of print.

    Article  PubMed  Google Scholar 

  15. Murrough JW, Huang Y, Hu J, Henry S, Williams W, Gallezot J-D et al. Reduced amygdala serotonin transporter binding in posttraumatic stress disorder. Biol Psychiatry 2011; 70: 1033–1038.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gressier F, Calati R, Balestri M, Marsano A, Alberti S, Antypa N et al. The 5-HTTLPR polymorphism and posttraumatic stress disorder: a meta-analysis. J Trauma Stress 2013; 26: 645–653.

    Article  PubMed  Google Scholar 

  17. Garpenstrand H, Annas P, Ekblom J, Oreland L, Fredrikson M . Human fear conditioning is related to dopaminergic and serotonergic biological markers. Behav Neurosci 2001; 115: 358–364.

    Article  CAS  PubMed  Google Scholar 

  18. Davidson JRT . Pharmacologic treatment of acute and chronic stress following trauma. J Clin Psychiatry 2006; 67: 34–39.

    CAS  PubMed  Google Scholar 

  19. Burghardt NS, Sigurdsson T, Gorman JM, McEwen BS, LeDoux JE . Chronic antidepressant treatment impairs the acquisition of fear extinction. Biol Psychiatry 2013; 73: 1078–1086.

    Article  CAS  PubMed  Google Scholar 

  20. Burghardt NS, Sullivan GM, McEwen BS, Gorman JM, LeDoux JE . The selective serotonin reuptake inhibitor citalopram increases fear after acute treatment but reduces fear with chronic treatment: a comparison with tianeptine. Biol Psychiatry 2004; 55: 1171–1178.

    Article  CAS  PubMed  Google Scholar 

  21. Houle S, Ginovart N, Hussey D, Meyer JH, Wilson AA . Imaging the serotonin transporter with positron emission tomography: initial human studies with [11C]DAPP and [11C]DASB. Eur J Nucl Med 2000; 27: 1719–1722.

    Article  CAS  PubMed  Google Scholar 

  22. Geracioti TD, Carpenter LL, Owens MJ, Baker DG, Ekhator NN, Horn PS et al. Elevated cerebrospinal fluid substance p concentrations in posttraumatic stress disorder and major depression. Am J Psychiatry 2006; 163: 637–643.

    Article  PubMed  Google Scholar 

  23. Mathew SJ, Vythilingam M, Murrough JW, Zarate CA Jr, Feder A, Luckenbaugh DA et al. A selective neurokinin-1 receptor antagonist in chronic PTSD: A randomized, double-blind, placebo-controlled, proof-of-concept trial. Eur Neuropsychopharmacol 2011; 21: 221–229.

    Article  CAS  PubMed  Google Scholar 

  24. Nakanishi S . Mammalian tachykinin receptors. Annu Rev Neurosci 1991; 14: 123–136.

    Article  CAS  PubMed  Google Scholar 

  25. Von Euler US, Gaddum JH . An unidentified depressor substance in certain tissue extracts. J Physiol 1931; 72: 74–87.

    Article  Google Scholar 

  26. Ribeiro-da-Silva A, Hökfelt T . Neuroanatomical localisation of Substance P in the CNS and sensory neurons. Neuropeptides 2000; 34: 256–271.

    Article  CAS  PubMed  Google Scholar 

  27. Ebner K, Singewald N . The role of substance P in stress and anxiety responses. Amino Acids 2006; 31: 251–272.

    Article  CAS  PubMed  Google Scholar 

  28. Fujimura Y, Yasuno F, Farris A, Liow J-S, Geraci M, Drevets W et al. Decreased neurokinin-1 (substance P) receptor binding in patients with panic disorder: positron emission tomographic study with [18F]SPA-RQ. Biol Psychiatry 2009; 66: 94–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Michelgård Å, Appel L, Pissiota A, Frans Ö, Långström B, Bergström M et al. Symptom provocation in specific phobia affects the substance P neurokinin-1 receptor system. Biol Psychiatry 2007; 61: 1002–1006.

    Article  PubMed  Google Scholar 

  30. Ebner K, Rupniak NM, Saria A, Singewald N . Substance P in the medial amygdala: Emotional stress-sensitive release and modulation of anxiety-related behavior in rats. PNAS 2004; 101: 4280–4285.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Heldt SA, Davis M, Ratti E, Corsi M, Trist D, Ressler KJ . Anxiolytic-like effects of the neurokinin 1 receptor antagonist GR-205171 in the elevated plus-maze and contextual fear-potentiated startle model of anxiety in gerbils. Behav Pharmacol 2009; 20: 584–595.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhao Z, Yang Y, Walker DL, Davis M . Effects of substance P in the amygdala, ventromedial hypothalamus, and periaqueductal gray on fear-potentiated startle. Neuropsychopharmacology 2008; 34: 331–340.

    Article  PubMed  Google Scholar 

  33. Kwako LE, George DT, Schwandt ML, Spagnolo PA, Momenan R, Hommer DW et al. The neurokinin-1 receptor antagonist aprepitant in co-morbid alcohol dependence and posttraumatic stress disorder: a human experimental study. Psychopharmacology 2015; 232: 295–304.

    Article  CAS  PubMed  Google Scholar 

  34. Etkin A, Egner T, Kalisch R . Emotional processing in anterior cingulate and medial prefrontal cortex. Trends Cogn Sci 2011; 15: 85–93.

    Article  PubMed  Google Scholar 

  35. Motzkin JC, Philippi CL, Wolf RC, Baskaya MK, Koenigs M . Ventromedial prefrontal cortex is critical for the regulation of amygdala activity in humans. Biol Psychiatry 2015; 77: 276–284.

    Article  PubMed  Google Scholar 

  36. Etkin A, Wager TD . Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. Am J Psychiatry 2007; 164: 1476–1488.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Bergström M, Fasth K-J, Kilpatrick G, Ward P, Cable KM, Wipperman MD et al. Brain uptake and receptor binding of two [11C]labelled selective high affinity NK1-antagonists, GR203040 and GR205171 — PET studies in rhesus monkey. Neuropharmacol 2000; 39: 664–670.

    Article  Google Scholar 

  38. Sergeyev V, Hökfelt T, Hurd Y . Serotonin and substance P co-exist in dorsal raphe neurons of the human brain. Neuroreport 1999; 10: 3967–3970.

    Article  CAS  PubMed  Google Scholar 

  39. Hafizi S, Serres F, Pei Q, Totterdell S, Sharp T . Evidence for the differential co-localization of neurokinin-1 receptors with 5-HT receptor subtypes in rat forebrain. J Psychopharmacol 2012; 26: 505–515.

    Article  CAS  PubMed  Google Scholar 

  40. Shirayama Y, Mitsushio H, Takashima M, Ichikawa H, Takahashi K . Reduction of substance P after chronic antidepressants treatment in the striatum, substantia nigra and amygdala of the rat. Brain Res 1996; 739: 70–78.

    Article  PubMed  Google Scholar 

  41. Tuominen L, Nummenmaa L, Keltikangas-Järvinen L, Raitakari O, Hietala J . Mapping neurotransmitter networks with PET: An example on serotonin and opioid systems. Hum Brain Mapp 2014; 35: 1875–1884.

    Article  PubMed  Google Scholar 

  42. Blake DD, Weathers FW, Nagy LM, Kaloupek DG, Gusman FD, Charney DS et al. The development of a clinician-administered PTSD scale. J Trauma Stress 1995; 8: 75–90.

    Article  CAS  PubMed  Google Scholar 

  43. Montgomery SA, Asberg M . A new depression scale designed to be sensitive to change. BJP 1979; 134: 382–389.

    Article  CAS  Google Scholar 

  44. 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 1998; 59 (Suppl 20): 22–33.

    PubMed  Google Scholar 

  45. Logan J, Fowler JS, Volkow ND, Wang GJ, Ding YS, Alexoff DL . Distribution volume ratios without blood sampling from graphical analysis of PET data. J Cereb Blood Flow Metab 1996; 16: 834–840.

    Article  CAS  PubMed  Google Scholar 

  46. Ginovart N, Wilson AA, Meyer JH, Hussey D, Houle S . Positron emission tomography quantification of [11C]-DASB binding to the human serotonin transporter: modeling strategies. J Cereb Blood Flow Metab 2001; 21: 1342–1353.

    Article  CAS  PubMed  Google Scholar 

  47. Innis RB, Cunningham VJ, Delforge J, Fujita M, Gjedde A, Gunn RN et al. Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab 2007; 27: 1533–1539.

    Article  CAS  PubMed  Google Scholar 

  48. Patlak CS, Blasberg RG, Fenstermacher JD . Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. J Cereb Blood Flow Metab 1983; 3: 1–7.

    Article  CAS  PubMed  Google Scholar 

  49. Meyer JH . Imaging the serotonin transporter during major depressive disorder and antidepressant treatment. J Psychiatry Neurosci 2007; 32: 86–102.

    PubMed  PubMed Central  Google Scholar 

  50. Tauscher J, Kielbasa W, Iyengar S, Vandenhende F, Peng X, Mozley D et al. Development of the 2nd generation neurokinin-1 receptor antagonist LY686017 for social anxiety disorder. Eur Neuropsychopharmacol 2010; 20: 80–87.

    Article  CAS  PubMed  Google Scholar 

  51. Hietala J, Nyman MJ, Eskola O, Laakso A, Grönroos T, Oikonen V et al. Visualization and quantification of neurokinin-1 (NK1) receptors in the human brain. Mol Imaging Biol 2005; 7: 262–272.

    Article  PubMed  Google Scholar 

  52. Svarer C, Madsen K, Hasselbalch SG, Pinborg LH, Haugbøl S, Frøkjaer VG et al. MR-based automatic delineation of volumes of interest in human brain PET images using probability maps. Neuroimage 2005; 24: 969–979.

    Article  PubMed  Google Scholar 

  53. Jonasson M . Automatic definition of volumes of interest using a probability template method (PVElab) without a structural MRI image. In: Poster presented at the 10th International Symposium on Functional Neuroreceptor Mapping of the Living Brain. Egmond aan Zee, the Netherlands 2014.

  54. Murrough JW, Czermak C, Henry S, Nabulsi N, Gallezot J-D, Gueorguieva R et al. Theeffect of early trauma exposure on serotonin type 1B receptor expression revealed by reduced selective radioligand binding. Arch Gen Psychiatry 2011; 68: 892–900.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Shin LM, Liberzon I . The neurocircuitry of fear, stress, and anxiety disorders. Neuropsychopharmacology 2010; 35: 169–191.

    Article  PubMed  Google Scholar 

  56. Sullivan GM, Ogden RT, Huang Y, Oquendo MA, Mann JJ, Parsey RV . Higher in vivo serotonin-1A binding in posttraumatic strss disorder: A PET study with [11C]WAY-100635. Depress Anxiety 2013; 30: 197–206.

    Article  CAS  PubMed  Google Scholar 

  57. Maldjian JA, Laurienti PJ, Kraft RA, Burdette JH . An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets. Neuroimage 2003; 19: 1233–1239.

    Article  PubMed  Google Scholar 

  58. Jovanovic H, Lundberg J, Karlsson P, Cerin Å, Saijo T, Varrone A et al. Sex differences in the serotonin 1A receptor and serotonin transporter binding in the human brain measured by PET. NeuroImage 2008; 39: 1408–1419.

    Article  PubMed  Google Scholar 

  59. Engman J, Åhs F, Furmark T, Linnman C, Pissiota A, Appel L et al. Age, sex and NK1 receptors in the human brain — a positron emission tomography study with [11C]GR205171. Eur Neuropsychopharmacol 2012; 22: 562–568.

    Article  CAS  PubMed  Google Scholar 

  60. Nyman MJ, Eskola O, Kajander J, Vahlberg T, Sanabria S, Burns D et al. Gender and age affect NK1 receptors in the human brain - a positron emission tomography study with [18F]SPA-RQ. Int J Neuropsychopharmacol 2007; 10: 219–229.

    Article  CAS  PubMed  Google Scholar 

  61. Pietrzak RH, Gallezot J-D, Ding Y-S, Henry S, Potenza MN, Southwick SM et al. Association of posttraumatic stress disorder with reduced in vivo norepinephrine availability in the locus coeruleus. JAMA Psychiatry 2013; 70: 1199–1205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Frick A, Åhs F, Engman J, Jonasson M, Alaie I, Björkstrand J et al. Serotoninsynthesis and reuptake in social anxiety disorder: a positron emission tomography study. JAMA Psychiatry 2015; 72: 794–802.

    Article  PubMed  Google Scholar 

  63. Näslund J, Studer E, Petterson R, Hagsäter M, Nilsson S, Nissbrandt H et al. Differences in anxiety-like behaviour within a batch of Wistar rats are associated with differences in serotonergic transmission, enhanced by acute SSRI administration and abolished by serotonin depletion. Int J Neuropsychopharmacol 2015; 18: pyv018.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Hwang BH, Katner J, Iyengar S . Corticotropin-releasing factor mRNA and substance P receptor binding in the paraventricular hypothalamic nucleus, central nucleus of the amygdala, and locus coeruleus of sprague-dawley rats following restraint-induced stress. J Mol Neurosci 2005; 25: 239–250.

    Article  CAS  PubMed  Google Scholar 

  65. Bassi GS, de Carvalho MC, Brandão ML . Effects of substance P and Sar-Met-SP, a NK1 agonist, in distinct amygdaloid nuclei on anxiety-like behavior in rats. Neurosci Lett 2014; 569: 121–125.

    Article  CAS  PubMed  Google Scholar 

  66. Truitt WA, Johnson PL, Dietrich AD, Fitz SD, Shekhar A . Anxiety-like behavior is modulated by a discrete subpopulation of interneurons in the basolateral amygdala. Neuroscience 2009; 160: 284–294.

    Article  CAS  PubMed  Google Scholar 

  67. Maubach KA, Martin K, Smith DW, Hewson L, Frankshun RA, Harrison T et al. Substance P stimulates inhibitory synaptic transmission in the guinea pig basolateral amygdala in vitro. Neuropharmacology 2001; 40: 806–817.

    Article  CAS  PubMed  Google Scholar 

  68. Morris MC, Compas BE, Garber J . Relationsamong posttraumatic stress disorder, comorbid major depression, and hpa function: a systematic review and meta-analysis. Clin Psychol Rev 2012; 32: 301–315.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Jessop DS, Renshaw D, Larsen PJ, Chowdrey HS, Harbuz MS . Substance P is involved in terminating the hypothalamo-pituitary-adrenal axis response to acute stress through centrally located neurokinin-1 receptors. Stress 2000; 3: 209–220.

    Article  CAS  PubMed  Google Scholar 

  70. Frick A, Ahs F, Linnman C, Jonasson M, Appel L, Lubberink M et al. Increased neurokinin-1 receptor availability in the amygdala in social anxiety disorder: a positron emission tomography study with [11C]GR205171. Transl Psychiatry 2015; 5: e597.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Furmark T, Appel L, Michelgård Å, Wahlstedt K, Åhs F, Zancan S et al. Cerebral blood flow changes after treatment of social phobia with the neurokinin-1 antagonist GR205171, citalopram, or placebo. Biol Psychiatry 2005; 58: 132–142.

    Article  CAS  PubMed  Google Scholar 

  72. Kramer MS, Winokur A, Kelsey J, Preskorn SH, Rothschild AJ, Snavely D et al. Demonstration of the efficacy and safety of a novel substance P (NK1) receptor antagonist in major depression. Neuropsychopharmacology 2004; 29: 385–392.

    Article  CAS  PubMed  Google Scholar 

  73. Kramer MS, Cutler N, Feighner J, Shrivastava R, Carman J, Sramek JJ et al. Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science 1998; 281: 1640–1645.

    Article  CAS  PubMed  Google Scholar 

  74. Keller M, Montgomery S, Ball W, Morrison M, Snavely D, Liu G et al. Lack of efficacy of the substance p (neurokinin1 receptor) antagonist aprepitant in the treatment of major depressive disorder. Biol Psychiatry 2006; 59: 216–223.

    Article  CAS  PubMed  Google Scholar 

  75. Ratti E, Bellew K, Bettica P, Bryson H, Zamuner S, Archer G et al. Results from 2 randomized, double-blind, placebo-controlled studies of the novel NK1 receptor antagonist casopitant in patients with major depressive disorder. J Clin Psychopharmacol 2011; 31: 727–733.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Supported by the Swedish Research Council; the Swedish Brain Foundation; Riksbankens Jubileumsfond—the Swedish Foundation for Humanities and Social Sciences; and the Swedish Research Council for Health, Working Life and Welfare. We would like to express our gratitude to all study participants, and to the staff of the Uppsala PET center for their assistance in data collection.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to A Frick.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Molecular Psychiatry website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Frick, A., Åhs, F., Palmquist, Å. et al. Overlapping expression of serotonin transporters and neurokinin-1 receptors in posttraumatic stress disorder: a multi-tracer PET study. Mol Psychiatry 21, 1400–1407 (2016). https://doi.org/10.1038/mp.2015.180

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2015.180

  • Springer Nature Limited

This article is cited by

Navigation