Advertisement

European Child & Adolescent Psychiatry

, Volume 26, Issue 2, pp 177–190 | Cite as

P300 amplitude and latency in autism spectrum disorder: a meta-analysis

  • Tingkai Cui
  • Peizhong Peter Wang
  • Shengxin Liu
  • Xin ZhangEmail author
Original Contribution

Abstract

Autism spectrum disorder (ASD) is an early onset neurodevelopmental disorder. Evidence suggests that ASD patients have abnormalities in information processing. Event-related potential (ERP) technique can directly record brain neural activity in real time. P300 is a positive ERP component which can measure the neuroelectrophysiological characteristics of human beings and has the potential to discover the pathological mechanism of ASD. However, P300 studies on ASD patients are incongruent and the disparities may be caused by several factors. By searching PubMed, Embase and Cochrane Library databases, a meta-analysis of P300 component difference between ASD group and typically developed (TD) control group was conducted. Results of amplitude and latency of P3b and P3a from included studies were synthesized. Random effect model was chosen and standardized mean difference (SMD) was calculated. Subgroup analysis was used to identify the source of heterogeneity and to test the effect of different experiment factors. A total of 407 ASD patients and 457 TD controls from 32 studies were included in this analysis. Reduced amplitude of P3b was found in ASD group (SMD = −0.505, 95 % CI −0.873, −0.138) compared with TD group, but no difference of P3b latency, P3a amplitude, or P3a latency was found between groups. Subgroup analysis showed that oddball paradigm elicited attenuated P3b amplitude in Pz electrode among ASD subjects. This meta-analysis suggests ASD patients have abnormalities in P300 component, which may represent for deficits in cognition, attention orientation and working memory processing, particularly in the decision-making processing condition.

Keywords

ASD P300 P3b P3a Meta-analysis 

Notes

Compliance with ethical standards

Conflict of interest

No conflict of interest exits in the submission of this manuscript.

References

  1. 1.
    American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders, 5th edn. American Psychiatric Publishing, ArlingtonCrossRefGoogle Scholar
  2. 2.
    Baio J (2014) Prevalence of autism spectrum disorder among children aged 8 years—autism and developmental disabilities monitoring network, 11 sites, United States, 2010. Morb Mortal Wkly Rep Surveill Summ (Washington, DC: 2002) 63(2):1–21Google Scholar
  3. 3.
    Lai MC, Lombardo MV, Baron-Cohen S (2014) Autism. Lancet 383(9920):896–910. doi: 10.1016/S0140-6736(13)61539-1 CrossRefPubMedGoogle Scholar
  4. 4.
    Chen Y, Norton DJ, McBain R, Gold J, Frazier JA, Coyle JT (2012) Enhanced local processing of dynamic visual information in autism: evidence from speed discrimination. Neuropsychologia 50(5):733–739. doi: 10.1016/j.neuropsychologia.2012.01.007 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Chien YL, Gau SS, Shang CY, Chiu YN, Tsai WC, Wu YY (2015) Visual memory and sustained attention impairment in youths with autism spectrum disorders. Psychol Med 45(11):2263–2273. doi: 10.1017/S0033291714003201 CrossRefPubMedGoogle Scholar
  6. 6.
    Russo-Ponsaran NM, McKown C, Johnson JK, Allen AW, Evans-Smith B, Fogg L (2015) Social-emotional correlates of early stage social information processing skills in children with and without autism spectrum disorder. Autism Res Off J Int Soc Autism Res 8(5):486–496. doi: 10.1002/aur.1463 CrossRefGoogle Scholar
  7. 7.
    Kayser J, Tenke CE (2015) Issues and considerations for using the scalp surface Laplacian in EEG/ERP research: a tutorial review. Int J Psychophysiol Off J Int Organ Psychophysiol 97(3):189–209. doi: 10.1016/j.ijpsycho.2015.04.012 Google Scholar
  8. 8.
    Sutton S, Braren M, Zubin J, John ER (1965) Evoked-potential correlates of stimulus uncertainty. Science 150(3700):1187–1188CrossRefPubMedGoogle Scholar
  9. 9.
    Polich J (2007) Updating P300: an integrative theory of P3a and P3b. Clin Neurophysiol Off J Int Fed Clin Neurophysiol 118(10):2128–2148. doi: 10.1016/j.clinph.2007.04.019 CrossRefGoogle Scholar
  10. 10.
    Jeste SS, Kirkham N, Senturk D, Hasenstab K, Sugar C, Kupelian C, Baker E, Sanders AJ, Shimizu C, Norona A, Paparella T, Freeman SF, Johnson SP (2015) Electrophysiological evidence of heterogeneity in visual statistical learning in young children with ASD. Dev Sci 18(1):90–105. doi: 10.1111/desc.12188 CrossRefPubMedGoogle Scholar
  11. 11.
    Samyn V, Wiersema JR, Bijttebier P, Roeyers H (2014) Effortful control and executive attention in typical and atypical development: an event-related potential study. Biol Psychol 99:160–171. doi: 10.1016/j.biopsycho.2014.03.006 CrossRefPubMedGoogle Scholar
  12. 12.
    Cygan HB, Tacikowski P, Ostaszewski P, Chojnicka I, Nowicka A (2014) Neural correlates of own name and own face detection in autism spectrum disorder. PLoS One 9(1):e86020. doi: 10.1371/journal.pone.0086020 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Lepisto T, Nieminen-von Wendt T, von Wendt L, Naatanen R, Kujala T (2007) Auditory cortical change detection in adults with Asperger syndrome. Neurosci Lett 414(2):136–140. doi: 10.1016/j.neulet.2006.12.009 CrossRefPubMedGoogle Scholar
  14. 14.
    van Dinteren R, Arns M, Jongsma ML, Kessels RP (2014) P300 development across the lifespan: a systematic review and meta-analysis. PLoS One 9(2):e87347. doi: 10.1371/journal.pone.0087347 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Dujardin K, Derambure P, Bourriez JL, Jacquesson JM, Guieu JD (1993) P300 component of the event-related potentials (ERP) during an attention task: effects of age, stimulus modality and event probability. Int J Psychophysiol Off J Int Organ Psychophysiol 14(3):255–267Google Scholar
  16. 16.
    Johnson R Jr (1989) Developmental evidence for modality-dependent P300 generators: a normative study. Psychophysiology 26(6):651–667CrossRefPubMedGoogle Scholar
  17. 17.
    Rosenfeld JP, Ward A, Frigo V, Drapekin J, Labkovsky E (2015) Evidence suggesting superiority of visual (verbal) vs. auditory test presentation modality in the P300-based, Complex Trial Protocol for concealed autobiographical memory detection. Int J Psychophysiol Off J Int Organ Psychophysiol 96(1):16–22. doi: 10.1016/j.ijpsycho.2015.02.026 Google Scholar
  18. 18.
    Combs LA, Polich J (2006) P3a from auditory white noise stimuli. Clin Neurophysiol Off J Int Fed Clin Neurophysiol 117(5):1106–1112. doi: 10.1016/j.clinph.2006.01.023 CrossRefGoogle Scholar
  19. 19.
    Simons RF, Graham FK, Miles MA, Chen X (2001) On the relationship of P3a and the novelty-P3. Biol Psychol 56(3):207–218CrossRefPubMedGoogle Scholar
  20. 20.
    Polich J, Criado JR (2006) Neuropsychology and neuropharmacology of P3a and P3b. Int J Psychophysiol Off J Int Organ Psychophysiol 60(2):172–185. doi: 10.1016/j.ijpsycho.2005.12.012 Google Scholar
  21. 21.
    Borenstein M, Hedges LV, Higgins JP, Rothstein HR (2009) Introduction to meta-analysis. John Wiley & Sons Ltd, UKCrossRefGoogle Scholar
  22. 22.
    Westerfield MA, Zinni M, Vo K, Townsend J (2015) Tracking the sensory environment: an ERP study of probability and context updating in ASD. J Autism Dev Disord 45(2):600–611. doi: 10.1007/s10803-014-2045-6 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Donkers FC, Schipul SE, Baranek GT, Cleary KM, Willoughby MT, Evans AM, Bulluck JC, Lovmo JE, Belger A (2015) Attenuated auditory event-related potentials and associations with atypical sensory response patterns in children with autism. J Autism Dev Disord 45(2):506–523. doi: 10.1007/s10803-013-1948-y CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Tye C, Asherson P, Ashwood KL, Azadi B, Bolton P, McLoughlin G (2014) Attention and inhibition in children with ASD, ADHD and co-morbid ASD + ADHD: an event-related potential study. Psychol Med 44(5):1101–1116. doi: 10.1017/s0033291713001049 CrossRefPubMedGoogle Scholar
  25. 25.
    Iwanami A, Okajima Y, Ota H, Tani M, Yamada T, Yamagata B, Hashimoto R, Kanai C, Takashio O, Inamoto A, Ono T, Takayama Y, Kato N (2014) P300 component of event-related potentials in persons with asperger disorder. J Clin Neurophysiol Off Publ Am Electroencephalogr Soc 31(5):493–499. doi: 10.1097/wnp.0000000000000080 Google Scholar
  26. 26.
    Gunji A, Goto T, Kita Y, Sakuma R, Kokubo N, Koike T, Sakihara K, Kaga M, Inagaki M (2013) Facial identity recognition in children with autism spectrum disorders revealed by P300 analysis: a preliminary study. Brain Dev 35(4):293–298. doi: 10.1016/j.braindev.2012.12.008 CrossRefPubMedGoogle Scholar
  27. 27.
    Clery H, Roux S, Houy-Durand E, Bonnet-Brilhault F, Bruneau N, Gomot M (2013) Electrophysiological evidence of atypical visual change detection in adults with autism. Front Hum Neurosci 7:62. doi: 10.3389/fnhum.2013.00062 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Clery H, Bonnet-Brilhault F, Lenoir P, Barthelemy C, Bruneau N, Gomot M (2013) Atypical visual change processing in children with autism: an electrophysiological study. Psychophysiology 50(3):240–252. doi: 10.1111/psyp.12006 CrossRefPubMedGoogle Scholar
  29. 29.
    Andersson S, Posserud MB, Lundervold AJ (2013) Early and late auditory event-related potentials in cognitively high functioning male adolescents with autism spectrum disorder. Res Autism Spectr Disord 7(7):815–823CrossRefGoogle Scholar
  30. 30.
    Tsai CL, Pan CY, Wang CH, Tseng YT, Hsieh KW (2011) An event-related potential and behavioral study of impaired inhibitory control in children with autism spectrum disorder. Res Autism Spectr Disord 5(3):1092–1102CrossRefGoogle Scholar
  31. 31.
    Kohls G, Peltzer J, Schulte-Ruther M, Kamp-Becker I, Remschmidt H, Herpertz-Dahlmann B, Konrad K (2011) Atypical brain responses to reward cues in autism as revealed by event-related potentials. J Autism Dev Disord 41(11):1523–1533. doi: 10.1007/s10803-011-1177-1 CrossRefPubMedGoogle Scholar
  32. 32.
    Gomot M, Blanc R, Clery H, Roux S, Barthelemy C, Bruneau N (2011) Candidate electrophysiological endophenotypes of hyper-reactivity to change in autism. J Autism Dev Disord 41(6):705–714. doi: 10.1007/s10803-010-1091-y CrossRefPubMedGoogle Scholar
  33. 33.
    Sokhadze EM, El-Baz A, Baruth J, Mathai G, Sears L, Casanova MF (2009) Effects of low frequency repetitive transcranial magnetic stimulation (rTMS) on gamma frequency oscillations and event-related potentials during processing of illusory figures in autism. J Autism Dev Disord 39(4):619–634. doi: 10.1007/s10803-008-0662-7 CrossRefPubMedGoogle Scholar
  34. 34.
    Sokhadze E, Baruth J, Tasman A, Sears L, Mathai G, El-Baz A, Casanova MF (2009) Event-related potential study of novelty processing abnormalities in autism. Appl Psychophysiol Biofeedback 34(1):37–51. doi: 10.1007/s10484-009-9074-5 CrossRefPubMedGoogle Scholar
  35. 35.
    Gunji A, Inagaki M, Inoue Y, Takeshima Y, Kaga M (2009) Event-related potentials of self-face recognition in children with pervasive developmental disorders. Brain Dev 31(2):139–147. doi: 10.1016/j.braindev.2008.04.011 CrossRefPubMedGoogle Scholar
  36. 36.
    Salmond CH, Vargha-Khadem F, Gadian DG, de Haan M, Baldeweg T (2007) Heterogeneity in the patterns of neural abnormality in autistic spectrum disorders: evidence from ERP and MRI. Cortex J Devot Study Nerv Syst Behav 43(6):686–699CrossRefGoogle Scholar
  37. 37.
    Kujala T, Aho E, Lepisto T, Jansson-Verkasalo E, Nieminen-von Wendt T, von Wendt L, Naatanen R (2007) Atypical pattern of discriminating sound features in adults with Asperger syndrome as reflected by the mismatch negativity. Biol Psychol 75(1):109–114. doi: 10.1016/j.biopsycho.2006.12.007 CrossRefPubMedGoogle Scholar
  38. 38.
    Lepisto T, Silokallio S, Nieminen-von Wendt T, Alku P, Naatanen R, Kujala T (2006) Auditory perception and attention as reflected by the brain event-related potentials in children with Asperger syndrome. Clin Neurophysiol Off J Int Fed Clin Neurophysiol 117(10):2161–2171. doi: 10.1016/j.clinph.2006.06.709 CrossRefGoogle Scholar
  39. 39.
    Senju A, Tojo Y, Yaguchi K, Hasegawa T (2005) Deviant gaze processing in children with autism: an ERP study. Neuropsychologia 43(9):1297–1306. doi: 10.1016/j.neuropsychologia.2004.12.002 CrossRefPubMedGoogle Scholar
  40. 40.
    Lepisto T, Kujala T, Vanhala R, Alku P, Huotilainen M, Naatanen R (2005) The discrimination of and orienting to speech and non-speech sounds in children with autism. Brain Res 1066(1–2):147–157. doi: 10.1016/j.brainres.2005.10.052 CrossRefPubMedGoogle Scholar
  41. 41.
    Ferri R, Elia M, Agarwal N, Lanuzza B, Musumeci SA, Pennisi G (2003) The mismatch negativity and the P3a components of the auditory event-related potentials in autistic low-functioning subjects. Clin Neurophysiol Off J Int Fed Clin Neurophysiol 114(9):1671–1680CrossRefGoogle Scholar
  42. 42.
    Lincoln AJ, Courchesne E, Harms L, Allen M (1993) Contextual probability evaluation in autistic, receptive developmental language disorder, and control children: event-related brain potential evidence. J Autism Dev Disord 23(1):37–58CrossRefPubMedGoogle Scholar
  43. 43.
    Verbaten MN, Roelofs JW, van Engeland H, Kenemans JK, Slangen JL (1991) Abnormal visual event-related potentials of autistic children. J Autism Dev Disord 21(4):449–470CrossRefPubMedGoogle Scholar
  44. 44.
    Erwin R, Van Lancker D, Guthrie D, Schwafel J, Tanguay P, Buchwald JS (1991) P3 responses to prosodic stimuli in adult autistic subjects. Electroencephalogr Clin Neurophysiol 80(6):561–571CrossRefPubMedGoogle Scholar
  45. 45.
    Ciesielski KT, Courchesne E, Elmasian R (1990) Effects of focused selective attention tasks on event-related potentials in autistic and normal individuals. Electroencephalogr Clin Neurophysiol 75(3):207–220CrossRefPubMedGoogle Scholar
  46. 46.
    Courchesne E, Lincoln AJ, Yeung-Courchesne R, Elmasian R, Grillon C (1989) Pathophysiologic findings in nonretarded autism and receptive developmental language disorder. J Autism Dev Disord 19(1):1–17CrossRefPubMedGoogle Scholar
  47. 47.
    Oades RD, Walker MK, Geffen LB, Stern LM (1988) Event-related potentials in autistic and healthy children on an auditory choice reaction time task. Int J Psychophysiol Off J Int Organ Psychophysiol 6(1):25–37Google Scholar
  48. 48.
    Courchesne E, Lincoln AJ, Kilman BA, Galambos R (1985) Event-related brain potential correlates of the processing of novel visual and auditory information in autism. J Autism Dev Disord 15(1):55–76CrossRefPubMedGoogle Scholar
  49. 49.
    Courchesne E, Kilman BA, Galambos R, Lincoln AJ (1984) Autism: processing of novel auditory information assessed by event-related brain potentials. Electroencephalogr Clin Neurophysiol 59(3):238–248CrossRefPubMedGoogle Scholar
  50. 50.
    August GJ, Raz N, Papanicolaou AC, Baird TD, Hirsh SL, Hsu LL (1984) Fenfluramine treatment in infantile autism. Neurochemical, electrophysiological, and behavioral effects. J Nerv Ment Dis 172(10):604–612CrossRefPubMedGoogle Scholar
  51. 51.
    Niwa S, Ohta M, Yamazaki K (1983) P300 and stimulus evaluation process in autistic subjects. J Autism Dev Disord 13(1):33–42CrossRefPubMedGoogle Scholar
  52. 52.
    Novick B, Vaughan HG Jr, Kurtzberg D, Simson R (1980) An electrophysiologic indication of auditory processing defects in autism. Psychiatry Res 3(1):107–114CrossRefPubMedGoogle Scholar
  53. 53.
    Kok A (2001) On the utility of P3 amplitude as a measure of processing capacity. Psychophysiology 38(3):557–577CrossRefPubMedGoogle Scholar
  54. 54.
    Corbetta M, Patel G, Shulman GL (2008) The reorienting system of the human brain: from environment to theory of mind. Neuron 58(3):306–324. doi: 10.1016/j.neuron.2008.04.017 CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Polich J (1987) Task difficulty, probability, and inter-stimulus interval as determinants of P300 from auditory stimuli. Electroencephalogr Clin Neurophysiol 68(4):311–320CrossRefPubMedGoogle Scholar
  56. 56.
    Happe F, Frith U (2006) The weak coherence account: detail-focused cognitive style in autism spectrum disorders. J Autism Dev Disord 36(1):5–25. doi: 10.1007/s10803-005-0039-0 CrossRefPubMedGoogle Scholar
  57. 57.
    Kornmeier J, Worner R, Riedel A, Bach M, Tebartz van Elst L (2014) A different view on the checkerboard? Alterations in early and late visually evoked EEG potentials in Asperger observers. PLoS One 9(3):e90993. doi: 10.1371/journal.pone.0090993 CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Feuerriegel D, Churches O, Hofmann J, Keage HA (2015) The N170 and face perception in psychiatric and neurological disorders: a systematic review. Clin Neurophysiol Off J Int Fed Clin Neurophysiol 126(6):1141–1158. doi: 10.1016/j.clinph.2014.09.015 CrossRefGoogle Scholar
  59. 59.
    Hartikainen KM, Knight RT (2003) Lateral and orbital prefrontal cortex contributions to attention. In: Detection of change. Springer, Berlin, pp 99–116Google Scholar
  60. 60.
    Verleger R, Jaśkowski P, Wascher E (2005) Evidence for an integrative role of P3b in linking reaction to perception. J Psychophysiol 19(3):165–181CrossRefGoogle Scholar
  61. 61.
    Misic B, Doesburg SM, Fatima Z, Vidal J, Vakorin VA, Taylor MJ, McIntosh AR (2015) Coordinated information generation and mental flexibility: large-scale network disruption in children with autism. Cereb Cortex 25(9):2815–2827. doi: 10.1093/cercor/bhu082 CrossRefPubMedGoogle Scholar
  62. 62.
    Qiu YQ, Tang YX, Chan RC, Sun XY, He J (2014) P300 aberration in first-episode schizophrenia patients: a meta-analysis. PLoS One 9(6):e97794. doi: 10.1371/journal.pone.0097794 CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Jiang S, Qu C, Wang F, Liu Y, Qiao Z, Qiu X, Yang X, Yang Y (2015) Using event-related potential P300 as an electrophysiological marker for differential diagnosis and to predict the progression of mild cognitive impairment: a meta-analysis. Neurol Sci 36(7):1–8CrossRefGoogle Scholar
  64. 64.
    Howe AS, Pinto A, De Luca V (2014) Meta-analysis of P300 waveform in panic disorder. Exp Brain Res 232(10):3221–3232. doi: 10.1007/s00221-014-3999-5 CrossRefPubMedGoogle Scholar
  65. 65.
    Wronka E, Kaiser J, Coenen AM (2013) Psychometric intelligence and P3 of the event-related potentials studied with a 3-stimulus auditory oddball task. Neurosci Lett 535:110–115. doi: 10.1016/j.neulet.2012.12.012 CrossRefPubMedGoogle Scholar
  66. 66.
    Merchan-Naranjo J, Boada L, Del Rey-Mejias A, Mayoral M, Llorente C, Arango C, Parellada M (2016) Executive function is affected in autism spectrum disorder, but does not correlate with intelligence. Rev Psiquiatr Salud Ment 9(1):39–50. doi: 10.1016/j.rpsm.2015.10.005 CrossRefPubMedGoogle Scholar
  67. 67.
    Evans DW, Maliken A (2011) Cortical activity and children’s rituals, habits and other repetitive behavior: a visual P300 study. Behav Brain Res 224(1):174–179. doi: 10.1016/j.bbr.2011.05.025 CrossRefPubMedGoogle Scholar
  68. 68.
    Ravizza SM, Solomon M, Ivry RB, Carter CS (2013) Restricted and repetitive behaviors in autism spectrum disorders: the relationship of attention and motor deficits. Dev Psychopathol 25(3):773–784. doi: 10.1017/s0954579413000163 CrossRefPubMedGoogle Scholar
  69. 69.
    Belmonte MK, Allen G, Beckel-Mitchener A, Boulanger LM, Carper RA, Webb SJ (2004) Autism and abnormal development of brain connectivity. J Neurosci Off J Soc Neurosci 24(42):9228–9231. doi: 10.1523/jneurosci.3340-04.2004 CrossRefGoogle Scholar
  70. 70.
    Muller RA, Shih P, Keehn B, Deyoe JR, Leyden KM, Shukla DK (2011) Underconnected, but how? A survey of functional connectivity MRI studies in autism spectrum disorders. Cereb Cortex 21(10):2233–2243. doi: 10.1093/cercor/bhq296 CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Chawarska K, Macari S, Shic F (2013) Decreased spontaneous attention to social scenes in 6-month-old infants later diagnosed with autism spectrum disorders. Biol Psychiatry 74(3):195–203. doi: 10.1016/j.biopsych.2012.11.022 CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Datta A, Cusack R, Hawkins K, Heutink J, Rorden C, Robertson IH, Manly T (2007) The p300 as a marker of waning attention and error propensity. Comput Intell Neurosci 93968. doi: 10.1155/2007/93968
  73. 73.
    Higashima M, Nagasawa T, Kawasaki Y, Oka T, Sakai N, Tsukada T, Koshino Y (2003) Auditory P300 amplitude as a state marker for positive symptoms in schizophrenia: cross-sectional and retrospective longitudinal studies. Schizophr Res 59(2–3):147–157CrossRefPubMedGoogle Scholar
  74. 74.
    Jiang S, Qu C, Wang F, Liu Y, Qiao Z, Qiu X, Yang X, Yang Y (2015) Using event-related potential P300 as an electrophysiological marker for differential diagnosis and to predict the progression of mild cognitive impairment: a meta-analysis. Neurol Sci Off J Italian Neurol Soc Italian Soc Clin Neurophysiol 36(7):1105–1112. doi: 10.1007/s10072-015-2099-z Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Tingkai Cui
    • 1
  • Peizhong Peter Wang
    • 2
  • Shengxin Liu
    • 1
  • Xin Zhang
    • 1
    Email author
  1. 1.Department of Child and Adolescent Health, School of Public HealthTianjin Medical UniversityTianjinChina
  2. 2.Division of Community Health and Humanities, Faculty of MedicineMemorial University of NewfoundlandSt. John’sCanada

Personalised recommendations