Reading skill and neural processing accuracy improvement after a 3-hour intervention in preschoolers with difficulties in reading-related skills

Brain Research

Volumn 1448, Issue , 2012, Pages 42-55

  Lovio, Riikka ^a,b   Halttunen, Anu ^a   Lyytinen, Heikki ^c,d   Näätänen, Risto ^a,e,f   Kujala, Teija ^a  

^a UNIVERSITY OF HELSINKI   (Finland)

^b KAROLINSKA UNIVERSITY HOSPITAL   (Sweden)

^c UNIVERSITY OF JYVÄSKYLÄ   (Finland)

^d Niilo Maki Instituutti   (Finland)

^e UNIVERSITY OF TARTU   (Estonia)

^f AARHUS UNIVERSITY   (Denmark)

Author keywords

Dyslexia; Event related potential (ERP); Intervention; Mismatch negativity (MMN); Reading

Indexed keywords

ARTICLE; BRAIN CORTEX; BRAIN FUNCTION; CHILD; ELECTROPHYSIOLOGY; EVENT RELATED POTENTIAL; FEMALE; HUMAN; HUMAN EXPERIMENT; MALE; MISMATCH NEGATIVITY; NORMAL HUMAN; PEDIATRICS; PHONETICS; PRESCHOOL CHILD; PRIORITY JOURNAL; READING; SKILL; SPEECH DISCRIMINATION;

AUDITORY CORTEX; AUDITORY PERCEPTION; CHILD; DATA INTERPRETATION, STATISTICAL; DISCRIMINATION (PSYCHOLOGY); DYSLEXIA; EARLY INTERVENTION (EDUCATION); ELECTROENCEPHALOGRAPHY; EVOKED POTENTIALS; FEMALE; GAMES, EXPERIMENTAL; HUMANS; MALE; PHONETICS; PSYCHOMOTOR PERFORMANCE; READING; RECOGNITION (PSYCHOLOGY); REMEDIAL TEACHING;

EID: 84858698325     PISSN: 00068993     EISSN: 18726240     Source Type: Journal    
DOI: 10.1016/j.brainres.2012.01.071     Document Type: Article

References (97)

1. Ahissar, M., Protopapas, A., Reid, M., Merzenich, M., 2000. Auditory processing parallels reading abilities in adults. Proc. Natl. Acad. Sci. U. S. A. 97, 6832-6837. (Pubitemid 30412800)
2. Ahonen, T., Tuovinen, S., Leppäsaari, T., 2003. Nopean sarjallisen nimeämisen testi (Rapid naming test). Haukkarannan koulun julkaisut, Niilo Mäki Instituutti, Lievestuore: ER-Paino OY.
3. Alku, P., Tiitinen, H., Näätänen, R., 1999. A method for generating natural-sounding speech stimuli for cognitive brain research. Clin. Neurophysiol. 110, 1329-1333. (Pubitemid 29333868)
4. Aro, M., 2006. Learning to read: the effects of orthography. In: Malatesha Joshi, R., Aaron, P.G. (Eds.), Handbook of Ortography and Literacy. Lawrence Erlbaum Associates Inc., New Jersey, pp. 531-550.
5. Baldeweg, T., Richardson, A., Watkins, S., Foale, C., Gruzelier, J., 1999. Impaired auditory frequency discrimination in dyslexia detected with mismatch evoked potentials. Ann. Neurol. 45, 495-503. (Pubitemid 29165816)
6. Bernal, J., Harmony, T., Rodriguez, M., Reyes, A., Yanez, G., Fernandez, T., Galan, L., Silva, J., Fernandez-Bouzas, A., Rodriguez, H., Guerrero, V., Marosi, E., 2000. Auditory event-related potentials in poor readers. Int. J. Psychophysiol. 36, 11-23. (Pubitemid 30105804)
7. Bishop, D.V., 2007. Using mismatch-negativity to study central auditory processing in developmental language and literacy impairments: where are we, and where should we be going? Psychol. Bull. 133, 651-672.
8. Bradley, L., Bryant, P.E., 1978. Difficulties in auditory organisation as a possible cause of reading backwardness. Nature 271, 746-747. (Pubitemid 8278339)
9. Brem, S., Bach, S., Kucian, K., Guttorm, T.K., Martin, E., Lyytinen, H., Brandeis, D., Richardson, U., 2010. Brain sensitivity to print emerges when children learn letter-speech sound correspondences. Proc. Natl. Acad. Sci. U. S. A. 107, 7939-7944.
10. Bruder, J., Leppänen, P.H.T., Bartling, J., Csépe, V., Demonet, J.-F., Schulte-Körne, G., 2011. Children with dyslexia reveal abnormal native language representations: evidence from a study of mismatch negativity. Psychophysiology 48, 1107-1118.
11. Byring, R., Järvilehto, T., 1985. Auditory and visual evoked potentials of schoolboys with spelling disabilities. Dev. Med. Child Neurol. 27, 141-148. (Pubitemid 15089020)
12. Castles, A., Coltheart, M., 1993. Varities of developmental dyslexia. Cognition 47, 149-180.
13. Castles, A., Bates, T., Coltheart, M., Luciano, M., Martin, N.G., 2006. Cognitive modelling and the behavior genetics of reading. J. Res. Read. 29, 92-103. (Pubitemid 43448447)
14. Čeponienė, R., Shestakova, A., Balan, P., Alku, P., Yaguchi, K., Näätänen, R., 2001. Children's auditory event-related potentials index sound complexity and "speechness". Int. J. Neurosci. 109, 245-260. (Pubitemid 32832166)
15. Čeponienė, R., Rinne, T., Näätänen, R., 2002. Maturation of cortical sound processing as indexed by event-related potentials. Clin. Neurophysiol. 113, 870-882.
16. Corbera, S., Escera, C., Artigas, J., 2006. Impaired duration mismatch negativity in developmental dyslexia. Neuroreport 17, 1051-1055. (Pubitemid 43948284)
17. Csépe, V., 2003. Auditory event-related potentials in studying developmental dyslexia. In: Csépe, V. (Ed.), Dyslexia, Different Brain, Different Behavior. Kluwer Academic/Plenum Publishers, New York, pp. 81-112.
18. Cycowicz, Y.M., Friedman, D., 1997. A developmental study of the effect of temporal order on the ERPs elicited by novel environmental sounds. Electroencephalogr. Clin. Neurophysiol. 103, 304-318. (Pubitemid 27351625)
19. Dehaene-Lambertz, G., 1997. Electrophysiological correlates of categorical phoneme perception in adults. Neuroreport 8, 919-924. (Pubitemid 27152147)
20. Ehri, L.C., Nunes, S.R., Willows, D.M., Schuster, B.V., Yaghoub-Zadeh, Z., Shanahan, T., 2001. Phonemic awareness instruction helps children learn to read: evidence from the National Reading Panel's meta-analysis. Read. Res. Q. 36, 250-287.
21. Escera, C., Corral, M.J., 2007. Role of mismatch negativity and novelty-P3 in involuntary auditory attention. J. Psychophysiol. 21, 251-264. (Pubitemid 351516010)
22. Escera, C., Alho, K., Schröger, E., Winkler, I., 2000. Involuntary attention and distractibility as evaluated with event-related brain potentials. Audiol. Neurootol. 5, 151-166. (Pubitemid 30312184)
23. Espy, K., Molfese, D., Molfese, V., Modglin, A., 2004. Development of auditory event-related potentials in young children and relation to word-level reading abilities at age 8 years. Ann. Dyslexia 54, 9-38. (Pubitemid 39159681)
24. Fried, I., Tanguay, P.E., Boder, E., Doubleday, C., Greensite, M., 1981. Developmental dyslexia: electrophysiological evidence of clinical subgroups. Brain Lang. 12, 14-22. (Pubitemid 11148734)
25. Gabrieli, J.D.E., 2009. Dyslexia: a new synergy between education and cognitive neuroscience. Science 325, 280-283.
26. Given, B.K., Wasserman, J.D., Chari, S.A., Beattie, K., Eden, G.F., 2008. A randomized, controlled study of computer-based intervention in middle school struggling readers. Brain Lang. 106, 83-97. (Pubitemid 352020415)
27. Guttorm, T.K., Leppänen, P.H.T., Richardson, U., Lyytinen, H., 2001. Event-related potentials and consonant differentation in newborns with familial risk for dyslexia. J. Learn. Disabil. 34, 534-544.
28. Hämäläinen, J.A., Leppänen, P.H.T., Guttorm, T.K., Lyytinen, H., 2007. N1 and P2 components of auditory event-related potentials in children with and without reading disabilities. Clin. Neurophysiol. 118, 2263-2275. (Pubitemid 47385355)
29. Hämäläinen, J.A., Leppänen, P.H.T., Guttorm, T.K., Lyytinen, H., 2008. Event-related potentials to pitch and rise time change in children with reading disabilities and typically reading children. Clin. Neurophysiol. 119, 100-115.
30. Häyrinen, T., Serenius-Sirve, S., Korkman, M., 1999. Lukilasse. Psykologien Kustannus Oy, Helsinki.
31. Heim, S., Eulitz, C., Elbert, T., 2003. Altered hemispheric asymmetry of auditory P100m in dyslexia. Eur. J. Neurosci. 17, 1715-1722. (Pubitemid 36628139)
32. Helenius, P., Salmelin, R., Richardson, U., Leinonen, S., Lyytinen, H., 2002a. Abnormal auditory cortical activation in dyslexia 100 ms after speech onset. J. Cogn. Neurosci. 14, 603-617. (Pubitemid 34553656)
33. Helenius, P., Salmelin, R., Service, E., Connoly, J.F., Leinonen, S., Lyytinen, H., 2002b. Cortical activation during spoken word segmentation in nonreading-impaired and dyslexic adults. J. Neurosci. 22, 2936-2944. (Pubitemid 37465842)
34. Klingberg, T., 2010. Training and plasticity of working memory. Trends Cogn. Sci. 14, 317-324.
35. Korkman, M., Kirk, U., Kemp, S.L., 1997. NEPSY, Lasten neuropsykologinen tutkimus (The assessment of neuropsychological abilities in children). Psykologien Kustannus Oy, Helsinki.
36. Kraus, N.,McGee, T., Carrell, T.D., King, C., Tremblay, K., Nikol, T., 1995. Central auditory system plasticity associated with speech discrimination training. J. Cogn. Neurosci. 7, 25-32.
37. Kujala, T., 2007. The role of early auditory discrimination deficits in language disorders. J. Psychophysiol. 21, 239-250. (Pubitemid 351516009)
38. Kujala, T., Näätänen, R., 2001. The mismatch negativity in evaluating central auditory dysfunction in dyslexia. Neurosci. Biobehav. Rev. 25, 535-543. (Pubitemid 32930014)
39. Kujala, T., Näätänen, R., 2010. The adaptive brain: a neurophysiological perspective. Prog. Neurobiol. 91, 55-67.
40. Kujala, T., Karma, K., Čeponienė, R., Belitz, S., Turkkila, P., Tervaniemi, M., Näätänen, R., 2001. Plastic neural changes and reading improvement caused by audiovisual training in reading-impaired children. Proc. Natl. Acad. Sci. U. S. A. 98, 10509-10514. (Pubitemid 32803050)
41. Kujala, T., Belitz, S., Tervaniemi, M., Näätänen, R., 2003. Auditory sensory memory disorder in dyslexic adults as indexed by the mismatch negativity. Eur. J. Neurosci. 17, 1323-1327. (Pubitemid 36459789)
42. Kujala, T., Lovio, R., Lepistö, T., Laasonen, M., Näätänen, R., 2006. Evaluation of multi-attribute auditory discrimination profile in dyslexia with the mismatch negativity. Clin. Neurophysiol. 117, 885-893.
43. Kujala, T., Tervaniemi, M., Schröger, E., 2007. The mismatch negativity in cognitive and clinical neuroscience: theoretical and methodological considerations. Biol. Psychol. 74, 1-19. (Pubitemid 44794431)
44. Lachmann, T., Berti, S., Kujala, T., Schröger, E., 2005. Diagnostic subgroups of developmental dyslexia have different deficits in neural processing of tones and phonemes. Int. J. Psychophysiol. 56, 105-120. (Pubitemid 40432275)
45. Leppänen, P.H.T., Pihko, E., Eklund, K.M., Lyytinen, H., 1999. Cortical responses of infants with and without a genetic risk for dyslexia: II. Group effects. Neuroreport 10, 901-905. (Pubitemid 29317962)
46. Leppänen, P.H.T., Richardson, U., Pihko, E., Eklund, K., Guttorm, T.K., Aro, M., Lyytinen, H., 2002. Brain responses to changes in speech sound durations differ between infants with and without familial risk for dyslexia. Dev. Neuropsychol. 22, 407-422. (Pubitemid 35204775)
47. Leppänen, U., Aunola, K., Niemi, P., Nurmi, J.-E., 2008. Letter knowledge predicts Grade 4 reading fluency and reading comprehension. Learn. Instrum. 18, 548-564.
48. Leppänen, P.H.T., Hämäläinen, J.A., Salminen, H.K., Eklund, K.M., Guttorm, T.K., Lohvansuu, K., Puolakanaho, A., Lyytinen, H., 2010. Newborn event-related potentials revealing atypical processing of sound frequency and the subsequent association with later literacy skills in children with familial dyslexia. Cortex 46, 1362-1376.
49. Loo, J. Hooi Yin, Bamiou, D.-E., Campbell, N., Luxon, L.M., 2010. Computer-based auditory training (CBAT): benefits for children with language- and reading-related learning difficulties. Dev. Med. Child Neurol. 52, 708-717.
50. Lovio, R., Pakarinen, S., Huotilainen, M., Alku, P., Silvennoinen, S., Näätänen, R., Kujala, T., 2009. Auditory discrimination profiles of speech sound changes in 6-year-old children as determined with themulti-feature MMN paradigm. Clin. Neurophysiol. 5, 916-921.
51. Lovio, R., Näätänen, R., Kujala, T., 2010. Abnormal pattern of cortical speech feature discrimination in 6-year-old children at risk for dyslexia. Brain Res. 1335, 53-62.
52. Lundberg, I., Olofsson, Å., Wall, S., 1980. Reading and spelling skills in the first school years predicted from phonemic awareness skills in kindergarten. Scand. J. Psychol. 21, 159-173.
53. Lyytinen, P., Lyytinen, H., 2004. Growth and predictive relations of vocabulary and inflectionalmorphology in childrenwith and without familial risk for dyslexia.Appl. Psycholinguist. 25, 397-411. (Pubitemid 38932688)
54. Lyytinen, H., Guttorm, T.K., Huttunen, T., Hämäläinen, J., Leppänen, P.H.T., Vesterinen, M., 2005. Psychophysiology of developmental dyslexia: a review of findings including studies of children at risk for dyslexia. J. Neurolinguist. 18, 167-195. (Pubitemid 40567927)
55. Lyytinen, H., Aro, M., Holopainen, L., Leiwo, M., Lyytinen, P., Tolvanen, A., 2006. Children's language development and reading acquisition in a highly transparent orthography. In: Malatesha Joshi, R., Aaron, P.G. (Eds.), Handbook of Ortography and Literacy. Lawrence Erlbaum Associates Inc., New Jersey, pp. 47-62.
56. Lyytinen, H., Ronimus, M., Alanko, A., Poikkeus, A.-M., Taanila, M., 2007. Early identification of dyslexia and the use of computer game-based practice to support reading acquisition. Nord. Psychol. 59, 109-126.
57. Lyytinen, H., Erskine, J., Kujala, J., Ojanen, E., Richardson, U., 2009. In search of a science-based application: a learning tool for reading acquisition. Scand. J. Psychol. 50, 668-675.
58. Maurer, U., Bucher, K., Brem, S., Brandeis, D., 2003. Altered responses to tone and phoneme mismatch in kindergartners at familial dyslexia risk. Neuroreport 14, 2245-2250.
59. Molfese, D.L., 2000. Predicting dyslexia at 8 years of age using neonatal brain responses. Brain Lang. 72, 238-245. (Pubitemid 30250069)
60. Näätänen, R., 1979. Orienting and evoked potentials. In: Kimmel, H.D., van Olst, E.H., Orlebeke, J.F. (Eds.), The Orienting Reflex in Humans. Erlbaum, New Jersey, pp. 61-75.
61. Näätänen, R., 1985. Selective attention and stimulus processing: reflections in event-related potentials,magnetoencephalogram, and regional cerebral blood flow. In: Posner, M.I., Marin, O.S.M. (Eds.), Attention and Performance. Erlbaum, New Jersey, pp. 355-373.
62. Näätänen, R., 1992. Attention and Memory Function. Erlbaum, New Jersey.
63. Näätänen, R., 2002. The perception of speech sounds by the human brain as reflected by the mismatch negativity brain response. Int. Congr. Ser. 1232, 97-105.
64. Näätänen, R., Winkler, I., 1999. The concept of auditory stimulus representation in cognitive neuroscience. Psychol. Bull. 125, 826-859.
65. Näätänen, R., Gaillard, A.W., Mäntysalo, S., 1978. Early selective-attention effect on evoked potential reinterpreted. Acta Psychol. 42, 313-329.
66. Näätänen, R., Lehtokoski, A., Lennes, M., Cheour, M., Huotilainen, M., Iivonen,A., Vainio,M., Alku, P., Ilmoniemi, R.J., Luuk, A., Allik, J., Sinkkonen, J., Alho, K., 1997. Language-specific phoneme representations revealed by electric and magnetic brain responses. Nature 385, 432-434. (Pubitemid 27065927)
67. Näätänen, R., Pakarinen, S., Rinne, T., Takegata, R., 2004. The mismatch negativity (MMN): towards the optimal paradigm. Clin. Neurophysiol. 115, 140-144. (Pubitemid 38045607)
68. Näätänen, R., Jacobsen, T., Winkler, I., 2005. Memory based or afferent processes in mismatch negativity (MMN): a review of the evidence. Psychophysiology 42, 25-32. (Pubitemid 40395412)
69. Pakarinen, S., Takegata, R., Rinne, T., Huotilainen, M., Näätänen, R., 2007. Measurement of extensive auditory discrimination profiles using the mismatch negativity (MMN) of the auditory event-related potential (ERP). Clin. Neurophysiol. 118, 177-185. (Pubitemid 44960930)
70. Pakarinen, S., Lovio, R., Huotilainen, M., Alku, P., Näätä nen, R., Kujala, T., 2009. Fast multi-feature paradigm for recording several mismatch negativities (MMNs) to phonetic and acoustic changes in speech sounds. Biol. Psychol. 82, 219-226.
71. Pennington, B.F., Gilger, J.W., 1996. How is dyslexia transmitted? Neural, cognitive, and genetic mechanisms underlying speech, language, and reading. In: Chase, C.H., Rosen, G.D., Sherman, G.F. (Eds.), Developmental Dyslexia. York Press, Baltimore, pp. 41-61.
72. Pihko, E., Leppänen, P.H.T., Eklund, K.M., Cheour, M., Guttorm, T.K., Lyytinen, H., 1999. Cortical responses of infants with and without a genetic risk for dyslexia: I. Age effects. Neuroreport 10, 901-905. (Pubitemid 29317962)
73. Pihko, E., Mickos, A., Kujala, T., Pihlgren, A., Westman, M., Alku, P., Byring, R., Korkman, M., 2007. Group intervention changes brain activity in bilingual language-impaired children. Cereb. Cortex 17, 849-858. (Pubitemid 46434624)
74. Poskiparta, E., Niemi, P., Lepola, J., 1994. Diagnostiset testit 1, Lukeminen ja kirjoittaminen (Diagnostic tests 1, Reading and writing). Oppimistutkimuksen keskus, Turun yliopisto.
75. Ramus, F., 2004. Neurobiology of dyslexia: a reinterpretation of the data. Trends Neurosci. 27, 720-726. (Pubitemid 39488075)
76. Renvall, H., Hari, R., 2002. Auditory cortical responses to speech-like stimuli in dyslexic adults. J. Cogn. Neurosci. 14, 757-768. (Pubitemid 34761797)
77. Renvall, H., Hari, R., 2003. Diminished auditory mismatch fields in dyslexic adults. Ann. Neurol. 53, 551-557. (Pubitemid 36529428)
78. Rinne, T., Särkkä, A., Degerman, A., Schröger, E., Alho, K., 2006. Two separate mechanisms underlie auditory change detection and involuntary control of attention. Brain Res. 1077, 135-143.
79. Rouse, C.E., Krueger, A.B., 2004. Putting computerized instruction to the test: a randomized evaluation of a "scientifically based"reading program. Econ. Educ. Rev. 23, 323-338. (Pubitemid 38708464)
80. Russeler, J., Kowalczuk, J., Sönke, J., Berdieke, M.W., Munte, T., 2002. Cognitive brain potentials to novel acoustic stimuli in adult dyslexic readers. Dyslexia 8, 125-142. (Pubitemid 40309982)
81. Saine, N.L., Lerkkanen, M.-K., Ahonen, T., Tolvanen, A., Lyytinen, H., 2010. Predicting word-level reading fluency outcomes in three contrastive groups: remedial and computer-assisted remedial reading intervention, and mainstream instruction. Learn. Ind. Differ. 20, 402-414.
82. Sams, M., Paavilainen, P., Alho, K., Näätänen, R., 1985. Auditory frequency discrimination and event-related potentials. Electroencephalogr. Clin. Neurophysiol. 62, 437-448. (Pubitemid 16230711)
83. Schulte-Körne, G., Deimel, W., Bartling, J., Remschmidt, H., 1998. Auditory processing and dyslexia: evidence for a speech processing deficit. Neuroreport 9, 337-340. (Pubitemid 28081412)
84. Sharma, A., Kraus, N., McGee, T.J., Nicol, T.G., 1997. Developmental changes in P1 and N1 central auditory responses elicited by consonant-vowel syllables. Electroencephalogr. Clin. Neurophysiol. 104, 540-545.
85. Sharma, M., Purdy, S.C., Newall, P.,Wheldall, K., Beaman, R., Dillon, H., 2006. Electrophysiological and behavioral evidence of auditory processing deficits in children with reading disorder. Clin. Neurophysiol. 117, 1130-1144.
86. Shaywitz, S., 2003. Overcoming Dyslexia. Vintage books, New York.
87. Snowling, M.J., Goulandris, N., Bowlby, M., 2000. Dyslexia, 2nd ed. Blackwell Publishing, Oxford.
88. Temple, E., Deutschs, G.K., Poldrack, R.A., Miller, S.L., Tallal, P., Merzenich, M.M., Gabrieli, D.E., 2003. Neural deficits in children with dyslexia ameliorated by behavioral remediation: Evidence from functional MRI. Proc. Natl. Acad. Sci. U. S. A. 100, 2860-2865. (Pubitemid 36297589)
89. Tiitinen, H., May, P., Reinikainen, K., Näätänen, R., 1994. Attentive novelty detection in humans is governed by pre-attentive sensory memory. Nature 372, 90-92. (Pubitemid 24339487)
90. Törmänen, M., Takala, M., 2009. Auditory processing in developmental dyslexia: An exploratory study of an auditory and visual matching training program with Swedish children with developmental dyslexia. Scand. J. Psychol. 50, 227-285.
91. Van Herten, M., Pasman, J., Van Leeuwen, T.H., Been, P.H., Van Der Leij, A., Zwarts, F.,Maassen, B., 2008. Differences inAERP responses and a typical hemispheric specialization in 17-month-old children at risk of dyslexia. Brain Res. 1201, 100-105.
92. Vellutino, F.R., Fletcher, J.M., Snowling, M.J., Scanlon, D.M., 2004. Specific reading disability (dyslexia): what have we learned in the past four decades? J. Child Psychol. Psychiatry 1, 2-40. (Pubitemid 38196253)
93. Veuillet, E., Magnan, A., Ecalle, J., Thai-Wan, H., Collet, L., 2007. Auditory processing disorder in children with reading disabilities: effect of audiovisual training. Brain 130, 2915-2928. (Pubitemid 350033972)
94. Wechsler, D., 1991. Wechsler Intelligence Scale for Children, (WISC-III). The Psychological Corporation/Psykologien Kustannus OY, Sidcup/Helsinki.
95. Wimmer, H., Schurz, M., Sturm, D., Richlan, F., Klack, J., Kronbichler, M., Ladurner, G., 2010. A dual-route perspective on poor reading in a regular orthography: An fMRI study. Cortex 46, 1284-1298.
96. Ziegler, J.C., Goswami, U., 2005. Reading acquisition, developmental dyslexia, and skilled reading across languages: a psycholinguistic grain size theory. Psychol. Bull. 131, 3-29. (Pubitemid 40130968)
97. Ziegler, J., Bertrand, D., Tóth, D., Csépe, V., Reis, A., Faisca, L., Saine, N., Lyytinen, H., Vaessen, A., Blomert, L., 2010. Orthographic depth and its impact on universal predictors of reading: a cross-language investigation. Psychol. Sci. 21, 551-559.