Cortical Development and Re- Organization in Auditory Deprivation.

Transcription

1 Cortical Development and Re- Organization in Auditory Deprivation. Anu Sharma, Ph.D., CCC-A Brain and Behavior Laboratory Dept. of Speech Language and Hearing Science, UCB Dept. of Otolaryngology and Audiology,, UCDHSC Funding: National Institutes of Health NIH NIDCD R01 DC NIH NIDCD R01 DC NOHR AHRF

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3 Michael Dorman Phillip Gilley, Ph.D Amy Nash, M.A. Peter Roland, M.D. Paul Bauer, M.D. Bob Peters, M.D Andrej Kral, M.D., Ph.D. Sandra Gabbard,Ph.D., Herman Jenkins M.D., Kristin Uhler, M.S.,CCC-A, Allison Biever, AuD, David Kelsall, M.D. Sten Harris, M.D., Ph.D. Kathryn Martin, M.S., CCC-A Ross Roeser, Ph.D. Emily Tobey, Ph.D. University of Colorado at Boulder Dallas, Texas Institute for Neurophysiologie, Hamburg, Germany Denver, Colorado Rikshospital, Olso, Norway

4 Aim To explore the deterioration, development and plasticity of the human central auditory pathway.

5 P1 cortical evoked potentials to speech High Density EEG normal children and children with implants 4 uv PET scans Children before implant Sharma, Gilley and Dorman Baldwin, MEG data Deaf duration (age) 6.5 y 6.5 y CID scores (years of training) 90 %(3.8 y) 67 %(1.1 y) Lee, Oh et al y 7 % (1.4 y) 20.3 y 0 % (1.9 y) Current source density layers 2-6 auditory cortex Deaf white kittens with implants Kral, Klinke, Hartmann, Tillein

6 Auditory Evoked Responses -reflect EEG activity in response to sound stimulation -can be recorded non-invasively from all levels of the auditory pathways

7 P1 Auditory Cortex Auditory Thalamocortical pathways Auditory Brainstem Cochlea

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9 P1 Cortical Auditory Evoked Response 4 uv Latency (msec)

10 P1 generators include the primary auditory cortex, including input from reciprocal cortico-cortical loops. (Liegeois-Chuvel et al.,1994; Eggermont and Ponton 2002; Sharma et al., 2007)

11 Cortical auditory evoked potential latencies reflect the accumulated sum of delays in synaptic propagation through the central auditory pathways.

12 P1 latencies are an index of the maturation of the central auditory pathways. Normal hearing children Sharma et al., 1997 Ceponiene et al., 1998; 2002 Eggermont & Ponton, 2003 Children with cochlear implants Ponton et al., 1996a and b Eggermont and Ponton, 2003 Singh et al., 2004 Ponton, Eggermont et al., 2000, 2002 Pang and Taylor, 2000

13 Normal Hearing Children (N=190) y = *LN(x) R 2 = p< Sharma et al., 2002; Ear and Hearing

14 Cochlear Implant Subjects 245 congenitally deaf pediatric cochlear implant users Age at implantation ranged from 7 months to 15 years Experience with implant ranged from 6 months to 10 years

15 Cochlear Implanted Children (N = 245)

16 There is a sensitive period of 3.5 years during which implantation occurs into a highly plastic central auditory system.

17 Implantation after 7 years occurs into a relatively degenerate central auditory system which shows reduced plasticity.

18 Children implanted under ages 3-4 years show significantly better speech perception and language skills compared to children implanted after ages 6-7 years. (Kirk et al., 2002; Summerfield, 2002, Manrique 2002, Waltzman and Cohen, 1998, Gantz et al., 1999)

19 Evidence for a Sensitive Period from Brain Imaging Studies

20 PET SCAN STUDIES Pre-Implant Hypometabolism Post-Implant Speech Perception Deaf duration (age) 6.5 y 6.5 y 11.2 y 20.3 y CID scores (years of training) 90 %(3.8 y) 67 %(1.1 y) 7 % (1.4 y) 0 % (1.9 y) CID score (%) n=10 r=0.81 p< Number of pixels with hypometabolism in (BA ) As the duration of deafness increased, the extent of hypometabolism was reduced Positive correlation between the hypometabolism in superior temporal gyrus (BA 41,42,22) and the speech perception ability Lee et al., (2001) Nature

21 After age 7 years implantation occurs into a reorganized auditory cortex.

22 Age of Implantation > 7 years years < 3.5 years P1 latency (ms) Age (years) Sharma et al., Dec 2002; Ear and Hearing

23 Age of Implantation > 7 years years < 3.5 years P1 latency (ms) Age (years) Sharma et al., 2002 From Lee et al. (2003)

24 Long term outcome of congenital deaf children Wide variability in age group between 4-7 years (n=22) Spearman s rho= p=0.001 Lee et al., Acta Otolaryngol 2003;123:

25 Other pre-operative predictors of performance Better speech understanding correlated with preoperative high levels of activity in frontal areas dorsolateral prefrontal region, the precuneus, frontopolar and occipito-temproparietal regions Courtesy Seung Ha Oh, M.D, Ph.D

26 How rapidly does the auditory pathway change following the onset of stimulation for early implanted children?

27 Early Implanted Children 400 Hook-up 350 P1 Latency (ms) LATENCY (ms) week 2 months 5 months 8 months 50 Normal Limits Sharma et al., Neuroreport 2002 AGE (years)

28 Age of Implantation: 13 Months Early Implanted Children 400 Hook-up Hook-up week 1 week LATENCY (ms) month 3 months 6 months 2 months 5 months months 50 Normal Limits Sharma et al., Neuroreport 2002 AGE (years)

29 Is plasticity absent in late implanted children?

30 Sharma, Dorman and Kral, Hearing Research (2005) n=12 n=8

31 Early Implanted (n=12) Hook-up Late Implanted (n=8) Latency (ms) week 1 month 5 months 1 month Hook-up 2 weeks months 14 months 50 Normal limits Age (years) 8 months 1.5 years Sharma, Dorman and Kral, Hearing Research 2005

32 Individual Developmental Trajectories n=(231)

33 Waveform Age-matched morphology: groups Age-matched of children groups (n=26) Time (ms)

34 Photo courtesy of A. Kral

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36 from higherorder cortex to thalamus Kral et al. (2005)

37 higher order cortex to thalamus Kral et al. (2005)

38 High Density EEG study Cortical Auditory Evoked Potentials from 64 scalp electrodes

39 Methods: Subjects Ten normal hearing children Mean age = years Eight congenitally deaf children early implanted children Mean age = years Implanted early (mean age approx. 3 years) Eight congenitally deaf children late implanted children Mean age = years Implanted late (mean age approx 8 years)

40 Methods: EEG/EPs Cortical auditory evoked potentials (CAEPs) from 64 channels on the scalp CAEPs in response to a speech stimulus CAEP activity and artifact separated by ICA Source Analysis on CAEP peak activity: sloreta and fixed, coherent dipoles

41 Cochlear Implanted Children: sloreta results Right ITG Bilateral STS Right ITG Contralateral STS Contralateral PT Gilley et al., 2006

42 Cochlear Implanted Children: Dipole Sources Normal Hearing Early Implanted Late Implanted Bilateral STS Contralateral STS Contralateral Parietal Normal hearing Early Implanted Late Implanted

43 Association Primary

44 Primary Association Recurrent activity may generate early cortical evoked activity (Ponton 2002; Eggermont 2002) From Thalamus Adapted from Kandel et al., 2000 To Thalamus To Thalamus

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46 360 Channel Magnetoencephalography (MEG) Somatosensory and visual stimulation

47 Sharma et al., 2007

48 Cross-Modal Plasticity fmri activity in deaf adults in response to visual stimuli Visual activity in temporal cortex at STS Finney et al., 2001

49 We found clear evidence that cortical reorganization underlies the end of the sensitive period. We are now exploring the functional consequences of cortical reorganization.

50 Auditory Visual Integration

51 Methods Subjects were 10 normal hearing children aged 7.4 to 12.8 years (mean=10.62) (NH). 8 normal hearing adults aged 23.7 to years (mean=24.46). 8 prelingually deafened children aged 9.57 to 14.7 years (mean=11.31), implanted early (mean=2.79 years). 8 prelingually deafened children aged 10.0 to 13.3 years (mean=11.33), implanted late (mean=7.84 years).

52 Methods Reaction times to Auditory (1000 Hz pure tone) Visual (1.2º white disk) Auditory-Visual (simultaneous) Mean reaction times compared Cumulative probabilities for reaction time calculated

53 * * * * ANOVA: Significant main effect of task condition for AV combined [F(3,30)=7.11, p=0.001] Gilley et al., 2006

54 * * AV A V A V AV * * * * * * ANOVA: Significant main effect of group [F(2,60)=39.28, p<0.0001] Gilley et al., 2006

55 Results Late Implanted do not violate the race model.

56 McGurk Effect Auditory-Visual Fusion e.g., hear /pa/, see /ka/ perceive /ta/

57 Fig. 2. Effect of age at the time of receiving a cochlear implant on auditory-visual fusion in speech perception Schorr, Efrat A. et al. (2005) Proc. Natl. Acad. Sci. USA 102, Copyright 2005 by the National Academy of Sciences

58 Multisensory integration may be abnormal in late implanted children.

59 BILATERAL IMPLANTATION

60 Mixed outcomes for speech perception in children who receive a second implant at a later age.

61 The effect of age at implantation of second ear Adapted from Peters et al., 2007

62 The effect of age at implantation of second ear Word score Wolfe et al. (2007)

63 Rubenstein et al., (2007) 2 congenitally deafened children who received the second implant as late as 8 and 11 years obtained good speech perception scores when tested with the second implant.

64 Zietler et al., (2008) 43 pediatric sequential bilateral implant patients Speech perception pre-implant and 3 months post implantation Age at second implant was a weak predictor of success with the second ear. Age at first implant was a contributing factor.

65 Aim To determine the factors which allow a second cochlear implant to be fitted into a highly plastic central auditory system.

66 Subjects 38 congenitally deaf children who underwent sequential bilateral implantation and have been fitted with their second implant for at least 1 year. All received their first implant under age 3.5 years. Second implant at ages ranging from 1.09 years to years. P1 latencies and speech perception were tested.

67 Relationship between P1 latency and Speech Perception

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69 Sequential Bilateral Implantation

70 Sequential Bilateral Implantation

71 Sequential Bilateral Implantation

72 Sequential Bilateral Implantation

73 Sequential Bilateral Implantation

74 Sequential Bilateral Implantation

75 Sequential Bilateral Implantation

76 Sequential Bilateral Implantation

77 Preliminary Conclusion Age at first implant is an important factor for preserving the plasticity for sequential bilateral implantation.

78 Photo courtesy of A. Kral

79 Binaural Cortical Representation Contralateral representation is always larger than ipsilateral representation in NH and CI cats CONTRALATERAL IPSILATERAL Ventro-Dorsal Position [µm] Stimulation Contralateral Ear Caudo-Rostral Position [µm] Stimulation Ipsilateral Ear Caudo-Rostral Position [µm] Potential amplitude [µv]

80 Kral et al., 2002; Cerebral Cortex Normalized activated area [r.u.] NM 3.5 mos. 5mos. 6mos. Age at 1 st Implant Ipsilateral Cortex Contralateral Cortex Ipsilateral Cortex Contralateral Cortex Ipsilateral ear ("Trained") Contralateral ear ("Untrained") Ipsilateral ear ("Trained") Contralateral ear ("Untrained") 1 st Implant 2 nd Implant Processor Processor

81 High Density EEG Study to Examine Cortical Activation in age matched NH and CI Children (mean age range 8-10 years) Normal Hearing n=10 First CI at age 2.9 years n=8 Bilateral STS Activation CI Contralateral STS Activation

82 Summary Early stimulation in one ear can lead to activation and preservation of plasticity of the binaural auditory cortex, allowing for fitting a second implant later in life.

83 Sequential vs. Simultaneous Bilateral Implantation at an Early Age

84 Early Sequential vs. Simultaneous Bilateral Implantation

85 Early Sequential vs. Simultaneous Bilateral Implantation No significant difference between the two groups Sharma et al., Audiological Medicine 2007

86 Early Sequential vs. Simultaneous Bilateral Implantation Simultaneous(<3yrs) Sequential (<3yrs) P1 P1

87 POTENTIAL CLINICAL APPLICATIONS

88 Relationship between P1 latency and Speech Acquisition

89 Age at Implantation: 13 Months Hook-up Precanonical Canonical Untranscribable 0.8 P1 Latency (ms) Week 1Month 3 Months Months Normal Limit s Age at Test (years) Sharma et al., 2004 P1 response latency Baseline Month 1 Month 2 Month 3 Pre-Implant Post-Implant

90 Age of Implantation: 14 months P1 Latency (m s) week 1 month 3 months Proportion of vocalization Precanonical Canonical Untranscribable 50 Normal Limits Baseline Baseline 1 Month 3 Months Age at Test (years) Pre-Implant Post-Implant Sharma et al., 2004

91 Biomarkers of deprivation and maturation

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93 P1 development following hearing aid fitting initial hearing aid fitting P1 response latency P1 Latency (ms) months post-hearing aid fitting 12 months post-hearing aid fitting Normal Limits Age at Test (years) Sharma et al., 2002

94 P1 development following cochlear implant fitting Sharma et al., 2002

95 Can we use P1 latency to tell us whether a hearing aid or cochlear implant has provided sufficient stimulation for normal development of the auditory pathway?

96 ASSESMENT PROTOCOL Audiological: ABR/Tympanogram/OAEs Tympanogram/OAEs.. Behavioral assessment of child s s hearing levels with and without hearing aids and child s s speech perception abilities. Hearing aids fit using prescriptive protocols. Speech and Language: Assessment of child s s expressive and receptive skills and speech production skills, appropriate expectations and follow-up program Pyschological: Counsel realistic expectations, ability to cope with device and follow-up program Medical/Radiological: General health, CT and/or MRI scan Electrophysiology: Cortical Auditory Evoked Response (P1) testing

97 University of Colorado at Denver Health Sciences Center

98 Age: 20 months Congenital, Moderate to Severe Hearing Loss, Bilaterally Unaided PTA: 75 dbhl Aided PTA: 40dBHL Hearing Aid Fit Age: 11 months

99 Age: 3 yrs, 2 mo Congenital, moderately-severe to severe, bilaterally Unaided PTA: RE: 86dBHL LE: 82dBHL Aided PTA: 40dBHL Hearing Aid Fit Age: 15 months P1 Latency (ms) HAF P1 Response Latency w/ HAs 1 mo post HAF 4.5 mo post HAF Age at Test (Years)

100 Age: 3. 5 years Congenital, Severe hearing loss, bilaterally P1 Auditory Evoked Potential Unaided PTA: 85dBHL Aided PTA: 45dBHL Hearing Aid Fit Age: 2. 5 years CI Candidate

101 Age: 2 years Congenital, severe hearing loss, bilaterally Unaided PTA: 75 dbhl Aided PTA: 47dBHL Hearing Aid Fit Age: 21 months CI Candidate

102 Age: 36 months Congenital, Severe to Profound Hearing Loss, Bilaterally Unaided PTA: 100 dbhl Aided PTA: 75 dbhl Hearing Aid Fit Age: 6 months LATENCY (ms) P1 response latency w/ HA P1 response latency w/ CI 16 month post HA fitting 19 month post HA fitting 1 week post CI fitting 3 month post CI fitting Normal limits Implant Fit Age: 28 months AGE (years)

103 From Basic Research to Possible Clinical Application? 10 years of basic research on effects of auditory deprivation on central auditory development and plasticity. We have collected data from over 1000 children with normal hearing, hearing aids and cochlear implants.

104 P1 testing is currently offered for hearing impaired pediatric patients at large facilities in Dallas and Denver. Clinical audiologists perform the testing. In a subset of patients under age 3 years, P1 results were cross-validated against gold standard audiological behavioral testing. Preliminary data show high sensitivity (89%) and specificity (85%) for P1 testing.

105 Several problems remain to be solved E.g., Scalp artifact in CI recordings

106 CONCLUSIONS P1 latency and morphology, are useful biomarkers to describe normal and abnormal development of the central auditory pathways. When used in conjunction with brain imaging techniques such as high density EEG, PET, fmri may help to better understand cortical development and reorganization in persons who experience auditory deprivation.

107 May serve as clinical indicators of central auditory development in children who receive intervention through conventional hearing aids and/or cochlear implants.

108 Brain and Behavior Laboratory Phillip Gilley Tracy White Amy Nash Ron Le Bel Julia Campbell Erin Castioni Megan Loehman Nils Penard Katy Brooks Madhu Sundarrajan Katrina Agung Tara Reed Jehan Alsalmi Justin Langran

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