Abstract
Objectives
Although published reports have not demonstrated a positive correlation between the number of residual spiral ganglion cells (SGC) and word recognition scores in patients with unilateral multichannel cochlear implants, this study was designed to retest this hypothesis in patients with bilateral multichannel cochlear implants.
Materials and Methods
From a pool of 133 temporal bones, all subjects with bilateral multichannel cochlear implants who were deafened bilaterally by the same etiology were studied. A total of 12 temporal bones from 6 subjects were identified and processed after death for histology. The SGCs were counted by standard techniques. The differences between left and right SGC counts as well as the differences in word recognition scores were calculated for each subject. Correlation analysis was performed between the differences of SGC counts and the differences of word recognition scores.
Results
Differences in SGC counts were highly correlated with the differences in word recognition scores (R=0.934, P-value= 0.006).
Conclusion
This study suggests higher residual SGCs predicted better performance after implantation in a given patient. The results also support attempts to identify factors which may promote survival of SGCs.
Keywords: Cochlear implantation, word recognition, performance, spiral ganglion cell, Correlation
Introduction
Spiral ganglion cells (SGC) are the first order neurons that transmit the electrical stimuli generated by cochlear implants to the central nervous system. Thus, it seems reasonable to assume that in subjects with profound hearing impairment, more residual SGCs would result in better word recognition and performance after cochlear implantation. This assumption has been the basis of many studies, which focused on identifying factors that tend to promote the number of SGCs or at least reduce the deleterious effect of insulting factors on the survival of spiral ganglion cells. Seyyedi et al. (1) and Leake et al. (2) reported that chronic bipolar stimulation through cochlear implants has a protective effect on the survival of SGCs. Likewise, It has been reported that some neurotrophins such as brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3) and cometin promote the survival of SGCs in subjects with profound hearing loss (3-5). However, the findings in some human temporal bone studies (6-8) raised a question about the validity of this assumption.
Khan et al. (7), in a postmortem temporal bone study of 15 human subjects with unilateral cochlear implants did not find a significant correlation between the number of residual SGCs in implanted ears and word recognition scores (WRS) after cochlear implantation. Xu et al. (6) reached similar conclusions in a human temporal bone study of 4 subjects. Fayad et al. (8), in histologic examination of 14 implanted temporal bones, reported a statistically significant negative correlation between total SGC count and word recognition scores (R= −0.632, P-value ≤ 0.047). These conflicting results suggested a need to revisit the question.
The critical factor in any comparison is the context in which the comparison takes place and certainly, comparison between highly matched subjects results in a stronger and more reliable outcome. In all previous human temporal bone studies, SGC counts and word recognition scores were compared across the implanted ears of different subjects, while other variables such as etiology of deafness, central processing, cognitive ability, and age were not controlled across the patients.
Nadol et al.(9) reported that patients with deafness due to different etiologies had different ranges of residual spiral ganglion cells. They also demonstrated that even in patients within each diagnostic subgroup there was great variability in the SGC counts. Likewise, in unilateral cochlear implant recipients (6-8), great variability in spiral ganglion cell count was observed in cases with similar word recognition scores.
On the other hand, Seyyedi et al. (10) in an attempt to find a desirable control in temporal bone studies evaluating the impact on SGC survival of a medical intervention, reported that one ear of the patient serves as a desirable control for the other ear. In the study of 42 temporal bones of 21 patients with profound hearing loss, the results demonstrated that the number of surviving spiral ganglion cells was similar between the ears of each patient when both ears of each patient were deafened by the same etiology and both ears had the same level of hearing loss.
Thus, based on the findings of Seyyedi et al. (10) and Nadol et al. (9) and using one ear as the control for the other ear in each patient, we designed this study to evaluate whether differences in word recognition score can be predicted by the differences in SGC count.
Subjects and Methods
All 133 implanted temporal bones from the collections of Massachusetts Eye and Ear Infirmary, House Research Institute and University of Minnesota constitute the statistical population of our study. All subjects who met the following criteria were included in the study: 1) bilateral implantation using multichannel cochlear implants; 2) post-operative documented word recognition scores were available for both ears; 3) both ears had been deafened by the same etiology. A total of 12 temporal bones from 6 subjects were identified.
The temporal bones were removed after death, fixed in Heidenhain Susa solution or 10% buffered formalin and decalcified in ethylene diamine tetra acetic acid (EDTA), and embedded in celloidin (11). The temporal bones were sectioned at a thickness of 20 μm in the horizontal plane, and every tenth section was stained with hematoxylin and eosin and mounted on a glass slide. Rosenthal's canal and the cochlear duct were reconstructed in two dimensions (Figure 1) by a method described by Schuknecht (12) and Otte et al. (13), and the length of Rosenthal's canal, cochlear duct and the depth of insertion of the electrode were calculated.
Figure 1.
Two dimensional reconstruction of left cochlear duct, Rosenthal's canal and path of electrode array of case 5. The vertical line divides Rosenthal's canal to 4 segments. The black circles on Rosenthal's canal and on the cochlear duct are 1 mm apart.
Using the method described by Konigsmark (14) and Nadol (15), all SGCs with visible nuclei were counted on every tenth section by an observer blinded to the performance of patients after implantation. SGC counts for the four cochlear segments, identified in Figure 1, were computed by adding all counts across slides from the same segment. Each segmental count was multiplied by ten to account for unmounted sections, and again multiplied by a correction factor of 0.68 (14,15) to account for doubly counted SGCs. The total spiral ganglion cell count was calculated as the sum of the four segmental counts (9,15).
In order to measure the strength of association between the values of word recognition score and SGC count, depth of electrode insertion, duration of implant use, and age at implantation between the ears of each patient, differences were calculated by the subtraction of values of the right ear from the left ear for each variable separately and then the differences were compared using Pearson's correlation analysis. For instance, case 1 had 5916 residual SGCs with 25% WRS on the left and 2326 SGCs with 5% WRS on the right. The differences for SGC and WRS were computed by subtracting the values of right ear from left ear for each variable (ΔSGC L-R = 5916- 2326 = 3590; ΔWRS L-R = 25-5 = 20). Similarly, the differences were computed for WRS and SGC in the other 5 cases, and finally using correlation analysis the association between the differences of WRS and SGC was evaluated.
In order to measure the rate of change in word recognition score as a result of a change in spiral ganglion cell count, for each patient the slope of the line connecting the data points of left and right ears (Figure 2) was determined and then the average of slopes was calculated and tested as to whether it was significantly greater than 0. The slope for each patient was calculated by dividing the difference in WRS between left and right ears by the difference in SGC (slope =m= ΔWRS L-R / ΔSGC L-R). The average of 6 slopes was computed and One Sample t-test (one-tailed) was used to evaluate whether the calculated average was statistically greater than 0. A positive slope suggested that an increase in spiral ganglion cell count was correlated with a higher word recognition score.
Figure 2.
Word recognition scores plotted as a function of spiral ganglion cell counts. The data points for both ears of each patient were connected by a line. The slope (m) of each line is shown.
Results
From 133 temporal bones, 12 temporal bones from 6 patients who were implanted bilaterally during their life with multi-channel electrodes met the criteria for inclusion. As shown in Table 1, there were 3 males and 3 females with an average age of 76 years. The etiology of deafness and the age at deafness (except in case 5) were the same across the ears of each patient. In all subjects both ears were deafened post-lingually and PTA test results bilaterally showed profound hearing impairment prior to implantation. In three out of six patients, both ears were implanted at the same time with the same type of electrode using a similar mode of stimulation and strategy (Table 2). In three others, there was an interval between the implantation of both sides that varied between 2 to 11 years.
Table 1.
Demographic data in the 6 patients studied.
| Patient | Age | Sex | Age at deafness AS | Age at deafness AD | Deafness etiology |
|---|---|---|---|---|---|
| 1 | 66 | M | 21 | 21 | Bilateral Mondini Malformation |
| 2 | 76 | F | 34 | 34 | Bilaterally Unknown |
| 3 | 74 | F | 12 | 12 | Bilateral Otosclerosis |
| 4 | 71 | F | 58 | 58 | Bilaterally Unknown |
| 5 | 88 | M | 26 | 70 | Bilateral Ménière's Disease |
| 6 | 83 | M | 70 | 70 | Bilateral Ménière's Disease |
AS: left; AD: right
Table 2.
Cochlear implant and strategies used in the 6 patients.
| Left ear | Right ear | |||||
|---|---|---|---|---|---|---|
| Patient | CI device | Stimulation mode | Strategy | CI device | Stimulation mode | Strategy |
| 1 | Nucleus 22 | BP | SPEAK | Nucleus 24 C | MP | ACE |
| 2 | Nucleus 24 M | MP | SPEAK | Nucleus 22 | BP | SPEAK |
| 3 | Hi Focus | MP | Hi Res 90k | Hi Focus | MP | Hi Res 90k |
| 4 | Nucleus 24 M | MP | SPEAK | Nucleus 24 M | MP | SPEAK |
| 5 | Nucleus 22 | BP | SPEAK | Nucleus Advance | MP | ACE |
| 6 | Nucleus 24 M | MP | SPEAK | Nucleus 24 M | MP | SPEAK |
AS: left; AD: right; BP: bipolar; MP: monopolar; CI: cochlear implant.
Table 3 and 4 illustrate the total spiral ganglion cell counts, word recognition scores, the depths of electrode insertion in the cochlea, duration of cochlear implant use, age at implantation and the differences across the ears of each patient (Left-Right). The evaluation of performance after cochlear implantation was reported using CNC scores in all cases except case 5 in which only the HINT scores were available. All word recognition scores used in the equations were the last available measurements, which were measured bilaterally for each patient at the same time. As can be seen in Table 3 and Figure 2, in the comparison across all 12 ears, the four ears with the largest number of residual SGCs did not have the highest word recognition scores. It can be seen also in Figure 2 that despite having similar word recognition scores, cases 3, 4 and 6 had great variability in SGC count.
Table 3.
SGC counts, word recognition scores, depth of insertion and other variables of the left and right ears of 6 patients.
| Right ear | Left ear | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Patient | WRS | SGC count | DI | Duration of IM use | Age at IM | WRS | SGC count | DI | Duration of IM use | Age at IM |
| 1 | 5 | 2326 | 6 | 1 | 65 | 25 | 5916 | 11 | 18 | 48 |
| 2 | 28 | 2326 | 17.8 | 4 | 70 | 30 | 2611 | 17.3 | 2 | 74 |
| 3 | 66 | 11635 | 18.3 | 8 | 66 | 66 | 12546 | 19.6 | 8 | 66 |
| 4 | 56 | 16000 | 19 | 11 | 60 | 60 | 16401 | 19.8 | 11 | 60 |
| 5 | 86 | 10064 | 10.6 | 6 | 82 | 80 | 8364 | 17 | 11 | 71 |
| 6 | 57 | 7548 | 19 | 12 | 71 | 58 | 8500 | 16.4 | 12 | 71 |
WRS: word recognition score; SGC: spiral ganglion cell; IM: implantation; DI: Depth of electrode insertion (mm)
Table 4.
The differences between the left and right ear values of SGC counts, word recognition scores, depth of insertion and other variables in the 6 patients.
| Patient | AS-AD WRS | AS-AD SGC count | AS-AD DI | AS-AD duration of IM use | AS-AD age at IM |
|---|---|---|---|---|---|
| 1 | 20 | 3590 | 5 | 17 | −17 |
| 2 | 2 | 285 | −0.5 | −2 | 4 |
| 3 | 0 | 911 | 1.3 | 0 | 0 |
| 4 | 4 | 401 | 0.8 | 0 | 0 |
| 5 | −6 | −1700 | 6.4 | 5 | −11 |
| 6 | 1 | 952 | 3.5 | 0 | 0 |
AS: left; AD: right; WRS: word recognition score; SGC: spiral ganglion cell; IM: implantation; DI: Depth of electrode insertion (mm).
Inter-aural comparison demonstrated (Figure 2) that patients with small differences in word recognition scores between both ears had small differences in surviving spiral ganglion cell counts and patients with larger differences had larger differences in spiral ganglion cell counts. Even more importantly, comparison between the ears of each patient showed that all the ears with higher score in word recognition had a higher spiral ganglion cell count (except case 5).
Pearson's correlation analysis was used to determine how the differences in SGC count, depth of electrode insertion, duration of cochlear implant use and age at implantation were associated with the difference in word recognition score. The results of correlation analysis (Table 5) showed that there was a significant positive correlation between the differences of word recognition scores and SGC counts between the ears of each patient (R= 0.934, P-value=0.006). There was no correlation between the differences of word recognition scores and the depth of electrode insertion (Table 5). Likewise, there was no significant correlation between the differences in duration of cochlear implant use, age at implantation and word recognition scores between the ears of each patient.
Table 5.
Bivariate correlation analysis of selected clinical variables in the 6 patients.
| AS-AD WRS | Sig. (2-tailed) | N | |
|---|---|---|---|
| AS-AD WRS | 1 | - | 6 |
| AS-AD SGC count | .934** | .006 | 6 |
| AS-AD DI | .167 | .751 | 6 |
| AS-AD duration of IM use | .760 | .079 | 6 |
| AS-AD age at IM | −.512 | .300 | 6 |
Correlation is significant at the 0.05 level (2-tailed).
AS: left; AD: right; WRS: word recognition score; SGC: spiral ganglion cell; DI: depth of electrode insertion; IM: implantation.
As shown in Figure 2, all had positive slopes except case 3 in which the slope was 0. The average of slopes was 0.005 and the t-test showed that it was significantly greater than 0 (t= 2.950, df= 5 and P-value (one–tailed) = 0.016). The slope of 0.005 implies that an increase of 1000 spiral ganglion cells was correlated with an increase of 5% in word recognition score.
Discussion
The outcome of cochlear implantation is evaluated by post-operative speech perception and word recognition scores. A wide spectrum of variables may affect post-implantation speech perception (16-18). These factors can be classified into two major groups: 1- device related factors such as electrode design, configuration and processing strategy and 2- patient's variables such as duration of deafness, duration of cochlear implant use, depth of insertion, age, age at implantation, etiology of deafness, and auditory neuroplasticity.
Otte et al. reported a positive correlation between the number of SGCs and word recognition score in a study of 82 unimplanted human temporal bones (13). In implanted animals a correlation between psychophysical parameters and residual spiral ganglion cell counts was reported (19,20). However, two histopathologic human temporal bone studies (6,7) reported no correlation between word recognition score and spiral ganglion cell count in implanted ears, and surprisingly, Fayad(8) et al. reported a significant negative correlation between the number of residual SGCs and the performance after cochlear implantation.
In all previous human studies of implanted ears (6-8) the SGC count and word recognition score of one patient were compared with the same variables in other patients where other possible factors affecting word recognition were not controlled. If we treat our data in a similar fashion as done in previous studies (6-8) (one ear from each patient), correlation analysis between word recognition scores and associated spiral ganglion cell counts yield similar results that is no significant correlation (R=0.599, P-value= 0.2, N=6).
Nadol et al. (9) showed widely variable SGC count in patients with profound deafness with different etiologies of deafness and a similar PTA, and in patients with a similar etiology of deafness and similar levels of hearing loss. Likewise, in the previous human studies (6-8) there were many cases with similar speech discrimination scores which had wide variability in spiral ganglion cell counts. This suggests that there are other factors that may alter the correlation of spiral ganglion cell counts with word recognition scores and comparison across the ears of different patients is not valid unless the effect of all other confounding factors are controlled across the ears.
On the other hand, a previous report (10) demonstrated that spiral ganglion cell counts in patients with symmetrical bilateral profound deafness were statistically not different in both ears of a given subject, if both sides were deafened by the same etiology. These findings suggested that a study of the correlation between the number of residual spiral ganglion cells and word recognition scores in cases with bilateral cochlear implants using one ear as the control for the other ear, where many variables such as etiology of deafness, age, and cognitive ability had been controlled was warranted. This matching technique in the methodology resulted in a very strong correlation between differences in word recognition score and differences in spiral ganglion cell count (R= 0.934, P-value= 0.006, N= 6), which confirms the assumption that a larger number of surviving spiral ganglion cells result in better performance after cochlear implantation in a given patient. This implies that in bilaterally implanted patients deafened bilaterally by the same etiology, patients have minimally different word recognition scores when they have roughly equal spiral ganglion cell counts in both ears and when there is a meaningful difference in word recognition score across the ears, the ear with greater residual spiral ganglion cell count tends to have a better performance. In this study, the findings of Otte et al.(13) in unimplanted ears were confirmed in ears with cochlear implantation. In the other bivariate correlation analyses, duration of cochlear implant use, depth of insertion and age at implantation did not show a significant correlation with word recognition score. The effect of these factors was variable in previous reports (17,21-23).
Conclusion
The results of this study suggest that the number of surviving spiral ganglion cells is positively correlated with word recognition scores after implantation in a given patient. This finding supports efforts to protect SGCs against deleterious factors such as implantation trauma.
Acknowledgments
This work was supported by grant R01-DC000152 from the National Institute of Deafness and Other Communication Disorders. We also want to thank Dr. Hang Lee from Harvard Catalyst Group for his statistical consultation.
References
- 1.Seyyedi M, Eddington DK, Nadol JB., Jr Effect of monopolar and bipolar electric stimulation on survival and size of human spiral ganglion cells as studied by postmortem histopathology. Hear Res. 2013;302:9–16. doi: 10.1016/j.heares.2013.04.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Leake PA, Hradek GT, Snyder RL. Chronic electrical stimulation by a cochlear implant promotes survival of spiral ganglion neurons after neonatal deafness. J Comp Neurol. 1999;412:543–62. doi: 10.1002/(sici)1096-9861(19991004)412:4<543::aid-cne1>3.0.co;2-3. [DOI] [PubMed] [Google Scholar]
- 3.Ernfors P, Duan ML, ElShamy WM, et al. Protection of auditory neurons from aminoglycoside toxicity by neurotrophin-3. Nat Med. 1996;2:463–7. doi: 10.1038/nm0496-463. [DOI] [PubMed] [Google Scholar]
- 4.Jorgensen JR, Fransson A, Fjord-Larsen L, et al. Cometin is a novel neurotrophic factor that promotes neurite outgrowth and neuroblast migration in vitro and supports survival of spiral ganglion neurons in vivo. Exp Neurol. 2012;233:172–81. doi: 10.1016/j.expneurol.2011.09.027. [DOI] [PubMed] [Google Scholar]
- 5.Staecker H, Kopke R, Malgrange B, et al. NT-3 and/or BDNF therapy prevents loss of auditory neurons following loss of hair cells. Neuroreport. 1996;7:889–94. doi: 10.1097/00001756-199603220-00011. [DOI] [PubMed] [Google Scholar]
- 6.Xu HX, Kim GH, Snissarenko EP, et al. Multi-channel cochlear implant histopathology: are fewer spiral ganglion cells really related to better clinical performance? Acta Otolaryngol. 2012;132:482–90. doi: 10.3109/00016489.2011.647361. [DOI] [PubMed] [Google Scholar]
- 7.Khan AM, Handzel O, Burgess BJ, et al. Is word recognition correlated with the number of surviving spiral ganglion cells and electrode insertion depth in human subjects with cochlear implants? Laryngoscope. 2005;115:672–7. doi: 10.1097/01.mlg.0000161335.62139.80. [DOI] [PubMed] [Google Scholar]
- 8.Fayad JN, Linthicum FH., Jr Multichannel cochlear implants: relation of histopathology to performance. Laryngoscope. 2006;116:1310–20. doi: 10.1097/01.mlg.0000227176.09500.28. [DOI] [PubMed] [Google Scholar]
- 9.Nadol JB, Jr., Young YS, Glynn RJ. Survival of spiral ganglion cells in profound sensorineural hearing loss: implications for cochlear implantation. Ann Otol Rhinol Laryngol. 1989;98:411–6. doi: 10.1177/000348948909800602. [DOI] [PubMed] [Google Scholar]
- 10.Seyyedi M, Eddington DK, Nadol JB., Jr Interaural comparison of spiral ganglion cell counts in profound deafness. Hear Res. 2011;282:56–62. doi: 10.1016/j.heares.2011.10.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Schuknecht H. Temporal bone removal at autopsy. Preparation and uses. Arch Otolaryngol. 1968;87:129–37. doi: 10.1001/archotol.1968.00760060131007. [DOI] [PubMed] [Google Scholar]
- 12.Schuknecht HF. Techniques for study of cochlear function and pathology in experimental animals; development of the anatomical frequency scale for the cat. AMA Arch Otolaryngol. 1953;58:377–97. doi: 10.1001/archotol.1953.00710040399001. [DOI] [PubMed] [Google Scholar]
- 13.Otte J, Schunknecht HF, Kerr AG. Ganglion cell populations in normal and pathological human cochleae. Implications for cochlear implantation. Laryngoscope. 1978;88:1231–46. doi: 10.1288/00005537-197808000-00004. [DOI] [PubMed] [Google Scholar]
- 14.Konigsmark BW. Methods for the counting of neurons. In: Nauta WJH, Ebbeson SOE, editors. Contemporary Research Methods in Neuroanatomy. Springer-Verlag; Berlin: 1970. pp. 315–38. [Google Scholar]
- 15.Nadol JB., Jr Quantification of human spiral ganglion cells by serial section reconstruction and segmental density estimates. Am J Otolaryngol. 1988;9:47–51. doi: 10.1016/s0196-0709(88)80007-3. [DOI] [PubMed] [Google Scholar]
- 16.Cosetti MK, Waltzman SB. Outcomes in cochlear implantation: variables affecting performance in adults and children. Otolaryngol Clin North Am. 2012;45:155–71. doi: 10.1016/j.otc.2011.08.023. [DOI] [PubMed] [Google Scholar]
- 17.Davidson LS, Geers AE, Blamey PJ, et al. Factors contributing to speech perception scores in long-term pediatric cochlear implant users. Ear Hear. 2011;32:19S–26S. doi: 10.1097/AUD.0b013e3181ffdb8b. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Holden LK, Finley CC, Firszt JB, et al. Factors affecting open-set word recognition in adults with cochlear implants. Ear Hear. 2013;34:342–60. doi: 10.1097/AUD.0b013e3182741aa7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Pfingst BE, Sutton D, Miller JM, et al. Relation of psychophysical data to histopathology in monkeys with cochlear implants. Acta Otolaryngol. 1981;92:1–13. doi: 10.3109/00016488109133232. [DOI] [PubMed] [Google Scholar]
- 20.Pfingst BE, Sutton D. Relation of cochlear implant function to histopathology in monkeys. Ann N Y Acad Sci. 1983;405:224–39. doi: 10.1111/j.1749-6632.1983.tb31635.x. [DOI] [PubMed] [Google Scholar]
- 21.Lee J, Nadol JB, Jr., Eddington DK. Depth of electrode insertion and postoperative performance in humans with cochlear implants: a histopathologic study. Audiol Neurootol. 2010;15:323–31. doi: 10.1159/000289571. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Holden LK, Finley CC, Firszt JB, et al. Factors affecting open-set word recognition in adults with cochlear implants. Ear Hear. 2013;34:342–60. doi: 10.1097/AUD.0b013e3182741aa7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Finley CC, Holden TA, Holden LK, et al. Role of electrode placement as a contributor to variability in cochlear implant outcomes. Otol Neurotol. 2008;29:920–8. doi: 10.1097/MAO.0b013e318184f492. [DOI] [PMC free article] [PubMed] [Google Scholar]