Plasticity after pediatric cochlear implantation: Implication from changes in peripheral plasma level of BDNF and auditory nerve responses

https://doi.org/10.1016/j.ijporl.2017.12.014Get rights and content

Abstract

Introduction

Sensory neural hearing loss could lead to some structural and physiological changes in the auditory pathways, such as alteration in the expression of neurotrophins. These factors, especially Brain-Derived Neurotrophic Factor (BDNF), play an important role in synaptic functions and experience-related plasticity. Restoring cochlear function after hearing loss is possible through cochlear implantation (CI). Evaluation of the blood concentration changes of neurotrophins as prerequisites of plasticity could help scientists to determine the prognosis of CI as in the candidacy procedure or enhancing prosthesis function by adding the exact needed amount of BDNF to the electrode array.

Methods

Here we have studied the plasma BDNF concentration before CI surgery and 6 months after using CI device in 15 pediatric CI recipients and compared this level with changes of BDNF concentration in 10 children who were using hearing aid (H.A). In addition, we searched for a possible correlation between post-surgery plasma BDNF concentration and electrical compound action potential (ECAP) and comfort-level (C-level) thresholds.

Results

Plasma BDNF concentration in children with CI increased significantly after CI surgery, while this difference in H.A group was not significant. Analysis of repeated measures of ECAP and C-level thresholds in CI group showed that there were some kinds of steadiness during follow- up sessions for ECAP thresholds in basal and E16 of middle electrodes, whereas C-level thresholds for all selected electrodes increased significantly up to six months follow-up. Interestingly, we did not find any significant correlation between post-surgery plasma BDNF concentration and ECAP or C-level threshold changes.

Conclusion

It is concluded that changes in C-level threshold and steady state of ECAP thresholds and significant changes in BDNF concentration could be regarded as an indicator of experienced-related plasticity after CI stimulation.

Introduction

Oral Communication as a reciprocal social ability needs to undergo a number of processing steps in order to be expressed in a perceivable form for humans. As a prerequisite for sound reception, vertebrates have developed the most highly specialized structures which perform the task of transducing sound vibrations into neural signals. The organ of Corti, which is the structure responsible for sound transduction is located in the inner ear from which auditory signals are transmitted to spiral ganglion cells (SGC) and then to the cochlear nucleus in the brainstem and finally to the auditory cortex [58].

Information flow between the inner ear and the cortex could be severely decreased or even completely disappear when sensory neural hearing loss (SNHL) occurs and result in the loss of language learning ability, which is normally present in communicative interactions and social experiences [65]. Lack of language input could impose certain anatomical and functional changes to the organization of brain language systems [61]. In fact, sensory deprivation leads to changes in the biophysical properties of neurons in the pathways connecting the auditory nerve to the auditory cortex. These changes in the number of neurons or their neurite growth could be related to some intrinsic or extrinsic cell factors [10].

Neurotrophins, as an important class of extrinsic factors, have pivotal effects on cell shape and fate [10]. Brain-derived neurotropic factor (BDNF), as a member of this class, regulates cell survival, activity-dependent plasticity, neurotransmitter and neuropeptide production, differentiation, and neurite growth through binding to the family of tyrosine kinase receptors (TrkB) [13]. Interestingly, it might cause cell death through binding to the P75 neurotrophin receptor (P75 NTR), as well [3].

BDNF is synthesized in an activity-dependent manner where it can affect different neurotransmitter systems of the brain and the cross-talks between them [17,25,60]. Unfortunately, after auditory deprivation, the expression level of BDNF declines in the cochlea, auditory pathway and cortex [77,92]. While, the infusion of BDNF can significantly prevent the degeneration of auditory neurons and rescue spiral ganglion neurons [22]. Fortunately, restoring cochlear function in SNHL is possible through cochlear implantation (CI) [41], which provides the physiological prerequisites for speech comprehension [42]. It has been reported that CI can induce morphological plasticity in the auditory pathway [40].

This initiation of the mentioned synaptic plasticity is related to the regulatory events of BDNF synthesis concentration following chronic CI stimulation [77]. So, monitoring the changes in BDNF concentration could be beneficial in different contexts. On one hand, this change could be regarded as a biomarker and might reflect the hidden aspects of plasticity after CI use [68]. On the other hand, it seems reasonable that the combination of CI surgery and BDNF administration may increase the level of spiral ganglion nerve fiber densities and positively affect the quality of oral communication after CI surgery [15,39,47,66,71,83].

Although there are different methods for simultaneous usage of BDNF and CI, no clear protocol exists describing the exact concentration of BDNF, which might impose some adverse reactions. These adverse reactions might be related to the activation of P75 NTR and subsequent cell death signaling pathways [29,33,66] or augmentation of the risk of tumorigenesis resulting from the increased concentration of BDNF in cochlea [64].

Interestingly, it has been shown that the brain and the immune system use a common biochemical language [11,51], where scientists can track changes of the central nervous system in the immune system [12]. Since BDNF crosses the blood-brain barrier [36], it is not far from reality to regard some kind of interrelationship between peripheral BDNF concentration and its changes in the brain. Similarly, there are many studies which have indicated this relationship between cognition, attention and peripheral BDNF concentration in different conditions in adults [14,37,89] and children [73,88]. But, to our knowledge, there is no study investigating the changes in the BDNF concentration in peripheral blood after CI.

Therefore, the aim of the present study was to investigate differences in the plasma BDNF concentration before and after CI surgery, at first as a marker of plasticity and secondly, as a measure for future electrode design in CI. Since there are some arguments about a large amount of plasticity in the first six months of implant use in children who receive their CI in their sensitive periods [43], we planned to evaluate this factor within six months of CI usage in preschool children. In addition, as a complementary assessment, we also followed up electrically evoked compound action potential (ECAP) changes during six months after receiving the device and monitored C-level extracted from behavioral measures of our participants. In fact, ECAP thresholds helps to monitor subsequent electrophysiological responses in the auditory nerve and to evaluate the speech processor function after CI [9]. Finally, we examined whether there is any correlation between post-surgery plasma BDNF concentration and ECAP and C-level thresholds.

Section snippets

Participants

Fifteen children (six boys) with unilateral CI and ten children (five boys) with hearing aid (H.A) (as the control groups for biological parts of the study) enrolled as qualified participants in this research (based on criteria mentioned below) (see Table 1 for demographic data). Informed consent was obtained from their parents for inclusion in the study. The study was approved by the Ethics Committee of Tehran University of Medical Sciences. All subjects in the cochlear implant group were

Results

The mean age at implantation for the CI group was 36.8 ± 6.8 months, whereas the average age for the H.A group was 34.0 ± 7.7 months. The outcome variables for plasma BDNF concentration in both groups were found to be normally distributed and equal variances were detected based upon results of the Levene's test. Mixed design analysis of variances (ANOVA) with treatment (CI vs H.A) as a between-subject factor and time (baseline, second measurement) as within-subject factor indicated a

Discussion

The aim of the present study was to investigate the difference between plasma BDNF concentration before and six months after switching on the CI device in pre-school children, as an index of brain plasticity and a measuring point for future electrode design. To our knowledge, this is the first study designed to understand the reflection of human brain plasticity after CI surgery on peripheral BDNF level. We observed that plasma BDNF level in children with CI increased significantly after CI

Limitation of the study

The results of the present study showed that it is possible to track the neurophysiological changes after a duration of chronic CI stimulation via blood analysis. In fact, reaching a good conclusion in each CI-related experiment needs to apply the procedure on a homogenized number of participants including similar age, same underlying etiology of hearing loss, same duration of hearing loss, same device and strategy and the same ear for CI surgery. In the present study, we sought to decrease

Conclusion

In the present study, we found that plasma BDNF concentration changes significantly after CI. Since CI will lead to structural and physiological changes in the auditory pathway, having knowledge about the exact level of BDNF could be regarded as an indicator of CI success and plasticity. Moreover, as this factor can be a future additive element to the CI electrode array, so knowing the exact concentration of changes of this factor in the pediatric population could be beneficial. Herein, we

Conflicts of interest

The authors declare no conflict of interest.

Acknowledgment

The authors wish to thank all the participants and their families, Mr. Reza Sadeghi for his help in recruiting participants of H.A group, Mr. Farzad Mubedshahi for his help in the audiological part of the study, and Dr. Alexandre Lehmann for his valuable comments on the manuscript. This work was done by grant support from Tehran University of Medical Sciences and Health Services (grant No. 94-02-87-29401).

References (92)

  • R. Karamert et al.

    Association of GJB2 gene mutation with cochlear implant performance in genetic non-syndromic hearing loss

    Int. J. Pediatr. Otorhinolaryngol.

    (2011)
  • F. Karege et al.

    Decreased serum brain-derived neurotrophic factor levels in major depressed patients

    Psychiatr. Res.

    (2002)
  • F. Karege et al.

    Postnatal developmental profile of brain-derived neurotrophic factor in rat brain and platelets

    Neurosci. Lett.

    (2002)
  • R. Katoh-Semba et al.

    Age-related changes in BDNF protein levels in human serum: differences between autism cases and normal controls

    Int. J. Dev. Neurosci.: Official J. Int. Soc.Dev. Neurosci.

    (2007)
  • A. Kral et al.

    Developmental neuroplasticity after cochlear implantation

    Trends Neurosci.

    (2012)
  • G. Leal et al.

    BDNF-induced local protein synthesis and synaptic plasticity

    Neuropharmacology

    (2014)
  • M. Lommatzsch et al.

    The impact of age, weight and gender on BDNF levels in human platelets and plasma

    Neurobiol. Aging

    (2005)
  • K. Miyazaki et al.

    Serum neurotrophin concentrations in autism and mental retardation: a pilot study

    Brain & Dev.

    (2004)
  • I. Nelken

    Processing of complex sounds in the auditory system

    Curr. Opin. Neurobiol.

    (2008)
  • S. Penicaud et al.

    Structural brain changes linked to delayed first language acquisition in congenitally deaf individuals

    Neuroimage

    (2013)
  • D. Ramekers et al.

    Neurotrophins and their role in the cochlea

    Hear. Res.

    (2012)
  • D. Rejali et al.

    Cochlear implants and ex vivo BDNF gene therapy protect spiral ganglion neurons

    Hear. Res.

    (2007)
  • R.T. Richardson et al.

    A single dose of neurotrophin-3 to the cochlea surrounds spiral ganglion neurons and provides trophic support

    Hear. Res.

    (2005)
  • S.H. Shim et al.

    Increased levels of plasma brain-derived neurotrophic factor (BDNF) in children with attention deficit-hyperactivity disorder (ADHD)

    Prog. Neuro Psychopharmacol. Biol. Psychiatr.

    (2008)
  • W. Singer et al.

    The function of BDNF in the adult auditory system

    Neuropharmacology

    (2014)
  • H. Staecker et al.

    Brain-derived neurotrophic factor gene therapy prevents spiral ganglion degeneration after hair cell loss

    Otolaryngol.–head and neck surg. : Official J. Am. Acad. Otolaryngol.-Head and Neck Surg.

    (1998)
  • L.F. Tanamati et al.

    Longitudinal study of the ecap measured in children with cochlear implants

    Braz. J. Oceanogr.

    (2009)
  • L.M. Telmesani et al.

    Electrically evoked compound action potential (ECAP) in cochlear implant children: changes in auditory nerve response in first year of cochlear implant use

    Int. J. Pediatr. Otorhinolaryngol.

    (2016)
  • S. Vlahovic et al.

    Differences between electrically evoked compound action potential (ECAP) and behavioral measures in children with cochlear implants operated in the school age vs. operated in the first years of life

    Int. J. Pediatr. Otorhinolaryngol.

    (2012)
  • A. Warnecke et al.

    Stable release of BDNF from the fibroblast cell line NIH3T3 grown on silicone elastomers enhances survival of spiral ganglion cells in vitro and in vivo

    Hear. Res.

    (2012)
  • H. Xiong et al.

    Plasma brain-derived neurotrophic factor levels are increased in patients with tinnitus and correlated with therapeutic effects

    Neurosci. Lett.

    (2016)
  • M. Zagrebelsky et al.

    Form follows function: BDNF and its involvement in sculpting the function and structure of synapses

    Neuropharmacology

    (2014)
  • Y. Abdurehim et al.

    Predictive value of GJB2 mutation status for hearing outcomes of pediatric cochlear implantation

    Otolaryngology-Head Neck Surg. (Tokyo)

    (2017)
  • A. Ajami et al.

    Changes in serum levels of brain derived neurotrophic factor and nerve growth factor-beta in schizophrenic patients before and after treatment

    Scand. J. Immunol.

    (2014)
  • S.J. Allen et al.

    Clinical relevance of the neurotrophins and their receptors

    Clin. Sci.

    (2006)
  • R.A. Altschuler et al.

    Rescue and regrowth of sensory nerves following deafferentation by neurotrophic factors

    Ann. N. Y. Acad. Sci.

    (1999)
  • F. Angelucci et al.

    The effects of motor rehabilitation training on clinical symptoms and serum BDNF levels in Parkinson's disease subjects

    Can. J. Physiol. Pharmacol.

    (2016)
  • R. Anomal et al.

    Manipulation of BDNF signaling modifies the experience-dependent plasticity induced by pure tone exposure during the critical period in the primary auditory cortex

    PloS one

    (2013)
  • D. Basta et al.

    Relationship between intraoperative eCAP thresholds and postoperative psychoacoustic levels as a prognostic tool in evaluating the rehabilitation of cochlear implantees

    Audiol. Neuro. Otol.

    (2007)
  • M. Bibel et al.

    Neurotrophins: key regulators of cell fate and cell shape in the vertebrate nervous system

    Gene Dev.

    (2000)
  • J.E. Blalock

    Shared ligands and receptors as a molecular mechanism for communication between the immune and neuroendocrine systems

    Ann. N. Y. Acad. Sci.

    (1994)
  • A.A. Boldyrev et al.

    Emerging evidence for a similar role of glutamate receptors in the nervous and immune systems

    J. Neurochem.

    (2005)
  • A.R. Carter et al.

    Brain-derived neurotrophic factor modulates cerebellar plasticity and synaptic ultrastructure

    J. Neurosci.

    (2002)
  • M. Corominas-Roso et al.

    Decreased serum levels of brain-derived neurotrophic factor in adults with attention-deficit hyperactivity disorder

    Int. J. Neuropsychopharmacol.

    (2013)
  • M. Davcheva-Chakar et al.

    Speech perception outcomes after cochlear implantation in children with GJB2/DFNB1 associated deafness

    Balkan Med. J.

    (2014)
  • B.S. Fernandes et al.

    Peripheral brain-derived neurotrophic factor (BDNF) as a biomarker in bipolar disorder: a meta-analysis of 52 studies

    BMC Med.

    (2015)
  • Cited by (2)

    • Expression pattern of brain-derived neurotrophic factor and its associated receptors: Implications for exogenous neurotrophin application

      2022, Hearing Research
      Citation Excerpt :

      For the inner ear, neurotrophins are essential for the connection of hair cells to auditory neurons during embryonic development (Pirvola et al., 1997, Pirvola et al., 1992, Flores-Otero and Davis, 2011) and for the maintenance and repair of the ribbon synapses in the adult cochlea (Wan et al., 2014, Mellado Lagarde et al., 2013, May et al., 2013, Bailey and Green, 2014). Maturation of the auditory pathway due to hearing restoration by cochlear implantation in young children is correlated with increased endogenous BDNF plasma levels (Alemi et al., 2018). In the central nervous system, BDNF is provided by astrocytes and microglial cells (Yang et al., 2012, Dougherty et al., 2000, Simard and Rivest, 2007).

    View full text