Erin Glennon Froemke and Svirsky Labs ACIA 7/11/19 Neuromodulation and Plasticity for a Rodent Model of Cochlear Implant Use
Transcript
Erin GlennonFroemke and Svirsky Labs
ACIA7/11/19
Neuromodulation and Plasticity for a Rodent Model of Cochlear Implant Use
Outline
• Background: hearing loss and cochlear implants
• Cochlear implant rat model: procedure and behavior
• Neuromodulation in cochlear implant and auditory learning
Presenter
Presentation Notes
In today's talk I'll first speak to you about some background on the problem of hearing loss and how cochlear implants can be used as an intervention. Next I'll describe a rodent cochlear implant model that has been developed in our lab, including how it has improved on previous models and the behavioral task we use to assess cochlear implant learning. Finally, I'll talk about my proposed work on the role of neuromodulation in cochlear implant learning. I'll be looking at the locus coeruleus, the source of norepinephrine in the central nervous system, which I will describe more later. Specifically, I will examine the activity of locus coeruleus during auditory perceptual learning in normal hearing and cochlear implanted animals. Then I will ask if silencing the locus coeruleus slows auditory perceptual learning in cochlear implanted animals. Finally, I will ask if stimulating the locus coeruleus will accelerate auditory perceptual learning in cochlear implanted animals.
Outline
• Background: hearing loss and cochlear implants
• Cochlear implant rat model: procedure and behavior
• Neuromodulation in cochlear implant and auditory learning
Presenter
Presentation Notes
As I mentioned, I'll begin with some background on hearing loss and how the neuro prosthetic, cochlear implants have been used as an important treatment.
Hearing Loss and Cochlear ImplantsW
ord
Reco
gniti
on (%
Cor
rect
)
Age
A
Roberts et al., Laryngoscope (2013)
Presenter
Presentation Notes
Save time here The implant restores hearing such that patients who previously had very low capabilities for word recognition can have huge improvements in recognition. On the left we see pre-op patients and on the right we see post-op patients. CNC: consonant nucleus consonant test gold standard for testing CI use A consistent but unexplained finding in CI research is the large variability in performance among CI users even when etiology, duration of deafness, electrode placement, and age of implantation are taken into account (Pyman et al., 2000; Blamey et al., 2013).
Hearing Loss and Cochlear ImplantsW
ord
Reco
gniti
on (%
Cor
rect
)
Age
A
B
AgeRoberts et al., Laryngoscope (2013)
Presenter
Presentation Notes
However, a portion of patients do not fully benefit from the cochlear implant. This variability in outcomes still exists after accounting for differences in duration of deafness, etiology, insertion technique, and implant type. CNC: consonant nucleus consonant test gold standard for testing CI use A consistent but unexplained finding in CI research is the large variability in performance among CI users even when etiology, duration of deafness, electrode placement, and age of implantation are taken into account (Pyman et al., 2000; Blamey et al., 2013).
Hearing Loss and Cochlear ImplantsW
ord
Reco
gniti
on (%
Cor
rect
)
Roberts et al., Laryngoscope (2013)
Age
A
B
Age
Presenter
Presentation Notes
Here we see a population of patients who even after cochlear implantation are only able to recognize 40% or less of words that they hear. CNC: consonant nucleus consonant test gold standard for testing CI use A consistent but unexplained finding in CI research is the large variability in performance among CI users even when etiology, duration of deafness, electrode placement, and age of implantation are taken into account (Pyman et al., 2000; Blamey et al., 2013).
Hearing Loss and Cochlear ImplantsW
ord
Reco
gniti
on (%
Cor
rect
)
Age
CA
B
Wor
d Re
cogn
ition
(% C
orre
ct)
Months Post-Implantation
Roberts et al., Laryngoscope (2013)Chang et al., JAAA (2010)Age
Presenter
Presentation Notes
Furthermore, there is a period of learning post cochlear implant insertion. [next slide] CNC: consonant nucleus consonant test gold standard for testing CI use A consistent but unexplained finding in CI research is the large variability in performance among CI users even when etiology, duration of deafness, electrode placement, and age of implantation are taken into account (Pyman et al., 2000; Blamey et al., 2013).
Hearing Loss and Cochlear ImplantsW
ord
Reco
gniti
on (%
Cor
rect
)
CA
B
Wor
d Re
cogn
ition
(% C
orre
ct)
Age
Months Post-Implantation
Roberts et al., Laryngoscope (2013)Chang et al., JAAA (2010)Age
Presenter
Presentation Notes
(describe graph) This variability and adaptation have led the field to hypothesize for a role of auditory plasticity in cochlear implant outcomes. However, it is difficult to address these kinds of questions in humans as they require invasive techniques. CNC: consonant nucleus consonant test gold standard for testing CI use A consistent but unexplained finding in CI research is the large variability in performance among CI users even when etiology, duration of deafness, electrode placement, and age of implantation are taken into account (Pyman et al., 2000; Blamey et al., 2013).
Outline
• Background: hearing loss and cochlear implants
• Cochlear implant rat model: procedure and behavior
• Neuromodulation in cochlear implant and auditory learning
Presenter
Presentation Notes
Therefore numerous animals models have been developed, including in cats, ferrets, guinea pigs, and rodents. Our lab has recently developed a rat cochlear implant model that has made advancements on previous models and in which we can reliably test cochlear implant learning using an auditory perceptual learning behavioral task. Congenitally deaf white cats (Fallon, Beitel) Ferret (Shepard)
Anatomical Confirmation of CI PlacementRat
3 mm
3 mm
1 mm
1 mm
Muller, Hear Res (1991)
King et al., J Neurophysiol (2016)
Human
Presenter
Presentation Notes
One full turn is comparable to the insertion in humans and covers three octaves in the rat cochlea. With this new technique, our CI insertion is similar to that of human CI depth and coverage. Additionally, with 8 channels, we are able to ask more complex behavioral questions. Landsberger, Ear and Hearing 2015 Describe shape Comparable to human depth and coverage One full turn 3 octaves
Acoustic Self-Initiated Go/No-Go Task
Target
Non-targets
Non-targets
Martins & Froemke, Nat Neuroscience (2015); King et al., J Neurophysiol (2016)Carcea et al., Nat Commun (2017); Insanally et al., eLife (2019)
d’ = z(hit rate) – z(false positive rate)
1.InitiationPort
2. Tone
3.DetectionPort
4. Reward
d’ = 3.0
Presenter
Presentation Notes
The behavioral assessment we do in the cochlear implanted animals is based on an acoustic self-initiated go/no-go task. In this task, animals are asked to discriminate between a target tone and several non-target tones. The animal initiates a trial by nosepoking in the initiating port. This triggers a tone. If the tone is the target tone, the animal should nosepoke in the detection port, and then receive a reward. On non-target tones, the animal should withhold. Performance is measured by d’, which is a measure of the discrimination based on the difference in the hit rate and the false positive rate. A d’ of zero is the inability to discriminate, while three is perfect discrimination. D’s of 1-1.5 are generally standards of animals being trained. In this psychophysical task, we can systematically explore detection thresholds and recognition limits. Measure of discrimination in behavioral task: 0 is inability; 3 is perfect performance; people use 1-1.5 as standards of being trained Why behavior: psychphysical testing systematic exploring detecgion thresholds and recognition limits (others: discrimination, detection limits), but fundamental auditory processing abilities relate to x and y axes auditory tuning curves this task does this (auditory processing on beyond sound localization) DETECT SOMETHING OCCURRED X = stimulus Y = response (relative to background…deteciton threshold) d'=z(H)-z(F)
Outline
• Background: hearing loss and cochlear implants
• Cochlear implant rat model: procedure and behavior
• Neuromodulation in cochlear implant and auditory learning
Presenter
Presentation Notes
So now that we have this cochlear implant system established in rats, we can ask questions about the involvement of neuromodulation and neuroplasticity in CI use.
stimuli, or ‘unexpected uncertainty’• Enables plasticity across sensory modalities
Locus Coeruleus
Martins and Froemke, Nat Neurosci (2015)
Glennon et al., Brain Res (2018)
TH YFP 200 µm
Optogenetic Pairing of LocusCoeruleus with Auditory Input
Locus Coeruleus Activity Promotes Auditory Learning
Glennon et al., Brain Res (2018)
TH YFP 200 µm
Optogenetic Pairing of LocusCoeruleus with Auditory Input
Locus Coeruleus Activity Promotes Auditory Learning
Youssef Zaim Wadghiri, NYU Preclinical Imaging Laboratory
= locus coeruleus= optic fiber
CT-MRI Co-registration
Glennon et al., Brain Res (2018)
TH YFP 200 µm
Optogenetic Pairing of LocusCoeruleus with Auditory Input
Auditory Behavioral Performance (Normal Hearing)
Locus Coeruleus Activity Promotes Auditory Learning
Glennon et al., Brain Res (2018)
TH YFP 200 µm
Optogenetic Pairing of LocusCoeruleus with Auditory Input
Auditory Behavioral Performance (Normal Hearing)
Locus Coeruleus Activity Promotes Auditory Learning
Locus Coeruleus Activity Promotes CI Learning
Locus Coeruleus Activity Promotes CI Learning
CI Stimulation Physiology
= stimulation artifact
Presenter
Presentation Notes
What is happening centrally during this adaptation though? To address this question, we record from the brains of animals acutely implanted with CIs and compare responses to those who have been trained with CIs – both with or without locus coeruleus pairing. On the left is the evoked compound action potential from cochlear implant stimulation of the auditory nerve and on the right it’s complementary multiunit activity in the auditory cortex.
CI Experience Potentiates Cortical ResponsesR
ecor
ding
site
Naive CI
Z score
CI Evoked Auditory Cortical Responses
Multi-unit activity
Channel number
Individual Animals
2 4 6 8
1
12
Presenter
Presentation Notes
However, if we simply compare the CI evoked cortical activity in acutely implanted, CI naïve animals to animals that have been trained with the cochlear implants, there is a significant difference.
CI Experience Potentiates Cortical Responses
= behavioraltarget channel
Rec
ordi
ng s
ite
LC paired + CI trainedNaive CI
Z score
CI Evoked Auditory Cortical Responses
Multi-unit activity
Channel number
Individual Animals
2 4 6 8
1
122 4
1
10
Presenter
Presentation Notes
However, if we simply compare the CI evoked cortical activity in acutely implanted, CI naïve animals to animals that have been trained with the cochlear implants, there is a significant difference.
CI Experience Potentiates Cortical Responses
= behavioraltarget channel
Rec
ordi
ng s
ite
LC paired + CI trainedNaive CI
Z score
CI Evoked Auditory Cortical Responses
Multi-unit activity
Channel number
SummaryIndividual Animals
2 4 6 8
1
122 4
1
10
Presenter
Presentation Notes
However, if we simply compare the CI evoked cortical activity in acutely implanted, CI naïve animals to animals that have been trained with the cochlear implants, there is a significant difference.
Conclusions and Future Directions• A physiologically calibrated and
behaviorally validated rat CI model replicates outcome variability observed in humans
CI P
erfo
rman
ce Human Rat
Time
• Neuromodulation paired with CI learning enhances behavioral outcomes and cortical representations
Behavioral Outcomes
Conclusions and Future Directions
2 4
1
10
5
CI Channel
CI P
erfo
rman
ce Human Rat
Auditory Cortical Responses
Locus Coeruleus Activity
Time
Rec
ordi
ng S
itedF
/F
• Neuromodulation paired with CI learning enhances behavioral outcomes and cortical representations
• Ongoing studies: monitoring LC spontaneous activity with fiber photometry during auditory and CI learning
• A physiologically calibrated and behaviorally validated rat CI model replicates outcome variability observed in humans
