 As I begin today, I would like to acknowledge the Pambalong clan of the Awabical people, the traditional custodians of the land in which I am presenting today. I pay my respects to Elders past, present and emerging. My name is Rebecca Lim. I am a researcher at the University of Newcastle and as a researcher affiliate with the Hunter Medical Research Institute where I am a member of the Brain Neuromodulation Research Program. Today I will be presenting some information about a type of tumour that grows on nerves and this is a condition called Acoustic Neuroma and I will be presenting this today for our Brain Awareness Week in 2023. So what is an Acoustic Neuroma? An Acoustic Neuroma is a tumour. It is a very slow growing tumour. It is considered benign or non-cancerous and this particular tumour grows on the nerve that carries information from our inner ear to the brain and it is carrying this information from our hearing and balance organs on that nerve. So the incidence of Acoustic Neuroma is between 3 and 5 people per 100,000 and the age is typically between 30 and 60 years. However we know that there are an increasing number of these Acoustic Neuromas being detected in people of advanced age and this is because as we are growing older we are having some more imaging done around our head and neck regions and therefore there is detection of quite small growing Acoustic Neuroma, these tumours growing on the nerve. These tumours are spontaneously occurring so the vast majority are spontaneously occurring so about 95% are spontaneously occurring and then 5% of these tumours are occurring due to the growth of a genetic disorder and this genetic disorder is called neurofibromatosis or NF2 so it is a genetic disorder where there are tumours that will grow along the nerves of the inner ear. So what are the symptoms of an Acoustic Neuroma? The first of one of these is hearing loss and most often people will start, as we get older we tend to lose our hearing but there is also this increased hearing loss in one ear and they can also develop a tinnitus or ringing in the ear so this is where it starts to differentiate from just a normal ageing process where we lose our hearing. So a person will have hearing loss as well as this ringing in the ear so it is in the same ear and there is also an increased pressure or aural fullness so just like when we go up in an aeroplane and we feel that pressure building in our ears that happens in people with Acoustic Neuroma on just one side. People can also develop dizziness as well as balance problems or unsteadiness on their feet and this is because the inner ear is responsible for both hearing and balance. Now these are the typical symptoms of an Acoustic Neuroma and people will typically then go to their doctor and become diagnosed with the condition. However as the tumour grows, if a person doesn't go and get a diagnosis, that tumour can become larger and as the tumour becomes larger it starts to press on other nerves that are really in close proximity to the nerve that carries the auditory and balance information to the brain. So that can cause facial numbness and or pain so pain around the face and it's always on that same side of the ear that has been affected with the hearing loss and dizziness issues. And if that tumour grows quite large without being treated then the tumour can begin to press on the brain part of the brain called the cerebellum that is responsible for coordinating and controlling our movement and gait. So tumours that go really large can compress those parts of the brain for movement and again if they're not diagnosed and not treated they actually can become fatal where they'll push on the brain stem and this brain stem is really important for controlling vital functions of our body. So let's think about what an Acoustic Neuroma is. When we hear the word acoustic that relates to our sound or hearing so we always think about the ear when we think about auditory and acoustic. Neuroma is the growth or tumour of nerve tissue. So here we've got a little picture that shows this dividing nerve cells and so that's what happens in a neuroma there's nerve cells that will grow and proliferate and form a tumour. But the interesting thing is with the acoustic neuroma is that it's a misnomer. What do we mean about a misnomer? Well it's inaccurately using that phrase or term or description because an acoustic neuroma isn't actually affecting the hearing itself and it's not affecting nerve cells. What it actually is is called a vestibular schwanoma but we always tend to refer to it and often in medical circles research we tend to still have this dual terminology of acoustic neuroma and vestibular schwanoma. So let's start looking at what a vestibular schwanoma is. So what is it? Vestibular is relating to our sense of balance and so we can see on this little movie here is somebody walking on a tightrope and so you've got to have a really great sense of balance to be able to to walk across a canyon like that on a tightrope. But for everyday life our balance system is constantly working. It's constantly working so that we can maintain and maintain an upright stance. It allows us to maintain and fixate our gaze appropriately so that when we're walking and moving we can look at our environment and see what it is without it looking to so it remains in focus. So our balance system is really incredibly important and we don't tend to think about our system of balance until something goes wrong. And when we see the word schwanoma what it's referring to is a tumour of schwan cells that surround the nerves and I'll talk about this in a little bit more detail in a little while. But what we can see here is a nerve so this is a nerve and when a surgeon opens up that nerve what there is is a tumour that's growing around these nerve fibres and that tumour can be removed. So schwanoma is an exacerbated growth of schwan cells. So now we know acoustic neuroma is actually a vestibular schwanoma. So let's now think about what our sense of balance is doing. So first we'll have a little look at our balance system. Our balance system is located in the inner ear with our hearing organs so we can see the external ear and we can see the ear canal which is here. We can see our eardrum and then in here deep in the temporal bone we have the organs of hearing and balance. So here we have the inner ear. This beautiful spiral shape structure for our hearing is referred to as the cochlea and this is how we can hear in all the different frequencies of hearing my voice. If you're in traffic you can hear the cars and things driving past. It's how we hear our music. The balance part of our inner ear is shown here and we have these three regions called semicircular canals and this will detect movement of our head in three different planes. So when we think about our mobile devices, our mobile phones, when we reorient them in a particular direction the screen changes and essentially that's what is happening within our in our ears. That's where we have these mini gyroscopes telling us which way is up. Information from our balance system will travel along this portion of the nerve and our auditory information travels along this portion of the nerve. Together they are forming the eighth cranial nerve or the vestibular cochlea nerve. Now this is important later on for when we start to look at what a vestibular schwannoma is doing. If we take a look in the inner ear the outside portion of the inner ear is really a hard bony structure. We refer to that as a bony labyrinth and then within it we have a membranous labyrinth and this is like the inner tubes of a bicycle where we pump up the air but instead of air it's filled with a fluid and this fluid is really important for activating our sensory cells and these sensory cells of our auditory system and our vestibular or balance system are called hair cells and these sensory cells are located wherever we can see this pink and all the way down here around the cochlea. So if we take a little look into those areas where it's pink we can see different types of hair cells. Now they're named hair cells because of the way they look. We have these bodies of the hair cells so here we have a body and then here we have a body and then poking up from the top of them up here we can see hair bundles and these hair bundles and both types of hair cells are responsible for detecting motion activity and that's motion activity as we turn our head from side to side as however we move our head around or it's movement of the fluid waves in response to sound activation. So our balance and hearing sensory cells are both hair cells and they're both activated in the same type of way they're just responding to different types of sensation either wavelengths of our sound or motion of our head. Now just take a quick look at how our hair cells are working and we don't need to go into too much detail here but what we have is a situation where we have our hair cell we have the hair bundles so here is our hair cell here is our hair bundle and if we move our head in a particular direction we have that fluid in the inner ear that moves and causes a force on the hair bundle. It deflects these hair bundles this causes a signalling to occur we don't have to worry about the details but this signalling involves an iron called potassium and that gets the cell excited then that cell will send the information along a nerve so shown here in red is a nerve and that information this their balance information is sent to the brain along this nerve. So these nerves are responsible for sending balance and hearing information to the brain. Now I showed you that eighth cranial nerve earlier and so that's what would be looked like it would look like as this orange nerve shown here and then within this really large nerve it breaks down smaller and smaller so that it shows those individual nerves from hair cells from each hair cell so they're all bundled together. What we can see here is one of these nerves a little one an individual part and this is part of an axon and that information gets transmitted into the brain. Now to make sure that that information is sent into the brain really quickly because we want that information to be received quickly so we can stay upright and for our hearing so we can hear what's coming in her environment. We have this specialization or a special type of cell that surrounds our axons of our nerves and these are called Schwann cells and our Schwann cells are cells that grow and wrap around you can sort of see that these circles like an onion ring surrounding the axons and these Schwann cells are responsible for insulating our nerve cells so it's like an electrical cable that's surrounded insulating it so this signalling can get to the brain really quickly and these Schwann cells forming this sheath is referred to as a myelin sheath. Now in acoustic neuroma or vestibular schwannoma the problem is these Schwann cells which were shown in this previous slide in purple these Schwann cells grow abnormally and when they grow abnormally we have a tumor forming and that tumor forms on the vestibular portion of that eighth cranial nerve so this is the vestibular portion growing along the nerve and this is where the tumor is forming so it's actually not forming on the auditory portion but you can imagine this is a really tight space within our ear within our brain making its way into the brain so as the tumor gets bigger it starts to compress and push against this auditory part of the nerve and so that's how these uh the Schwann cells that are growing and forming a tumor will result in problems with hearing in our environment because the nerves that would typically take the information from our hearing organ the cochlear to the brain are now being compressed it's also compressing the vestibular portion of the nerve and causing dizziness and balance problems. As I mentioned earlier if that tumor is not diagnosed or if it is grows too large then this uh acoustic neuroma of vestibular schwannoma can become very large what we have here is a picture of the brain and this is the underside of the brain so if we're looking up this way we would see the underside of the brain here is this acoustic neuroma or vestibular schwannoma and we can see here it's really starting to push against some important parts of the brain and if it becomes too large it can become life threatening. So why do our Schwann cells sometimes grow abnormally? As I mentioned earlier this growth is spontaneous and when we have spontaneous growth of our Schwann cells we don't understand why it happens. So what are the treatments for acoustic neuroma or vestibular schwannoma? The first treatment is watch and wait because these tumors are quite slow typically quite slow growing that's an advantageous thing because it's slow growing we can watch and wait so imaging will be done to measure the size of the tumor and then after a period of time if there is no progression of those balance or hearing problems or if there's no development of facial numbness or pain then what can be done is that a rescan can be done at various intervals. So a second thing that can be done is radiotherapy. Radiotherapy can be done where radiation doses are typically done stereotactically and this is usually done with a single or very small number of doses that are administered and the third option as a treatment for acoustic neuroma is the surgical removal and in some instances depending on the size and the location of the neuroma means that sometimes if it's a smaller tumor if it hasn't really impacted or impinged too much on the auditory nerve sometimes then a cochlear implant can also be done to restore some of the hearing capacity for the patient. So these are the treatments for acoustic neuroma as things currently stand. What we don't have now are therapies for acoustic neuroma and I've been fortunate with my team to receive funding from the Brain Foundation to start developing some therapies for acoustic neuroma. So this is some research that we've begun. This is tissue from a person that has donated the portion of their inner ear, the vestibular portion of their inner ear during surgical removal for treatment of the acoustic neuroma, the balance portion of the inner ear has to be removed. So this is a part of the balance organs and what we can see here is a portion of tissue and in red are some hair cells and we can see that there's hair cells still remaining. We can see cell nuclei of all of these hair cells as well as the supporting cells around it and we can also see in green some structural protein and this is a fairly normal looking piece of vestibular tissue. So what this indicates is that the tissue is fairly normal looking. So if we can develop treatments and therapies for the acoustic neuroma we might be able to prevent any further degradation of balance and dizziness and hearing problems that occur in acoustic neuroma. So what are we going to do? Okay so what we're going to do is first up look at what other treatments have been done in other types of cancer. So we have here is a schematic diagram and this is a diagram we're not going to go into too much detail but this is a diagram of what we're going to target and within our nervous system we have a complement of these proteins called neurotrophic factors and our neurotrophic factors are really essential for the differentiation proliferation and survival of our neural cells. However there are instances where these neurotrophic factors under some signalling have triggered the stimulation and survival of cancer cells and so we're going to target a particular set of these neurotrophic factors. So we have a neurotrophic factor called nerve growth factor, NGF. We have a precursor protein to that called pro NGF which is this protein here. Nerve growth factor or NGF and pro NGF will activate these signalling processes via receptor. This receptor is called P75 NTR. So NGF can directly target P75 NTR whereas pro NGF has to target or has a co-factor called sotalin and together these will then activate the P75 NTR receptor and when these are activated we have this intracellular signalling pathway and this can cause survival and proliferation of our Schwann cells. What we've done already is looked for these particular proteins in the tissue from a vestibular schwannoma donor or acoustic neuroma donor. So here on the very left hand side we have P75 NTR. In the middle we have sotalin and on the right hand side we have NGF. So these particular trophic factors receptors and co-factors are present within the tissue from a donor with acoustic neuroma. So what we're going to do is use inhibitors and these inhibitors are going to block NGF, P75 NTR and sotalin and if we can block those particular trophic factors and their associated factors what we're hoping is that we will knock out this pathway and if we knock out this pathway we're going to stop or slow tumor growth in people with acoustic neuroma and so that will prevent or delay the surgery that is required for the treatment of acoustic neuroma because they're slow growing. Our aim is to really add these inhibitors in and to slow or stop growth and the other potential is to add these in for people that have had a removal to prevent a recurrence of the tumor growth. So this is the team that will be working on the project, our in-nose throat surgeon, Associate Professor Rob Eisenberg, Professor Alan Brickter is working on the vestibular tissue with me and we also have our cancer collaborators Professor Hubert Honda Mark and Associate Professor Phil Jobling. I would like to thank our donors for generously supplying and donating their inner ear tissue for this project. I would also like to thank the generosity of the Brain Foundation for funding our project and if anyone has any questions about acoustic neuromas or vestibular schwannomas as you now learn the correct name please contact me on my email rebecca.lim at newcastle.edu.au