Pathophysiology-Based Treatments for Tinnitus

so I will be approaching tinnitus now from a very practical approach what what can you as a health care provider use as knowledge in order to try and help people with with tinnitus even though the pathophysiology is not completely unraveled yet there is some information that we can use in order to try and develop new treatments for tinnitus it's a common problem seems to be somewhat may more predominant in males and in females there is a difference in lateralization of the tinnitus perception and it is more common in patients with hearing loss now many people with tinnitus can perfectly well live with it but a small population about 20% of those who have it really suffer from it and what do you suffer in it from not or not as has not a lot to do with a lot of things that you can control but but the way your brain is wired also with H with increase in age there is an increasing and prevalence of tinnitus for War veterans actually it's the most important or the most prevalent problem of all the problems that War veterans have when they come back and also more and more young people who expose themselves to noise because of leisure purposes do tend to develop tinnitus grossly you can you can subdivide it in and pulsatile tinnitus or in non-pulsatile tinnitus and this is just a practical division you can also talk about objective and non objective tinnitus i will predominantly talk about non-pulsatile subjective tinnitus the way we try when we see somebody in the clinic to look at tinnitus is that we do a certain amount of standard testing basically to analyze the tenant list so you can retain this matching where you present the time where you present tones and see whether they match what the perceives both and pitch or in frequency and in loudness and then you also look at how much this tinnitus interferes with the personal life how distressing it is how it interferes with their mood and you do that by by standardized questionnaires now because tinnitus is most commonly related to a hearing problem of course you also have to analyze the function of the auditory system which is done by ents and audiologists by using by looking by doing a clinical exam during know geometry tempo nama tree and and sometimes a brain stem evoked potentials or auto acoustic emissions and then after you've looked at the function you also want to look at the structure of the extended auditory system not just the auditory system itself because we know there is also a lot of non auditory brain areas involved and this you can't most commonly do it in MRI or with the CT scan and then ultimately what we want to get through that in the future is that we that we have a way to objective eight a tinnitus so that without anybody telling us by doing testing we can tell whether somebody has tinnitus or not and secondly whether that tinnitus is bothersome and how loud it is this could theoretically be done by fMRI but also in an easier way by aegs and together with marco congedo from the intern in france we're trying now and and with Sven is help to use a multi-dimensional classifier which is actually up to now in the first testing that we've done extremely good and telling what if somebody has tinnitus or not but whether it is distressing or not is not very well predicted just from the activity of the EEG so in the future that will advance to a level where we'll have something that is that can objective eight the tinnitus now it's important to know that you can that D afferent ation so a lack of sensory input does not equal or is not the same as hearing loss some forms of auditory the afferent ation cannot be discovered by a geometry so you can have a perfectly normal audiometry but still have a lack of sensory input and one of the ways that could be is because the tuning curves of activation overlaps so you can have a small lesion and end the cochlea and because the tuning curves overlap you won't even notice it on audiometry this has been shown in humans and in animals where you can cut part of the auditory nerve and still have normal auditory function as measured behaviorally but that does not mean that the brain does not sense there is a lack of input and will respond to that lack of input by generating tinnitus in general dependent discovers the area of hearing loss so if you have a hearing loss hearing dip let's say at 4,000 Hertz in general the sound that effect that the person will perceive is around 4,000 Hertz so it covers the area of the hearing loss but tinnitus is not just an ear problem because it's a lack of sensory input just like if you have an amputation in your hands your brain will respond to this lack of input by generating a phantom hand the brain will generate a phantom sound and ideally you try to look for a cost so initially when somebody presents you want to look for a cause for tinnitus and there is multiple causes predominantly from for pulsatile tinnitus and in general if somebody comes with a pulsatile tinnitus which which can be either heart beat synchronous or respiration synchronous and about 85 percent of the times you should be able to find a cause whereas the non-pulsatile and it is there is it's less easy to find a cause and if you cannot find a cause then you can still try symptomatic treatment so if somebody presents to you in the clinic how how do you want to find a possible cause well usually you look for associated some that might help to distinguish for example if you have tinnitus with vertigo and there are short paroxysm short bouts of tinnitus and short bouts of vertical associated with hemifacial spasm which is twitching in the eye or at the mount at the mouth associated with your Nicollet neuralgia which is a short blasting stabbing feeling in the ear then the most common cause is a macro vascular compression where you have a blood vessel that impinges on the auditory vestibular nerve now if if you have tinnitus vertical but you also hear yourself and you have a Tullius phenomenon which means that if you hear sound you become dizzy then that is mostly associated with a canal dehiscence so where one of the semicircular canals which are involved in the equilibrium system where the bony covering is lost if the episodes of vertical or longer lasting instead of seconds to maybe minutes hours and and they have an aura so they have a kind of predictive kind of feeling then it's more likely to be many years disease so just just the fact that there is tinnitus associated with vertigo you can still split it up and different forms of tinnitus if tinnitus is associated with headache which could be unilateral and throbbing then it then it can be migraine which is often associated with tinnitus now if the headache is occipital and worsening when you cough or sneeze or bend over to put your shoes on for example then it is morally mostly related to an increase in intracranial pressure and if that is for example associated with with lymph weakness or numbness or a feeling that that you can't that part of your arms or legs are feeling colder or warmer and if you have hick hiccups or or other dysphagia or dysphasia then you could have a Chiari syndrome because it still it is associated with headache and other symptoms now if you have similar symptoms as and and microvascular compression but associated with headache then it might be related to an arachnoid cyst or a tumor that compresses on a nerve so just depending on the clinical picture you can already try this to see which might be the reason why somebody has tinnitus now what is the pathophysiology of the tinnitus well from a conceptual point of view you've got different pathways that bring auditory information from the cochlea to the auditory cortex there is one pathway that just brings the auditory information to the cortex and that's a discriminatory aspect it will say what frequency do you hear where do you hear it how loud do you hear it etc and then there is a medial pathway which has not been well described which goes to the to the insula and to the interior saying that other other parts of the brain that are common to all sensory systems so it's the same pathway that is probably involved in in pain and this encodes more the affective component of the pain the distress at sorry distress that's associated to the tinnitus and also and encodes the attention or the focus that somebody has to the tinnitus now these two different pathways bring information to the brain just like in pain information is brought from the periphery to the brain and then there is a kind of a noise canceling mechanism which starts from the from a different part of the signal the pre general and rostral and that goes to the tech the longitudinal column and that actually suppresses further input of paints on the one hand you've got a kind of an accelerator and on the other hand you've got a break for more input and most likely it's the balance between the two so you can either have a deficient noise cancelling mechanism or an ink or an increased eighth hour hyperactive ascending pathway that can result in hyperactivity which is then associated with the percept of tinnitus now tinnitus in itself is can be perceived as a pure tone as a noise lacks as a noise like phenomenon can be multi multi multiple tones it can have mood changes it can cause depression it can decrease cognition concentration problems memory problems and it can cause distress and the stress is different from mood and defense that the stress is more related to your autonomic nervous system it's more related to an anxiety like feeling whereas mood is it's different now all these but the patient perceives the tinnitus as a combination of all of these together as one unified percept and so you can try to then disentangle all these different aspects of the tinnitus by doing different imaging techniques here these are all IEDs where you try to find which areas in the brain are more active associated which each with each of these characteristics and this has come up this has resulted in the idea that actually one from a brain point of view that tinnitus the unified percept is actually a grouping of all different networks that interact at certain areas but all these different networks can be separated and most likely although it's still hypothetical all these networks run at the different at a different frequency a little bit like a radio system where you can broadcast at different frequencies and if you tune in on a certain frequency on a certain carrier wave you have a certain clinical emergence that comes from it and these different networks they all communicate most likely at discrete frequencies to each other just like in a radio system you have to go on on a specific frequency to get the content of what is being transmitted and in the brain it's probably likely that it occurs that it occurs at the same thing so from a practical point of view if you have tinnitus and you're not bothered by it what you have is you can have different modules in your brain and one when you're not distressed all these modules kind of works separately now when you begin to have a little bit a little bit distress then the auditory networks which are called here in blue the auditory modules are connected and distress modules the ones in and purple are connected but the two are not interconnected yet whereas if you develop tinnitus this real tinnitus distress where the sounds itself becomes bothersome that's when you develop a connection between the loudness brain networks and the distress networks and when you get very distressed than the frequency of information transmission between the two just seems to increase so in other words tinnitus distress is probably two separable networks when they get when they start firing together then they're perceived as unified percept so theoretically if you can cut it you will still have the tinnitus but it won't be distressing anymore and the where this is exactly located as between your between the sub channel and piercing that and if our hippocampal hair and it's up that's not that important but what is important is that the PI rape example area is known as an area that encodes or processes anything which is contextual so all contextual information that poles actually do tinnitus from memory that's the hypothesis and links it to the autonomic nervous system which will then cause your distress like feeling because your sympathetic or parasympathetic activity will change so basically this these connections from a brain point of view are very logical so how can we use this information for treatment now first of all it is important to know that from a clinical point of view some people on more difficult to treat and others people who have tinnitus for a very long time so we know for example that if you have somebody with a microvascular compression would have explained earlier on if they have a blood vessel that impinges on on the nerve that the longer they have it the more difficult it becomes even after surgery for the tenant is to go away which might seem very logical because if the longer it the blood vessel taps on the auditory nerve the more damage you get and then you can remove the blood vessel but the damage is done and so it becomes more difficult to treat but you see the same thing with magnetic stimulation well if you do transcranial magnetic stimulation that the longer it exists the less beneficial the results seem to be genitals are completely non modulated and many are in most patients tinnitus is modulated for example trésor fatigue or loudness or noise and in the environment and some patients say well my teen is always exactly the same whether a tired would I'm stressed whether I'm in an environment but there is lots of noise it's always the same these are more this is a more difficult group to treat musicians are also very difficult to treat because they're very for them any sound is a salient and they're focused on sound is more important than for many other people of course people with OCD obsessive compulsive disorder can have a problem when you treat them so for example you treat them and and the sound loudness goes from eight out of ten to three out of ten well for somebody with OCD they can focus as much on the tree as they were focusing before on the on the eight even though from from practical point of view we said well it's it should be better but it's there the problem is not the loudness it's the focus on the on the tinnitus people who are control freaks often very very wealthy businessmen when I'm in Davos people we tend to have everything under control in their lives except for their tinnitus have a hard time and you have a hard time and treat those patients and of course also people who are completely psychologically decompensated so how do you how do you go well as mentioned earlier around you start with the case history in order to see if you can try and find a cause then you do the assessment as mentioned before you give some questionnaires to see whether the Tinder's really has an impact on the person who has a tinnitus you do a clinical examination of course you don't want to treat somebody with with the brain and plaintiff if it's just some walks in the ear that's causing your tinnitus and in pulsatile tinnitus of course you also do auscultation and you do an audiological examination as i've mentioned before and then you can basically start by saying well as the tenant to spells it out or is it infinitive pulsatile or non-pulsatile and then you can ask the guiding questions as i mentioned before that might try to help you find a cause and if you don't find a cause then you go to symptomatic treatment so what works for tinnitus what do we know what can help tinnitus well most commonly now we use what is called evidence-based medicine and for tinnitus there's no evidence that anything works so basically here I could stop giving my presentation but there is something which is very important it's not because it's not proven that it doesn't work it means that and sometimes you have a subgroup where a treatment might be working perfectly well but if you look at it and the total group and you mix every all the subgroups of tinnitus together then statistically you won't find anything even though for a subgroup it really works very well for example there is a form of type rat typewriter tinnitus which is where you have this micro vascular compression that responds perfectly well to carbamazepine the tinnitus disappears if it's the correct diagnosis now if you give carbamazepine to anybody else when to attend it it won't work so if you do a study and you try carbamazepine hundred patients statistically it won't work but for the subgroup it will work very well so it's not because it's not proven that it doesn't work or it can be best it can be tested but but the study was poorly performed and that's why this study doesn't show anything so it's not because something does has no proof yet that it works that it means that it can't do anything and there is a difference between statistical significance and clinical relevance you can have a statistical significance study where you improve if you have a huge amount of patients and you do a study and you say well treatment X works but it reduces the tenant is allowed a scale from eight to seven point six well it might be statistically significant but it's can come clinically completely irrelevant and you can have clinically relevant data that are statistically completely in that are statistically not significant as I mentioned you can have a small subgroup that really responds very well where the clinical relevance but if depending on the study it might not be statistically significant so that just means how good it works so what treatments are there well then it's miracle cures don't exist whatever they might say on the Internet these these miracle cures don't exist unfortunately there is a certain amount of different kinds of treatments that you can try and attempt to do if your tender space to undergo or as a health kind health provider to give now on average if you have a large tinnitus clinic I think it's fair to say that the success rate of every of these of these treatments is not higher than twenty to thirty percent which means that like in a headache if you have a patient with a headache sometimes you might have to try three four five six different painkillers or different kinds of medication before you find something that treats the headache well is exactly the same unfortunately it's still trial in there there is no there is no clear biomarkers yet there so that show you well for this kind of tinnitus this will work so unfortunately in general it's trial and error the load individual success rate but that doesn't mean that you should not do it because from a practical point of view as a patient and the patients in general they don't care they want to be treated whether the success rate is twenty twenty or thirty percent is still better than then somebody who tells you well you have to learn to live with it but you might have to undergo multiple difficult trials of treatment before you find something that works for the individual patient so the concept is you treat the cause if it can be found so for example if we go to non-pulsatile tinnitus you can have an acoustic neuroma that cause tinnitus you have to know that depending on the size and depending on the treatment the tinnitus might persist after the surgery if the tinnitus is not bothersome before then after the surgery tennis will not be bothersome if it is bothersome before then then it might disappear but if it does not disappear it will be even more bothersome after the surgery you might have cysts that were would that deviate the auditory nerve that if you treat that can get benefit if you have many years disease you can cut off a Stabler nerve or the cochlear nerve and while you cut the vestibular nerve for the cochlear nerve the results are the same with regards for the tinnitus you can have small lesions close to the auditory cortex that if you remove that can remove the tinnitus you can have a Chiari syndrome or you have part of your cerebellum that that sings to you foramen magnum that can give two different kinds of tinnitus pulsatile and non pulse it out and it is that usually responds to the surgery you can have micro vascular compressions as I mentioned earlier on and both it out then it is you have more causes you have more causes that you can find in order to treat the most common cause which is actually not very well as benign intracranial hypertension where actually is just an increase in pressure and in the brain that is transmitted puffs possibly provide a cochlear aqueduct to the cochlea where you have an increased pressure in the cochlea a little bit like Meniere's disease that can be treated just by putting first by giving some furosemide or by inserting a shunt that drains the fluid to the abdomen or to the heart and thereby decreases the pressure and in the brain apart from from from that as I mentioned Kyary syndrome can give pulsatile tinnitus you can have an abnormal blood vessel like a high jugular bulb which drains the blood from the head to the heart and if this it comes too high too close to the cochlea and auditory nerve that can be perceived as as pulsatile tinnitus you can you can have fistulas which go into the into the mastoid and the mastoid i'm acts like a kind of resonance chamber that you will hear as a pulsatile tinnitus you can have stenosis in the intracranial part of the carotid artery which supplies the blood to the to the brain and if this is if this is narrowed then you will get a turbulence which which you will hear as a pulsatile tinnitus and which can be treated by inserting extend just like they do for aneurysms in your brain or for for stenosis in your heart you can have a Glomus tumor which is a very vascularized but benign tumor that can cause pulsatile tinnitus and and if you embolize it then so this is all I've no more blood vessels if you amble eyes it then the pulsatile tinnitus is gone and depending on the size you might not have to do anything else because they're extremely slow growing so you might just leave the lesion there if it doesn't cause any other problem and embolize it for to get rid of the troublesome they notice here you have a vascular lesion and in the mastoid which you will perceive a senator's or a vascular lesion in the clivus before and after surgery which can remove sir the pulsations of the abnormal blood vessels even though they're far away from the ear might be perceived as pulsatile tinnitus you can even have cutaneous or subcutaneous abnormal blood vessels that you will pick up as pulsatile tinnitus you can have abnormal connections between arteries and veins that presenter spells about tinnitus or even just in your neck a tortuous blood vessel so if your carotid artery and your neck makes makes a twist it can cause turbulence which you can perceive and then by trying to straighten it surgically you can you can improve the Metta notice or you can have a loop inside the acoustic meatus which can cause turbulence there which can be treated also by inserting Teflon a kind of isolation layer and between the the cochlea and the and the vascular loop or you can even have a blood vessel that them that impinges on the cochlear aqueduct where you can put teflon as well so there is a lot more treatments for pulsatile tinnitus than for non-pulsatile and for pulsatile tinnitus where you hear your heart beat or your respiration it's definitely worthwhile if it's bothersome to have it checked now if you don't find a cause then the first approach is use the counseling which can be either cognitive behavioral therapy like or RT RT basically tinnitus retraining therapy is a combination of explaining how tinnitus develops from a conditioning point of view associate associated with white noise basically it's an attempt to tell that the tempters is not dangerous and and to have bitchu a to the sounds by masking it partially with with white noise the idea the background idea is that the specific sound that you hear activates a fight and flight response and that if you can mask it that the new sound that you will hear if that sounds if you hear that and it is and you develop it basically because it's it's broaden too into your ear by a masker if you develop it on the moment that you're not in the fight and flight response that it will actually reduce the stress associated to the tinnitus so in fact the tinnitus retraining therapy improves the distress associated to the sound but not the sound itself so the sound is basically replaced by a masking sound and it seems to be better to combine masking with this explanation than just presenting masking by itself cognitive behavioral therapy does the same thing it improves the distress the affective component of the sound but not the sound itself and of course if we do it in a combination and in a structured way the results seem to be even better now what about hearing aids or noise generators so you can you can the idea is that as tenant assist depends on a lack of auditory input if we increase the auditory input that you can then suppress the brains response to generate a tinnitus by adding by either passive amplification which our hearing aids and of course the problem is that the hearing aids actually only work when there is environmental sound because there is no environmental Sanders not a lot to amplify and then you'll be in the same thing and therefore you might in quiet periods actually use active amplification which could be a noise generator or masking device or other sound therapies now clinically hearing aids can benefit patients with chronic tinnitus even though there is no evidence at meta-analytic level which means if you look at all the studies together and then say well do hearing aids work or not they don't for the whole group but as I mentioned in about 20% of the patience they will give they will give relief but in 40% of the page they will know really they will give no relief whatsoever but in about 20% they will give market relief but of course because there is more people where it doesn't help then there is where it helps then on the total group unfortunately it doesn't seem to help but that doesn't mean that it's worthless to prescribe hearing aids because they can benefit even if it's just a small subgroup if you if you add masking to the hearing aids and the masking you add to create another sound which is not disturbing or to add another sound when it's quiet and hearing aid doesn't do a lot then it seems to be more beneficial than then one or the other but again if you look at all the studies together statistically speaking there is no benefits from hearing aids and masking but it's always the same thing there is a subgroup who does seem to benefit from it there is some modern forms of active hearing aid which is for example neuromonics and neuromonics actually try at tries to even though nobody really knows what it exactly does it is suggested that it increases the the sound or the music that is at the level of the hearing loss so the concept is the tinnitus is usually covering the area of hearing loss if we just accentuate the music at the level of hearing loss it should be it should give some benefit on average 50% of the patients think it's worth the cost that they paid for the device and 50% improve distress but not sound so basically most of the treatment except for the hearing aids have actually resolved on how it affects the the distress rather than the sound itself there was an idea of using phase-out which which is kind of an anti sound the idea was if you hear certain sound and give an anti sounds a little bit like the noise canceling earphones that you can use in an airplane that that would work we tried it and it didn't work actually it worsened the tinnitus when the frequent or you can theoretically we know that if you have a hearing loss and you fill this up theoretically you should get rid of the Tinder's because the brain gets all the input and it won't make the tinnitus by itself so we set out to do an eye pop study where if this is the audiogram so you've got normal hearing and then in hearing depth and that if we fill it up then the brain should not create tinnitus anymore or you could even do better we thought you can you can over accentuate you can over compensate the gap and thereby the brain would definitely not make the brain that was that that was the idea so the way we did it we had we had some iPods we adjusted the music to the to the to the audiometry for example if you have a hearing loss here this is the music spectrum you just accentuate it or you create a little dip before and you make it even stronger so what happened well the compensated music was not better than than doing nothing then overcompensated music actually made it worse and this is because we've gotten one thing that what we were looking at was trying to follow the pathophysiology but what we forgot is that tinnitus is actually or in the brain of somebody who has tinnitus who's suffering from it then it is as an abnormal salience as an abnormal value attached to it normally everything which is constant is disregarded by our brain we don't feel our clothes because it's always the same stimulus and it brings us well there is no new information and and constantly feeling our clothes so we suppress it now the fact that people constantly hear their tinnitus by definition means that there is a paradoxical salience so if you're going to increase the sound which has already and pathological salience to it then you might actually worsen and so it's probably a salience problem rather than a physiological filling up now what we found is that one we overcompensated the music actually the gamma band activity in the auditory cortex which we know so it's high frequency over activity in the auditory cortex wind up and the the area and the cingulate which which is important for salience actually was up as well so we think that actually the problem was even though theoretical concept was good that salience overrides physiology so if that doesn't work if adding the missing information doesn't work well maybe we should do the opposite try to decrease it at the phase of the changes by cutting out some of the tinnitus completely and this is a study that was done by Pontiff where if this is a benefice frequency actually they notched the music so that it was completely cut out so that there was no salience whatsoever and what they found is actually that there was a benefit but you have to be careful with these results because if you see the improvement that and the ones who did not get this this treatment actually they worsen a little bit so if is so the result might actually be because the control group worsened rather than that the other ones really improved so and then you can do well if even just imagine that the concept works now we might have to enforce this by doing the same thing but you add vagal nerve stimulation to it and this has been developed here and Mike and Michael garde group where you add where you present tones except for the tenant stones or the turns at the patients here and simultaneously you give a Vegas stimulation and the idea goes back to the physiology where if you have normally and the cortex every frequency arrives at a specific structured order in a nicely ordered way at different frequencies arrive at places one next to the other when you develop tinnitus this and this whole orderly system becomes this organized but you know that if you pair if you if you present an auditory stimulus at a specific frequency and you give simultaneously stimulation of the vagal nerve that you can strengthen that that frequency at least at at the level of the cortex which means that as we know that in tinnitus there is a problem of this reorganization that with this theory if you can if you can make a system that does it that it should work and indeed in rats it works in 100% of rats that can abolish the percept of tinnitus and so what what Mike did and correct me if I'm wrong and so if you present a tone and simultaneously you present a stimulation if you only present the tone then the tinnitus remained if you only present the stimulation electrical stimulation attendez remained but if you pair them together then the tinnitus gets improves it's critically important that the tone presentation and the vagal stimulation becomes becomes associated so how do you do that while your implant an electrode on the vagus nerve which you can see here and this is the internal comes out the the electrode comes out of the abdomen is connected to your computer and you hear you have earphones on these earphones then basically activate tones except for the tinnitus tone so it's a little bit like pump test concept but a strengthened version of it and simultaneously you get a stimulation electrically and the vagus nerve and Ana tone and what we did that in humans what we saw is there were actually two groups one group that improved on one group that did not improve and the difference we think was that the this group there were first of all there were the patients who were worse from the start and they were all on medication that interfered with the mechanism of release of acetylcholine and noradrenaline which is critically important in order to get this reorganization and so the ones that that respond did not take the medication so which means that sometimes that if you want this to work that the patients should probably be medication free so and if that works for a group but not for everybody then you can still try to treat synchrony now there is a hypothesis that you can do that with coordinated recent auditory stimulation the idea sounds very good and that normally and the auditory cortex you've got all these cells and in a structured way that process information but they're all active in a little bit of a chaotic way and if they become hyper synchronised then they behave like a choir and the message will be lot stronger and you will hear it as a sound so the synchrony might be related to the tinnitus and the ideas that if you present sounds by by a kind of a and by kind of hearing aids that has a stimulator in it that you can de synchronize these activities so the concept is that if you hear a tone at six thousand Hertz then you give sounds surrounding these six thousand Hertz to D synchronize the six thousand Hertz which is somewhat counterintuitive because theoretically you would have to end to stimulate within this pool in order in order to do that so there is a small discrepancy between the theory and practice but they have shown that again a subgroup of patients seems to respond to it and this subgroup who responds they're the normal they're the brain activity malaises as well whereas in a subgroup of patient who do not respond there is there is no been there is no normalization of abnormal activity so this is this these are their their data so what you see in color is basically what is abnormal that's pathological activity and then the group who responds well as the one on the last line and over here as well and the group that does not respond does not have a difference between the pre treatment and not only activity but also connectivity so the influence of one area on the other seems to normalize after the treatment but only in the group who responds to the treatment so just imagine you've tried you've tried you didn't find a cause you've tried hearing a chief tried masking it doesn't help what else can you do well you can try some medications now medications there's lots of medications that have been tried and there is no medication that works at a global level but then the virtually some medications are very beneficial like I mentioned the carbamazepine and the typewriter tinnitus now the combination that I often use is a combination of the Yonge Street and River Trail basically it's a dirty cocktail it's a cocktail of Miletus on a tricyclic antidepressant it's an it's an anti-psychotic it's the dopamine influencing drug and it is a clonazepam which is a benzodiazepine they say why would you try to use a cocktail and sorry a cocktail instead of one pure drug or probably because any tinnitus brain there's not just one one neurotransmitter that's that's non-functional we know from other diseases like depression where they say well depression is simple it's a lack of serotonin so you increase the serotonin and they're cured that it doesn't work now if one neurotransmitter changes it will automatically alter other neurotransmitters as well or if you look at it from a network point of view if you have a network and you block it at one spot basically what will happen is the information in your brain will just take a route around it and the changes will come back now if you can if you can stop it at multiple areas then you've got less chance that the system can adjust to it and that the tinnitus comes back so why do we use this cocktail well flip n ticks all I think is is the most important part this is a very old drug it's more than 40 years old and it's one of the only drugs that block dopamine d1 receptors there's five receptors now that's not that important except that's what's happening is normally when you're exposed to the environment you get a lot of inputs simultaneously the dopamine d2 receptors are the most sensitive so they will respond first and they will basically get act they will activate every for every stimulus that comes in so you pick up whatever is happening in the environment and then if the stimulus is strong enough your dopamine d1 receptors become activated and they only zoom in or focus on the strongest stimulus so the concept is because your brain focuses on the tinnitus that's why you hear it because normally it should be like you're close it should be disregarded where the dopamine d1 blocker you should be able to defo 'kiss the brain from the input which also means that there is a very simple question to know whether they should work or not if you ask a patient well how much of the time what percentage of the time is the tenant is dominantly present in other words are you in this dopamine d1 hyperactivity state whether they say 5% you can try and the medication won't work if they say 85% then it might work because you're trying to cut exactly this hyper focusing on the sound and so when we did the first study trying to be scientific you say well we take the first the patients that come in they all get the medication and it did something but it didn't do a lot which makes sense because we if you don't ask the specific question you won't get the right subgroup and if you get the right subgroup then the medication might work so the there's other medications that have been tried like I myself right and melatonin basically you also try to work on your dopamine system cyclobenzaprine which is a muscle relaxant which seem which might benefit patients predominantly who have tinnitus that is motivated modified by neck movements or by some other sensory interactions naltrexone which is a drug that works on your opioid system alprazolam which is simultaneously simultaneous to the clonazepam why would you use a problem or clonazepam well these these drugs actually increase your GABA a and we know that in tinnitus there is a and a gaba a is basically a break so if you have hyperactivity it's either too much acceleration or not enough braking and we know in tinnitus that in the cochlear nucleus there is not enough braking going on so if you can increase the break by adding gaba a which you do by a clonazepam or alprazolam then you might get some benefit and actually if you add if you combine them with this dopamine influence you like I said you try to modulate different systems simultaneously which might be better in trying to get control of the sound and a compass that is actually a drug that is used for people who who want to stop with alcohol addiction in order to prevent withdrawal symptoms and that seems to be beneficial for tinnitus as well and a certain subgroup of patients but definitely not in all so basically what does it mean it means that you might have to try different medications you do and in headaches in order to find something that gives benefit a realistic improvement that you can get with these medications because you have to give them in low doses so you don't get side effects is that you get an improvement of two in between two and four points on a numeric rating scale from one to ten so if they score let's say eight out of ten you can drop it to four but probably not to not below that level so if the medication doesn't work either then you can go to neuromodulation and there are modulation the idea is that whatever we know about the changes in the brain that are associated with the changes that we try to normalize or we try to influence them you can do that non surgically or you can do that surgically and non-surgical modulation is TMS or transcranial magnetic stimulation so you apply magnetic pulses to the brain in transcranial electrical stimulation and there's different versions of that you can use direct current stimulation which is basically the car battery with an anode and a cathode you can use alternating current stimulation random noise stimulation or variations of these stimulations or you can use mirror feedback or you can use electro convulsive therapy and maybe auntie puncher also falls under this non-surgical neuromodulation or you can go to surgical modulation where you can implant electrodes on different parts of the brain so the most commonly used non-surgical neural modulation techniques are tense where you modulate the the c2 nerve and I'll explain why in order to try and treat the tinnitus you can use a magnetic stimulation targeting the auditory cortex the frontal cortex or even a singlet you can use direct current stimulation with an anode and a cathode where the current goes from one pole to the other Pole 50% goes to the skin but also 50% goes to the brain and then you can modulate brain areas because whatever is under the anode you will increase activity and excitability and everything cat you will decrease excitability and activity and you've got alternating current stimulation which is more time trying to drive the normal activity of the brain to a certain frequency or random noise where we don't really know very well what it does but it's hypothesized that it can be synchronize ongoing activity and then of course ECT can be tried although that there is very very little literature on ECT and neurofeedback can be tried where basically you record brain activity the patient looks at the screen and you say well this is the pathological activity and we want to normalize this and the way you do it at this because the brain constantly changes activity whenever it's and within the good range you give a positive reward which could be a green light whenever it's it's pathological activity you give a red light or you can have a movie that continues when it's good activity or stops when it's not good activity so this is neurofeedback now what all of these techniques have in common is basically that they change functional and effective connectivity so basically what they all have in common is that they change the connections between the brain between different brain areas and we don't know for many of these techniques what they actually do for example for TMS then suggested that they change synchronization but what it does is whenever you give a pulse you get an action potential which is different from all the other techniques with tDCS the acs trns implants ECT and neurofeedback you don't get action potentials when you stimulate with direct current stimulation we know that you depolarize and hyperpolarize depending on where the anode and the cathode is with alternating current stimulation as I suggested that it didn't rains specific frequencies that that you want to modulate trns as I mentioned we don't know it is hypothesized that the D synchronizes activity implants work predominantly by creating virtual lesions ECT electroconvulsive therapy is a kind of global reset to renewal to an epileptic seizure that you induce and and hope is that one the brain circuits reset that they will reset in a non tinnitus way and neurofeedback is where you try to train the oscillations there is variations of that there is different kinds of of non of neuromodulation techniques but the most important thing which might be actually the one that changes the clinic is that it changes the connection between the auditory cortex Paraiba campo REM to your cingulate insula those areas of the brain that are involved in tinnitus generation now how do you know well we we once did a study where there was patients who received all three so they received magnetic stimulation their current stimulation and fen stimulation in the neck and based on the results of these studies were we hypothesized actually that magnetic stimulation has a double effect first of all it has a direct effect on the auditory cortex if you target the auditory cortex but it also modulates the superficial nerves and why do we know that because the tense only stimulate the superficial nurse and ten stimulation can even though it's not a lot predict whether tDCS over the TMS will work and so the same for direct current stimulation has a double effect it modulates your auditory cortex indirectly even if you put the electrodes on the frontal cortex and it activates your trigeminal nerve and both your trigeminal nerve and your c2 nerve have direct connections to the auditory pathways and can be inhibitory on the auditory pathways so the effect that you have is directly on the cortex and indirectly on compensation so neuromodulation has changed in recent times the old idea was very simple the auditory cortex is a final common pathway of tinnitus so if we suppress the hyperactivity and the auditory cortex theoretically we should be able to cure everybody and there were some arguments because there was changes on PET scan on EEG on magneto encephalography on fMRI which all pointed at the involvement of the auditory cortex so it was the most logical target to try and suppress and if the treatment doesn't work well maybe it's because we're not communicating in the right way with the cortex we're talking to the cortex by electrical or magnetic magnetic stimulation in a language it doesn't understand so if we change the language if we if we change the stimulation design then maybe it will work and indeed and some of the patient we did not respond to the classical stimulation one which changed to another stimulation enzymes such as birth stimulation we could rescue some of those people who did not respond so it the idea was it's easy target the other final common path with the auditory cortex and the problem is solved now unfortunately even for this and a meta analytic level so when you could look at all the studies that have been done for magnetic stimulation of the auditory cortex it doesn't work if you look at the same thing for direct current stimulation it seems to do a little bit but not a lot because if you can only reduce the intensity by 13% that's not clinically beneficial enough to do any anything as a routine treatment so what we then did as we compared to direct current stimulation to alternating current stimulation to random noise stimulation see what the different techniques do on the auditory cortex and what you could see is indeed at direct current an alternating current stimulation doesn't do a lot but that we only had a beneficial effect both on loudness and the amount of distress would random noise stimulation so random noise stimulation seemed to be more beneficial for one or another reason if you applied this kind of current and if you look more closely actually what you see is that it benefits if you look if you use low frequency random noise and high frequency random noise low frequency random noise means that you use frequencies between 0.1 Hertz and 100 Hertz randomly and high frequency means that you use frequencies between one hundred and six hundred and forty Hertz randomly and interestingly if you combine them nothing happens so low frequency seems to do something and high frequency seems to do something but the combination doesn't do anything which again exemplifies that if you do studies and you would do a study on random noise stimulation for tinnitus and you would use the normal machine settings which has just used everything that's there from 0.1 to 640 you won't get a result but if you go to such two different stimulation design or sub stimulation design then you do see some benefit so and recently we also looked at at neurofeedback because we know that the posterior part of the of the singlet is involved in cognition and also in the end distress associated with tinnitus so some patients were we targeted this posterior part of the of the cygnets and some we targeted another area and then some patients were in a waiting list and what you see is that if you compare before and after that it changed something only and when you target the past ear singlet with neurofeedback that you had a clinical effect on the stress and then it makes sense that the the patients with high distress that they have a better effect and the patients with low distress and that some of the patients moved from from that at the end of the neurofeedback there was less people in the high distress group and more people in the lower distress groups than before so it seems to do something on the stress but not on loudness so even though we were treating the patients basically that the tinnitus was not bothersome not as bothersome but the loudness did not change just like what we've seen in cognitive behavioral treatment and and and GRT and in some of the medication so then the question is what what can we still do or are we running out of ideas well similar like the dirty drug where you try to act it to interfere with multiple multiple sites in a network then we you can do that with stimulation as well so the concept is if you if you're on a highway and the highway is blocked everybody will take the route around it so if you could also block block the route around it and you have to go even further so the more routes you can block the less chance you have of getting where you want to get in time so the concept is just like in a dirty drug why not use call it dirty stimulation where you use multiple targets in order to to have an effect or you can use another target you could say well the auditory cortex works but not not very well let's try other targets for example the frontal cortex or the single cortex or the parietal area so and how do you do that while you look at imaging so you look at eg activity in a specific individual patient where it is abnormal and comparison to controls or an fMRI where the activity is abnormal you use non-invasive stimulation for example transcranial magnetic stimulation targeting this specific area that is abnormal in this specific patient and if you get a benefit you do it repetitively if it doesn't last long enough then you can implant for example in electrodes so you can look for another spots or like they did like they suggested in Germany you can target multiple simultaneously so the network doesn't have a chance to reset so when we implanted the first electrodes on the auditory cortex what we saw is that if the patient had pure-tone tinnitus they responded well if they had a noise like tinnitus that did not respond at all and if they had a combination they responded with a pure tone went away but not the the noise lack component and so then we changed we developed at birth stimulation design and what we saw is that the initial study where we did where we implanted 43 patients with electrodes on the auditory cortex and we stimulated them in a classical way actually two out of three did not respond the inclusion criteria were that they responded to magnetic stimulation twice in a placebo controlled way but they did not respond and to the to the implant whereas we only one out of three did respond so when we then switched them to burst mode actually half of them could be rescued so half of the non-responders could be rescued and the ones that responded could be further improved that's very good because you can help more people with it but you still have a fair amount of non responders and then the question is why do they not respond we know we're at auditory cortex so we thought well that's the final common pathway they should respond so one with what we then did is we looked at people with who did respond and compared them to people who did not respond and we subtracted the activity to see the difference and what we expected to see was that there was a difference in the auditory cortex because that's where we put the electrode now to our surprise the auditory cortex there was no difference whatsoever but there was a difference in the parahippocampal area here which is involved in auditory memory it's like an entry to entry and exit gates to memory so you pull auditory memory from the hippocampus through the parahippocampal so you put it in to the hippocampus Friday para hippocampus but that's strange because the electrode is there and whether or not you will respond to to the auditory cortex implant depends on activity deep in the brain so the way to look at that then is to look at functional connectivity and this is how the brain communicates so these red lines just means that there is communication between the auditory cortex and the para hippocampus and those who responded to the treatment of the Ettore cortex were those who have good connections those who did not not have connections did not respond and then it makes sense if you stimulate there but the problem is there and if you've got a good connection well the information that you put in there goes there and you've got and you've got a response so basically probably with the wrong theory we had a beneficial effect but we didn't know a little bit like talis of malate a predicted to solar eclipse and 580 something before Christ with the wrong model with with the geocentric model used the wrong model for that right prediction and we seemed and to have some good results even though probably the model might have been wrong so since then electrodes have been implanted on the dorsal lateral prefrontal cortex to my knowledge only in two patience met many more but still not a lot on the auditory cortex there have been some results of electrodes that are implanted in the caudate not because of tinnitus they were implanted there because of movement or the trajectory went through the caudate nucleus on the way to the telomers for movement disorders and they saw when they were going through the thalamus called it and were stimulating their that the tonight is improved we've put electrodes on the on the in two paces on the anterior singlet and when twitch worked in one very well and the other one it didn't do a lot so the question is well we haven't found a cause TRT or CBT doesn't might might improve the distro hearing aids seem to work in about 20% of the patients as there's the noise generators the combination might be even better medication work predominantly if the patients have suffered from it for a long or if it's dominantly present during a long part of the day and neuromodulation ISM predictable in a certain way because we don't know exactly where to stimulate and we'll have to go to individualized treatments but justing the treatment to what the patient has which is for example by vagal nerve stimulation pairing it with sounds but specific sounds not any sound sounds that are related to the hearing loss of the patient and there are other treatments which you can find acupuncture any systematic review as of no evidence of efficacy hyperbaric oxygen therapy Madonna is this no evidence of benefit laser therapy no efficacy longer than three months so basically where do you end up well in conclusion since a couple of years we know a lot more about the pathophysiology of tinnitus and a lot of treatments have been tried none of them works for everybody there is no golden bullet that works but for subgroups of patients some of these treatments are actually very good but if you look at the whole group that won't work but in subgroups it will work so from starting point is the best ways to find a cause and you do that predominately by looking at associated symptom and treat it if you can't find the cause then giving information about what tinnitus is how it develops that it is not life-threatening combining it with with red noise as an trt might actually be beneficial for the distress if hearing loss at the tinnitus frequency if there is hearing loss at the peak the tenant is frequency and why at the tinnitus frequency because that means that this is related to the hearing loss and then it might be worthwhile to try hearing aids and are masking where you have 20 to 30 percent chance that you will have a beneficial effect if there is no benefit and in a high percentage of the day the tempters is predominantly present interfering with concentration sleep memory etc then you might be worthwhile trying medication and there is a couple of medications that seem to be have the physiologically reasonable to use and if nothing works you can still try neuromodulation and if neuromodulation does not work well then i would propose to try any of the studies that are going on in order to see if you can still get any benefit and that was basically a summary of the possible treatments for tinnitus I thank you for your attention

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