Safety

welcome to this lecture on physiological safety of transc cranium magnetic electric and ultrasonic stimulation this is one of those topics that is absolutely essential before you start your experiment or your therapeutic treatment when we talk about physiological safety we're mostly referring to the safety Beyond structural damage such as secondary effects adverse effects risks of transient effects and that means um in this lecture we're not going to consider that somebody is using the t-mass coil as a hammer we're not going to you consider the electronic safety of the device but critically we're also only going to talk about stimulation intensities whether magnetic electric or ultrasonic that where we know that it doesn't cause any structural damage so it's often at lower intensities within that domain it we can still expect many different effects effects that we do not intend as our targeted effect now this is what we'll consider in the lecture and we'll be going through this first starting with TMS there we'll set the grounds we'll give a long or a slightly more comprehensive overview of the international consensus on reported effects and some recommendations how to deal with them and we'll use that framework to look at the physiological safety of transcanal electric stimulation and lastly of ultrasonic stimulation we have less reported sessions and data on ultrasonic stimulation so to make some expectations for the future of physiological safety of ultrasound stimulation we'll be handling that in a different um lecture and here we mostly look at the current evidence let's Dive Right In so some definitions up front if we have an intervention that could be your TMS then we have a participant and we have of course the context in which we're stimulating and all three of them have an impact on your primary effect your intended reaction we also call that this is what you hope to cause with your stimulation but obviously um you have a large array of secondary effects uh and that's the focus mostly for today's lecture these secondary effects can be related to your stimulation maybe they're related they could be suspected or they can just happen uh regardless right somebody can grow hungry during a session or they can go tired but that isn't caused by your brain stimulation it's just something that happens as part of your study these are unrelated secondary effects now the definitions here those that are strictly or suspected related you cause them with with your intervention we call those secondary reactions and if they are UNT which means you might not entirely like them and they have a medical character we call them Adverse Events but you can see that Adverse Events we don't know if they're related or unrelated actually we Encompass both of these um most Adverse Events probably are unrelated to your stimulation or intervention itself imagine that you have a study with four sessions a week apart and your participant in that study they fall down the stairs and they break their leg that too is an adverse event even though you definitely didn't cause it but it was part or um associated with your study during your study particip participation therefore for Adverse Events we again make the same same distinction an adverse reaction are those Adverse Events that are directly caused by your intervention and the far majority um might be unrelated now it's important we highlight serious Adverse Events there's a strict definition uh it might require hospitalization or even result in death or deformations lifelong changes and in in in all of those cases again for serious adversity defense we're going to make an association whether they are related to the stimulation to the participation of the study or or just happen because of chance we can make a further dimension on whether these adverse effects are expected or unexpected and the more we use a technology the better we report them the more expected Adverse Events we can have and also the better we can characterize the risk assessment uh we can also inform our participants these um definitions especially of Adverse Events and serious Adverse Events are well structured in by regulatory bodies both in giving two examples of these regul in the US and in Europe and actually they're closely aligned there isn't a a large difference on the international definition so learn them by heart we're going to uh expand on this because we're going to fill this diagram with examples of secondary effects and we're going to categorize them as reactions events or adverse or not uh we'll first be doing this for transcranial magnetic stimulation this uh technology has been around for a few decades now which means that every decade there's maybe an update of the international consensus from a safety group and here I'm just listing um displaying the most recent one this update or consensus is focused on recommendations uh it should be probably obligatory reading material if you're in thinking about getting started in trans Cranium magnetic stimulation and that consensus often refers back to other papers that do meta analysis or that report on secondary effects and I'm giving one example one of the earlier ones where they referring to a Theta burst stimulation protocol in TMS and you can see how how such what the result of such a meta analysis might be uh first they look at all studies that use this technology then they categorize who actually reports Adverse Events uh ridiculously enough this is that only tiny red sliver we definitely do not report or Adverse Events often enough uh we're not consistent here because they should be expected every study will have Adverse Events somebody will have develop a light headache that is an adverse event and indeed for those study that do report it you can see that the majority of it are are mild Adverse Events somebody gets tired um they get a headache because they of the tapping of their head or because of the sitting still for a longer period um but there are also some more moderate listing here I'm not going to go through all of them uh for one particular protocol such as Theta bir stimulation in fact the consensus often have a has a good overview the guideline papers for different Technologies even emerging Technologies and they often report back to a paper from 2009 that tries to characterize for different protocols and for different possible Adverse Events How likely they are to occur and How likely they are to be related um I'm not going to read all of this up in fact I would like to refer you to that specific paper but you can see some of the considerations How likely it is it that with TMS we might evoke a seizure uh or are mood changes related to the TMS or not such a table is this is going to give an authorative expert overview and consensus has been reached for this overview um focusing here on the Adverse Events we can go we can expect and we'll go through some of them in a minute but the other approach is where you look at which protocols have been used and where no serious or safety concerns were raised right this is the other side of the coin you can either see what has happened and look at the frequency or you can say these are the protocols are up to these intensities and repetition frequencies um we have stimulated and nothing went wrong in a larger population this is critical because you cannot prove safety itself without having um stimulated everybody on the planet how can you prove that nothing is going to happen now instead the argument here is we're going to look for overwhelming evidence that nothing has gone wrong under an arbitrary limit the listing that you see here the intensities and the frequencies those aren't safety limits right they're not saying if you go above the intensity or above this stimulation frequency something will go wrong no it's the other way around these are arbitrary limits that say below this there is excessive and overwhelming evidence of safety now um that safety still mostly refers to structural damage it's not the same as no aders event should be expected under these limits but often this is what we refer to as the 2009 guidelines intensities and frequencies as reported in this table um everything below these boundaries is deemed with anable risk but let's look at the expected uh secondary effects the first and I'm going to start at the top is probably fatigue it is kindly tiring to participate in a brain stimulation experiment people will grow U tired over that course with all of the consequences if you ask somebody uh do you feel tired do you feel itchy do you feel lightheaded they might answer yes if they had to sit still for half an hour or even longer in a chair and even more so if they were physically constrainted and restricted in their movements they're going to develop pain in the neck or in the back they're going to be uncomfortable a large number of Adverse Events are related to study participation itself and some are dur even more directly related to your intervention such is a headache the most common at adverse event if somebody's tapping on your head repeatedly even though One Tap doesn't hurt if you do this for a longer period of time you will sensitize and it might develop an transient and L light or mild headache and the brain stimulation on top of it stimulating the peripheral nerves will only compound this and make the risk for a light headache stronger but these uh mild headaches they respond very well to overthe counter uh pain medic ation um often we're not medical doctors or wouldn't prescribe it ourselves but um over the counter medication you can recommend or that people would be using but generally these mild headaches are like any mild headache they would disappear very shortly after and they're often related to sitting in a chair for a longer time and somebody touching and tapping on your head many of the Adverse Events below are often related to study participation rather than the stimulation the neurom ation itself um in the past there has been a consideration if possible fainting or known as Syncopy is also an adverse event for TS because it does occur uh not too uncommonly in fact now the consensus is that TMS doesn't cause the fainting now it is they having to sit still for a longer period of time and listen to these or being in a small room with all the daunting equipment all the technical stuff stuff and cables around you that can make you feel anxious um or having to do this for a longer period of time without enough fresh air or even daylight this is a trigger for fainting and Syncopy so it is important that you know that this is an expected adverse event of your study even though it's not an adverse reaction of the brain stimulation you should be training how to deal with fainting so you can um assure and ensure the safety of your participants in summary over uh more than 300,000 reported and there are many more sessions there are no longlasting or um persistent adverse effects reported uh in clinical studies people are reporting that symptoms might deteriorate but it's unclear if this is just a coincidence because symptoms often fluctuate over time or if it's directly related to the brain stimulation now the upper cordant let's move to known and um reactions secondary reactions either adverse or not people often don't report them in their studies uh we don't consider if stimulation is at Target or of Target and only more recently are we doing a better job of electric field modeling or seeing what side of Target regions we might have stimulated so this is a corner to look out if there are secondary reactions that are aren't immediately intended and if we can do a better job of reporting them but the most um important or here severe adverse event for a TMS is a seizure that doesn't mean that it's the most common effect it is considered very rare the safety guidelines from 2009 um if you adhere to them the frequency or or the uh occurrence of a seizure for TMS is about one or two in 100,000 sessions that is very rare but importantly if you stimulate at higher frequencies higher intensities or in an at risk population the risk of seizure also increases and it can increase quite dramatically like U if you stimulate people with a history of epilepsy the risk can be 40 times higher than in the not at risk population we need to prepare for the possibility of a procedure but if we adhere to the safety guidelines these are arbitrary threshold we can actually see that there isn't a difference in low frequency or high frequency TS there isn't a risk difference between single pulses and Theta burst stimulation in fact it's it's equally common it looks like in these sessions and it's not too different from the base rate of a seizure one in 10 people will experience one or more seizures in their lifetimes um nonetheless because of the um severity of this adverse event we say it is very unlikely to happen but it would be a severe adverse event and therefore the risk is the combination of the two we still prepare for this we train how to deal with seizures now um let's move on to very well-known secondary reactions but not in the brain in fact outside of the brain we're going to look at peripheral effect of auditori and somata sensory and the auditor for TS is this very sharp click and the smat sensory you you will feel it it might even be the muscle contraction it's a direct stimulation of your nerve endings it might release uh feelings of sharp pain depending on where you stimulate and then leading to muscle contractions and eye twitches we can underestimate um the impact of these peripheral effects or in fact we we often do in our papers and I want to highlight just one of those studies where we're looking here at the effect of delivering a TMS pulse in an detection task so participants need to press a button when they see their target uh that it's a speeded Reaction Time task you can see the Baseline on the left and if we deliver a TMS pulse before their expected reaction time then this TS plus it advances it triggers their response so they're preparing a response and if you hear a click then you press faster if the TMS is later and people are expecting it they're actually going to wait for the TS and you see that they're slower but importantly this is a very strong cognitive and behavioral effect but it is not due to the TS to the brain stimulation itself we also see it if we deliver a click with Sham stimulation um without any effective neuromodulation it's the click it's the auditory the secondary effect that drives this very strong behavioral effect and often these effects can be much larger than your intended neuromodulatory or brain response so to watch out but also for safety reasons the TS click is um deceptively soft in fact The Click is so short we don't really consciously perceive how loud it can be it can go up to 120 or even 130 DB and your pain threshold is 134 DB that means that your participant if they would receive multiple TMS pulses especially the the higher the intensity and the longer they need to wear air protection because they're not going to be aware of the potential risk for hearing damage because it doesn't they don't perceive it as loud even though it does have high pressures the same holds for you as an operator if you're going to be close to to the coil for extended sessions at higher intensities and frequencies please do wear ear protection um you're going to be thankful later on similarly we need to be wary of the risk of um skin stimulation the periph somato stimulation and maybe even if we do this repeatedly it might lead to skin irritations now here is a total overview for you to take a snapshot we went through SEC all secondary um uh events both those are related or unrelated and we had some specific attention to adverse uh events and adverse reactions but let's now move to transcranial Electric stimulation and here we can rely on a lot of that happened in magnetic stimulation so we're able to go a little bit faster again in this domain there is an international consensus um I'm now highlighting one of those papers this is for regulatory considerations from 2015 that mostly holds recommendations on physiological safety there are also evidence-based uh reports uh that you can look at which uh adverse effect effects could be expected and in summary many of the secondary and Adverse Events are very similar between noninvasive brain stimulations because study participation leads to fatigue leads to many of these side effects these secondary effects but there are a few critical differences trans cranial electric stimulation you don't hear it generally uh also reducing the um secondary reaction and the uh adverse effect for hearing but most importantly transc crano electric stimulation at low voltage does not cause synchronized brain activity so there is also no seizure risk for transcranial electric stimulation and that has quite a an an impact on the total risk consideration because there are no known U moderate or severe adverse reactions expected for TS nonetheless if you do not administer your electrodes properly uh there can be scalp pain at higher uh intensities at higher uh ampir and if the uh impedance isn't correct there's also a risk of skin irritation skin retinas phase of delation because there's a lot of current going through uh immediately below the electrodes and through the skin now be wary of this it means that everybody needs to be trained in how to handle the equipment and how to prepare the electrodes and your participants but let's move to transcranial ultrasonic stimulation there is no consensus reported in fact we're working on this within the International Community but there are a few papers that do a retrospective analysis of these secondary effects and I'm listing one of them here this is multiple studies from a single lab uh you can see in in blue where there is no effect but actually some of these possible secondary effects they occur a few times in the participants and in a systematic review across multiple Labs here is a a depiction of the many different applications of ultrasound in the paper they also review the uh secondary effects and uh the the result to date is in fact that the these effects are very similar also for Ultrasonic stimulation as they are for magnetic and electric it's the same list that we see over here and across a much smaller number now 704 participants there are no longlasting or persistent um Adverse Events everything so far is light mild and transient uh we still as a community we are only starting so let's be wary to also report our on and off Target effects for ultrasound this might be even more important consider when you're stimulating on the amigdala if your focus isn't right or if there's energy delivered beyond your target you might for example deliver that energy to the brain stem with another risk assessment on the possible secondary effects than you would have for uh the amula your intended target we should beware on for the distinction between on and off of Target effects that means we often minimize our energy delivery for these critical structures or even better you could verify your exposure that isn't readily available for human application yet but in the future we hope it will be and it's also one of the reasons why we recommend that in your studies you monitor the neural engagements perhaps with neuroimaging or with High Fidelity physiological measures and again here for ultrasound we can expect peripheral effects for peripheral stimulation at both auditory and somato sensory in other lectures we're discussing how an ultrasound effect might appear directly related to the stimulation but is only due to the sound that is evoked or the sound that is produced by the stimulation not by the neurom modulation itself these secondary effects these a specific secondary effects can be much stronger than your expected effect size for your intended neurom it also means that we should be considering the safety of peripheral stimulation for auditory safety there might be participants where their skull structure is such that a puls and audible tone can be excessively loud even painfully loud and if your coupling isn't proper or your intensity at the peripheral at the scalp might be too high we can lead to um skin and peripheral effects maybe skin irritation or redness at the uh at the least so be prepared for proper coupling proper preparation and reduce your intensity also in the periphery now there's in in other um lectures and in lab demos we'll go through these recommendations on how to prepare your participant well uh one by one but it's important that we are training our new participants properly and that you if you're starting this technology in a new lab uh that you go through other already experienced users to learn the tricks of the trait for Adverse Events or adverse reactions specifically there isn't a lot reported but maybe we can expect a few so maybe if we're stimulating on deep brain structures such as the thalamus or we could expect nausea or or dizziness because if there is true neuromodulation these will be expected for example as we learned from deep brain stimulation and can we learn something from animal studies well here we might have very strong and effective neuromodulation that could even lead to Behavioral or induced behaviors um would that possibly in the future lead to I don't know a modulation of breathing or balance when we're stimulating brain stem regions or other critical uh deep brain structures nonetheless evidence-based we can learn a lot from high high intensity focused ultrasound over 10,000 patients have received this much higher ultrasound stimulation at the focal do at Deep brain structures primarily the thalamus but that also means that there is a strong exposure in other deep brain structures around this Target and here there are um no seizures reported no longlasting physiological changes apart of course from the intended ablation and that gives um an strong evidence-based prediction of the future of uh ultrasound for neurom modulation even at higher intensities because these are clinically very strictly monitored uh studies where we have a full reporting on Baseline and after the intervention so here in in summary uh we might not expect such serious Adverse Events at the intensities that we're currently using uh nonetheless we can expect from other non-invasive brain stimulations that people might faint because they're too impressed with all the technology or from sitting in such a crowded room or that if we're going for clinical trials we can have a fluctuation or even a deterioration of symptoms none of this should be unexpected for transia Ultrasonic stimulation so here's an overview of the whole set uh for you to take a a snapshot and take home but I would like to uh wrap up this lecture uh here we were going through the physiological safety Beyond or what would happen before you induce structural damage and we were looking at International consensus and recommendations for TMS and the reported effects we did the same thing but a little bit shorter for TS and ultrasound because the primary um concept here is that the secondary effects are actually quite similar across non-invasive brain stimulation and many are related to participation of your study such as fatigue or headache uh there are clear recommendations in TMS we might have an synchronized activity that is evoked so there is a very small risk of seizure that we need to be prepared for in ultrasound and in electric stimulation this hasn't been seen or might not even be expected nonetheless there are quite moderate Adverse Events such as fainting that aren't a reaction to the stimulation but are related to the study participation itself that we should prepare for so we recommend all of you to follow an First Aid course and safety instructions in your lab for now thank you very much