Use of Transcranial Electrical Brain Stimulation tES to Manage Acute and Chronic COVID-19 Symptoms

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we are live now and welcome to another episode  of the Machine Medicine um Interview Series on   neuromodulation and we're delighted this  week to have Professor Leigh Charvet and   Dr Giuseppina Pilloni from New York uh with us  here today welcome both of you and and i wonder   perhaps we could start with you Giuseppina   could you um uh give us a brief um overview   of how you got into this fascinating field and  and uh yeah i'm delighted just have you here can you can you hear us Giuseppina hmm maybe not okay so perhaps we'll start with  you Leigh if that's all right and Giuseppina will   Giuseppina is sorting out her sound issues  yeah would you mind giving us a little overview   of how you got into this area Giuseppina are you  on yeh I'm on so you can start with your background okay yeah okay so but i cannot hear the  other people oh okay i can see you   but like i can i cannot see the other  people and i cannot hear the other people um are you in the same building yes would it be would  it be all right if you went down the corridor   and you both sit next to one another i think rather  than finding a technical solution that might be   yeah so yeah yeah maybe you would start Leigh i  can start talking so i'm a neuropsychologist   um clinician and i've worked in neurology  um primarily people living with multiple   sclerosis or MS um but you know really all  different types of neurologic conditions with uh   cognitive and psychiatric problems resulting  from their conditions and so um you know and   have done a lot of research around that and always  with the research focus on what we can do tools   to improve quality of life and reduce reduce  the disease burden that they have um and so i was doing i did a large trial of cognitive  remediation with people living with MS and that   trial was telemedicine and that actually brought  me into the world of tDCS because we were very   interested to see if we could pair stimulation  in the rehab setting to see if we could boost   uh benefit of cognitive training to help get  greater benefit and shorter amounts of time and so   that was about 8-9 years ago that i started  partnering with with uh biomedical engineers   and and immediately because of my background in  telerehabilitation to tDCS at home for clinical   application and that's you know uh directed the  journey that's been quite an intense journey   um this part got you but so you really came to  it from a from a very clinical kind of place with a significant sort of tech uh element   yeah and Giuseppina be interesting to  hear how how you got into this what your   general background is and how you got into this  area so i'm a biomedical engineer and i started   working with the Charvet since 2018 i went here  in New York the first time from Cagliari in Italy   or as a as a visiting PhD student  and then i joined the team last year   and um so my main focus was like the PhD was like  the quantitative assessment of gate and balance   uh with inertial sensor and first platform and  so i apply this technology to see if like some   like rehabilitative intervention uh can um like  improve gait and balance in neurological disorder   and specifically in multiple sclerosis  gotcha so so yes it's kind of nice um   asymmetry so you came to this field from really a  very different place i suspect several years ago   you were studying systems of partial differential  equations um and that kind of thing right and now   and now you guys are working together so that's  fantastic and and and that's without further ado   it'd be great to get on to the the the meat of  your of the your this recent publication on the   uh on the use of transcranial electrical brain  stimulation to manage the acute and the chronic   uh Covid-19 symptoms so i think as i mentioned  briefly Leigh when we were talking before i think   it comes as a surprise to people to learn that  neuromodulation and bioelectrical medicine more   generally has a role in inflammatory disease but  it really does and it could potentially be very   impactful indeed right is this what's  the best way to sort of think about it   um i think absolutely and and i think it's  also driven by the accessibility safety and   tolerability of these tools so it's a non-drug  intervention that patients can have immediately   it can be applied anywhere and you know as we just  mentioned our our focus is on on home use um and   so it and if you look at uh the the the growing  literature um there's there's a lot of potential   direction that can go for evaluation and  potential application of these stimulation   therapies and in managing Covid throughout  it's you know from acute through um you know   persistent symptoms and recovery but if i can play  devil's advocate for a moment i think you know   certainly when i was studying neuroscience um um  i i think the the kind or or even medical science   more generally i think the kind of the way that  we sort of conceived of the nervous system was   as an information processing system and in that  regard sort of certainly conceptually seemed to   sort of consider the immune system and other sort  of related system say the endocrine system as   somewhat sort of in parallel but sort of separate  and yet and yet there seems to be a premise   underlying here that actually by intervening  with you know electrical kind of um interventions   we can actually modulate the immune system sort of  i guess indirectly through the nervous system or   so indirectly is key so we're not saying  that this treats Covid um i think that   it it it treats the effects of Covid on  the system and manages you know the sequel   of what Covid does to somebody and i think that  what it does in the acute infection and the   persisting symptoms is really unknown and still  being characterized and so it's just catching up   to seeing if we can apply some of what we know in  other syndromes and other situations to be of help   here and to evaluate um but again with we have to  remind ourselves too that this is an accessible   tolerable safe therapeutic approach and so really  you know a call for research a call for evaluation   um you know and that's really the point of our  paper too is just for it to be considered um   fitting in really in an area we don't have  many other therapeutic options right now   yeah it's a great point isn't it because you know  drugs are our sort of go-to as clinicians and uh   and i i do remember as a junior doctor myself  the kind of sense of terror that it induced in   me at just how common prescribing errors and  and sort of you know maybe even ignorance of   what the effects of drugs how much of that  there was uh and and yeah they were our kind of   main tool at least as as physicians for treating  disease and yet it was anaphylaxis and all kinds   of unpleasant side effects and so forth so they  really are very dangerous things right drugs so so   are there any deleterious effects i mean one  would one would have thought that the power   to do good would imply the power to do harm and  yet it doesn't seem very easy to actually damage   people with with these technologies what's what's  the underlying intuition for that yeah so i i you   know especially with uh transcranial electrical  stimulation it comes from just a really strong   record of safety and tolerability and no serious  adverse events reported in clinical trials to date   certainly in our high high volume of experience  it's really well tolerated and so um you know   you know everything has side effects as far  as but they're they're usually you know at the   site of the electrode you know discomfort that  kind of thing that that's not something that um   would prevent you from concern for for  evaluating in a therapeutic context um   and we've you know but uh we're learning more and  more and um we definitely need more evidence for   sustained continued use of these therapeutics  you know a lot of the trials have been really   limited to few applications and so if we look  at we really believe that there's accumulative   benefit so you need repeat ideally daily  application for that benefit extended periods   of time and and and we just don't have the the  full body of evidence that we need to really guide   dosing parameters and and and what we would  expect for long-term use but with that there's   nothing yet that would would make us think that  or or or anticipate a worry about continued use   so yeah yeah so we're cautiously moving forward  but i do want to you know always note that there's   caution and that more evidence is really needed  especially for dosing guidance and parameters in   this field yeah no absolutely i mean there's so  while the empirical it seems to be quite a lot of   encouraging empirical evidence that this stuff  works and works quite well in contexts like Covid   and and actually you know many different aspects  of the disease right you discuss in your paper   that the fact that it seems to be it can be  used in the early stages when there's an acute   inflammatory response it can also apparently  help with uh supporting respiration through   vagal nerve stimulation uh can also help with uh  you know the neuralgia the the pains that are pain   chronic pain syndromes that may be associated  with sort of long Covid if indeed that exists   um beyond a psychiatric phenomenon but um  but so it's a very very powerful but um   but so much ignorance too right like  you said we don't really know how   how this stuff is being affected i guess that's  an interesting point for you Giuseppina if i   may what are the sort of what are the sort of  interesting problems that attract an engineer   and uh someone with your your sort  of skills and background to this area   uh so there is a lot of technical thing  in transcranial direct current stimulation   and especially all the modeling of electric field  so how the electric field propagates in the brain   uh so and this means which is the best target  area uh to reach the best um the optimal benefit   from the treatment uh how how the brain  activation change with current intensity so   we should increase the current intensity or we  should use the standard 2.1 milliamp for example   how long the treatment has to be  so 20 minutes or we we can increase   so there is a lot of like unknown things that  we are like actually investigating and also for   example the real the real-time effect of tDCS on our brain with like tDCS and MRI uh protocol   and so there is a lot of like interest yeah  i mean i guess there's a lot of different sort   of levels of analysis you can look at  like you said you could you can model the   the current the current and and and i guess that  would be helpful for things like building systems   that could uh predictively target a particular say  deep nuclei in the brain or indeed a superficial   um uh module of the brain but then i also guess  there's the you could you can model the sort of   interaction of population of neurons with  that with with those currents from a sort   of um electrophysiological perspective but then  at a i guess at a deeper level there does seem   to be this sort of question of a neural  code right like somehow somehow we're re   programming nervous systems which are and in  turn reprogramming remodulating uh inflammatory   systems or or even cardiovascular or respiratory  systems um and and and i guess it comes back to   um this sort of question that we had there seemed  to be something of a paradox that when you sort   of intervene although we have very little idea  what we're actually saying in the neural code   it almost always seems to be either i  either have no effect or to be beneficial doesn't that strike you guys is curious  it strikes me as very curious indeed um so i i i guess just I was  saying is that you know i i was noting that   we need dosing parameters from the clinical  perspective but we you know as with many you   know we're not unique in this field the mechanism  remains largely unknown as well and so we really   need the work to understand especially when we use  it to target to match what we think is a model of   an illness and how that's effective yeah then we  need to understand mechanistically to drive how   we would use these and so again right now where it  it's it's theoretical mechanism you know or built   on on use and symptomatic use in other trials  or rehabilitative use in other trials and and   bridging that to potential use in Covid but i  think that with the work and exactly what you're   saying as far as as you know modulating neural  code modulate you know influencing the neuroimmune   response those are are largely theoretical right  now and we really need imaging models and markers   you know Giuseppina has done a lot of we have  a simultaneous tDCS MRI study going on you know   modeling the effects of tDCS application in  real-time and with the effects on the brain and   then looking at the um the consecutively applied  results to that so to see how it changes the brain   um but that all of that is so preliminary and so  so i think that that it you know i just want to   point out that we're in the theoretical kind of  matching of disease to disease i guess you know   what do they say like in theory theory and  practice should be the same but in practice   they're not right yeah but um yeah that's that's  right so i i i guess another interesting aspect   is one of the other kind of compliments i mean  you mentioned yourself Leigh that you actually had   a bit of a background in telehealth as well even  prior to getting into uh into neuromodulation and   so um there's a very there's very sort of what do  you think the most sort of complementary kind of   subsets of technologies are i mean i think in in  your paper you discuss the possibility of doing   uh you know remote uh neuro rehabilitation which  is augmented by you know transcranial electrical   stimulation so a very kind of like cool um sort  of nexus of technologies delivering a therapy   remotely you know at scale right right and that's  how we actually started with tDCS because of the   handheld portability of the devices and we  telemedicine and we know from almost every   rehabilitative therapy you need consecutive  near daily application for extended periods   of time and so so tDCS can be fair or tES can  be therapeutic on its own for certain uses but   also you compare it um to boost the learning that  occurs with with a simultaneous learning activity   whether it's physical or cognitive  rehabilitation for instance and so   with that angle especially home-based therapy is  really important um to provide the ongoing daily   sessions we do it remotely supervised through  telehealth so it's it's very structured very   guided but the technology is sent to patients at  home and they're guided through it in that way   um and so we had actually developed a whole  system for that um eight years of development   to be able to reach patients in their homes  to deliver tDCS for that purpose um and i   we with Covid again every you know especially  that uh we suddenly were moved to telemedicine   across the board patients were isolated in need  of treatment so it really lends itself well to   that model to both reach patients in need and also  to provide that ongoing daily type of therapeutic   activity to boost recovery gotcha so that kind  of yes is that is that how you decided to do this   working in Covid just because well it's obviously  very topical at the moment uh obviously a lot of   people that have uh the condition and suffering  from the security so it's a very you know major   topic of just because everybody's trying to  think of what can we do therapeutically to help   all of the patients with Covid and particularly  with you know we see a lot of people who have   those persisting symptoms we work with patients  with neurologic disorders who then get Covid   so there's just a tremendous therapeutic need  across the board and so you know it was positioned   in that way but also we have a um through NYU Langone here we have an innovative care uh   policy that allows us so it's not approved here  in the United States um but but it's considered   innovative care so we have a clinical service  where we provide uh tele-tDCS um to patients   in their homes therapeutically or clinically  and so we began to get people uh recovering   from Covid and that that service as well and  so that's that's kind of informed a lot of our   thought trying to optimize their rehabilitation  their recovery and to help them in that way   and so when you're doing a sort of tele um uh  session the are you why is it why do you have to   why can't it be done asynchronously do you have to  guide the positioning of the device that you have   to guide why do you have to be yes yes you don't  um you know we come from you know our primary um   activity here is research and so  with all the rigor of research you   we you know and also from the abundance of  caution again as you noted earlier you know   you know so so these are patients often with with  a high level of neurologic impairment who are self   administering tDCS in their homes and it can be  complicated there's technology involved and so   we we built a system around live video connection  at every point and um especially important if   we're pairing it with an ongoing therapeutic  activity we can just really enable that and um   so it's not necessary i wouldn't say and i think  there is definitely technology and models where   people can self-administer i do think though that  especially in the beginning it's very it lends   itself really well to a daily contact therapeutic  model and then both for safety and clearance   checks but also just to checking in reaching a  patient at home every day is very powerful and can   also ensure adherence to the therapy and make sure  everything's going okay so there's a lot of kind   of soft therapeutic benefits around that daily  connection model too um gotcha yeah okay but if   you're thinking about making it sort of truly very  scalable right absolutely and if the technology   were sort of suitably productized i guess and made  for easier the technology is for self administration or   for um asynchronous administration as you said  which can still be clinician guided at   a lower level than live video connection um and  i definitely think that that's where we're going   but again we need that guided use and um um you  know and always want to come from an abundance of   safety precaution that you know especially where  in the home in somebody's home for their use   so so another interesting aspect that we often  think about and i'd be interested to hear your   thoughts on it because obviously one of the one  of the advantages of this is it's non-invasive   um but then one of the one of the interesting  things that happen has happened in invasive   uh neuromodulation for example in deep brain  stimulation is that you can now record at the same   time stimulating and there's a lot of excitement  although not a lot of proof i have to say yet but   one hopes a lot of excitement about being able to  record simultaneously and use that signal uh as a   feedback signal in order to optimize the as it were  the forward stimulation if you see what i mean   and so um and so what what kind of paradigms do  you have in non-invasive uh this non-invasive   context for getting a feedback signal to tell you  maybe you know as a teaching signal is it worth   to update your parameters ultimately or even  tell you if you know you're having any effect   i can tell you that's a very topical question  that's a great question we think about that a   lot do you want to you know so we won't be able  to use uh uh to monitor or to monitor real-time   related variability because can be used it has  a bio feedback uh for like uh to see if really   there is like a change and um like an answer  from your body to this kind of like so that was   what was the metric you were measuring the  heart rate variability or right the heart rate variability   right so the insert the the inter  beat variability so the entropy of this   sort of uh this interval is that right that's  interestingly sort of the the entropy is uh   is sort of correlated with health right  right exactly in a sort of broad kind of   way that you know and then as people get sort of  more as they get closer to right death i suppose um yeah so biomarker feedback is just is really  important um so far EEG has not been helpful   for us to it really to inform it so that was  probably the first go-to and so one of the   other things that we can simultaneously acquire  that would inform both the treatment response   verification of treatment response help us  predict individual differences and somehow   mark response other than symptomatic reporting  um i think it's really really important and   um right now we're just not there but i think  that the technology is going to enable us to be   even right now when we're at home with devices we  can collect a lot of data on patients um i mean so   there's a lot of potential that i don't think it's  it's there yet but um right but you you looked at   heart rate variability did i understand  correctly and but it didn't seem to really   give you no it was EEG it was was our kind of the first simultaneous oh EEG sorry EEG yeah   okay that didn't really give you  the answers that you wanted and so   now you're looking at more i guess well less  neurological ones or more general kind of   as a first step yeah so just things that  we can collect and we can definitely   collect vitals and monitor vitals in  real time through the devices and so   you know so but that's definitely an area of great  potential because these you know with technology   enabling ongoing biometric data collection there's  lots of you know ways that we can and i think to   your point that that's going to be a very powerful  tool in the end for optimization of how we use   these tools yeah so so just to sort of be clear  about what you think is kind of not there yet   because there are there's a lot of you know  Fitbits and and various medical grade kind of uh   equipment hardware that can be attached to people  you know the Apple Watch now has a whole health   kit kind of software development kit attached to  it um so and but but are you really talking about   the kind of the ability to simultaneously capture  data across multiple hardware devices and also to   integrate that data in a clinically usable way is  that the kind of and specifically in response to   the use for tES therapeutics so that that i you  know across studies across uses is definitely our   experience there's a lot of individual differences  in responses yeah and especially bringing back to   code if you look it's a Covid especially post  Covid is multi-systemic right so there's a lot   so what indicator can help us with the patient in  real life and so that's what always drives us is   the clinical challenge and what we can do so that  was uh you know so we're trying to think of ways   you know and you're right that there's a lot of  technology in some ways though there's no clear   path to exactly what technology is going to  be useful sometimes the complexity and the   availability of the technology makes it harder  to move forward so we think about that a lot and   i think that soon that will be really part of  the use of these kind of therapeutics for sure   yeah yeah i see so the the the people that are  developing the devices are generally not kind of   developing these additional tools for the kind of  if we can call it kind of there's the obviously this   kind of device data where it sort of i think the  next step i think that there is i think there's a   lot of interesting device designs coming down and  i also think that the devices may be able to also   deliver digital health therapeutics so carrying  the stimulation you know so we believe very much   that that uh ongoing therapeutic activity  training rehab um with the stimulation the   stimulation boost that that benefit um potentiates  the benefit and so if the device can deliver the   digital therapeutics i think there's a lot of  interest early development in pairing the digital   health therapeutics with the stimulation therapies  as well yeah i see what you mean yeah um because   there's a sort of synergy between them and if you  can do that one in one fell swoop that would be   obvious and Giuseppina from from from  your view from your perspective what are the   one of the main technical challenges for the  next few years say five to five to ten years as a biomedical engineer as a biomedical engineer  um for sure like uh being like able to more this   like more specific in the stimulation of the  target of the brain target so because of course   we are using some like electrode montage that  are standard but like on standard measure but   of course like a lot of difference between um  between patients and so i think the next step   will be reduce this like variability in between  subjects yeah and this maybe you will get like a   better like result in terms of like uniformity of  response to them so what we i mean what we really   need ultimately right is a kind of digital  twin a digital double of the patient right   in silico uh sort of experiments  on and work out what the best   what the best sort of location and and and  protocol would be for that individual right but   that's no no mean feat but i guess are these  are these primarily are they primarily software   innovations then we're talking about rather than  hardware innovations or the is there as much work   to be done on the hardware as   there is with the with the software I think we need to work more  on the software because then the output would be just an adaptation it's  just like our like understanding or also in like   matching different like uh speciality life like  uh um and like um activation of the brain and so   what is like all the world of like functional  MRI with like all this like trying to find the   best target so you mean it's kind of like uh okay  so it's more it's almost more like a scientific   question how are these how does the brain we  need to understand kind of how the brain works if we want to deliver we'll definitely have it solved within the next   three hundred years i was gonna  say if we have to wait for that so that's that's great but i think you know the  you know so individualization of you know   so i think in the end i would agree with you  in that we'll have technology that'll drive   individualization of the therapeutic use and also  combined across different stimulation therapies um   so uh so you know yeah invasive and non-invasive  and i you know we're very early and a lot of   exciting advances on the forefront with all of  this for sure for sure and yeah i mean also i   guess yeah there's so many different um so many  different targets and you know as you say there's   why why wouldn't two targets be better than one  you know maybe there's and so the complexity just   becomes bewildering doesn't it when you think  of the number of places that you could kind of   relocate your stimulator and the number of  different parameter settings i had a chat with   a Boston Scientific engineer the other day about  their their basically their their their their   vanilla DBS system if i can call it that and even  that has 250 million different possible settings   you know so that the chances of finding you know  the optimal ones for any given patient scene   right in settings matter i think you know  we always just call attention to dosing parameters   because if you look at reviews of studies uh  you know some studies use one session some use   five everybody uses different intensities and  all of that probably matters i mean if you made   an analogy to medicine if somebody took one  pill somebody took five pills somebody took   one dose something to and then you try to analyze  the fact of that one drug across all these studies   so you know the dosing parameters matter  tremendously just even with our standard first   entry so we can understand yeah well a lot of  interesting work to be done in the future and no   doubt you guys will be instrumental in doing much  of that work so we'll look forward to uh to seeing   uh and following your your work in in the future  um so yeah i'm afraid we've reached the end of   our allotted 30 minutes but it's been a pleasure  Giuseppina and Leigh to speak to you both and just for for just bringing attention to  all these great topics that you're covering so   um we really appreciate the opportunity to  speak with you brilliant thank you very much

2021-09-02

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