Neuromodulation for Eating Control in Women
Fantastic okay so welcome to another edition of Machine Medicine's um Interview Series and we are delighted and privileged to have Priscila Giacomo Fassini who's a professor at the University of Sao Paulo here to talk about her work um and and related works in non-invasive neuromodulation in the context of young women with obesity and and just more generally in the context of sort of eating disorders and stuff so thank you very much for being with us Priscila and and as usual it would be fantastic if you could give us a short introduction to your background how you got into into science how you got into this area in particular and why you decided to sort of focus on this relatively niche area of neuromodulation arguably although very exciting and growing very rapidly great thanks Jonathan for the invite is an honor for me to be here today and talk to you to show a little bit of my work so as you said I'm a professor at University of Sao Paulo that's in the southeast of Brazil and I am a dietitian with research experience and clinical practice focus on clinical nutrition so i have been working now on evaluating the efficacy of tDCS or transcranial Direct Current Stimulation which is non-invasive neuromodulation to improve eat control in women with obesity and obviously we know that obesity is a very complex disease smooth factorial and the prevalence of obesity is increasing at alarming rates in many countries and the epidemic of obesity is now recognized as one of the most important public health problems facing the world today and the most widely recommended therapy for obesity is a lifestyle modification which includes diet and exercising uh that sounds to be easy but it is not actually implementing change that can lead to weight loss is difficult and maintaining weight long term weight loss is even more challenging we know that more than 80 percent of people who start a diet regain weight regain the initial weight loss or even more so we are talking about a very complex and important disease that also a pandemic in the actual scenario you need to have effort, academic effort to start to look at this and try to understand better to to figure out new ways of treatment so um the control of food intake is also highly complex involving neuronal hormonal and nutritional control and individuals with obesity they show a decreased activity in the prefrontal cortex which is a key brain region supporting eating behavior regulation so recent evidence in the field of obesity and the brain-based integration indicates a potential for designing new therapeutic strategies of an intervention because we needed to try uh to understand and uh and have new ways of treating these species so in this context a non-invasive neuromodulation of brain activity has been shown in the literature to be a technique that uh could help reduce food intake uh and actually appetite and food craving that also can lead to reduced of food intake and body weight um so tDCS targeting the dorsal lateral prefrontal cortex ehh could reverse these abnormalities and maybe a potential benefit for people who are trying to lose weight because yes it modifies the cortical with stability and may facilitate an improvement of eating control however we have limited studies in the literature now and then most of the studies are short-term studies and present a very high variability between individuals um that's it that's that that's fantastic fascinating Priscila and there's a lot in there um i wonder if i can get you to just sort of back up a little bit for some of uh for some of uh our listeners um and talk a little bit about you know uh so so for example the dorsolateral prefrontal cortex um you mentioned that it's it's been implicated in uh appetite and eating and and so forth but actually there's a there's a very uh broad and varied literature on this area and can you say a little bit about the kind of um the kind of functionality that the dorsolateral uh prefrontal cortex has been associated with it uh with previously i mean another way of putting the same question might be um why do we think this is a good place to uh stimulate or or inhibit or or whatever it is um in terms of a kind of mechanistic kind of understanding what do we think is going on here that we're trying to change that great question Jonathan and that's so the target area of the brain that we are looking at stimulating is related to cognitive control so we know that people with your obesity they have impairment of this function so it's not because they don't want to follow a diet or because they are they do not understand it but it's because they have difficult real difficult related with impairment in the brain network that leads them to have a poor cognitive control so uh so when we look at the brain of obese people comparative to lean individuals we can see this difference of activity in this area of the brain so we think that oh maybe if we try to uh reverse disability normalities could we help these patients to have more control of the food choice they are going to have uh and maybe this could help them to lose weight that is like what we think is our hypothesis so maybe we reverse these abnormalities in this area could we um help them but the real mechanisms behind all this is still unclear because you know that's brains very complex and also uh regarding how the networks and i think you still need to learn a lot most of the the studies published uh until now are focused on the left or the right side of the dorsolateral prefrontal cortex interesting and why do we think um for example somebody might wonder why haven't we developed a drug to to treat obesity is this what do we think that what are the problems with sort of a pharmacological treatment would you in your judgment that mean that we have to take you know arguably this sort of more extreme step of actually trying to directly stimulate neurons yeah yeah there are options of pharmacological treatments and also surgeries and i think which is right for everyone it really is very individual it's but also we have seen some studies associating tDCS with other strategies i think that would be uh future of the the field because associating tDCS with people polarity diet that's what we did in our study or associating tDCS um we're seeing studies like associating the german communication associating tDCS um with medications and pharmacological therapies uh looking at depression so yeah i think we need to explore not just looking at tDCS alone we need tDCS only in our study but also in association with other therapies to see if they could improve the therapy that we are looking for fascinating and there's a thought behind that that we could we could somehow um when you say associate um uh do you do is the thought there that we could somehow um take advantage of the brain's natural capacity for plasticity in order to sort of place the brain into a a healthy as it were a healthy state or the diet into a healthy state and then and then use neuromodulation in order to elicit plasticity that would hopefully sort of uh solidify that that change like yeah that's that that what would be great so in our study we were looking at um uh investigating the effects of a nodal tDCS over the left dorsolateral prefrontal cortex in young women who visit over a period of 12 months because we do not have studies following these patients after the intervention that's i think is the the question so do we need to stimulate these people to see these results or we can how they um they love so i think we we need more studies looking at the follow-up period like this is the first study we publish our first six months follow-up and we followed these patients until 12 months so we did like a three days uh intervention so phase one was target engagement we are looking at the only single section of tDCS phase two the patients uh receive ten sections of tDCS from Monday to Friday to two weeks during two weeks and after this period they were admitted in our clinical hospital to follow hypocaloric diet in an inpatient setting to reduce compliance then we can make sure that the the diet is really um is a supervised diet and also associated tDCS so we have like these two phases of the patients the volunteers completed a month of intervention and after this period we followed them uh over 12 weeks so what we saw and so we did like it was a randomized and double-blinded control it shall control it so we have a group receiving real tDCS and another group receiving placebo so what we saw uh after intervention uh and also i would like to highlight that the hypoallergenic diet not like a restricted diet is what we really recommend so we measured individually the resting metabolic rate based only direct calorimetry so after determining the total and requirement to reduce the 30 percent of energy intake and also the macronutrients of this diet was balanced like normal distribution of carbohydrates protein and lipids so what we saw in in this intervention that we didn't find contrary to our hypothesis so actually yes did not promote uh beneficial and the weight loss in the active group so both groups chem and real tDCS reducing three percent of body weight it at the end of the intervention uh and also uh doing the follow-up real uh the volunteers receiving real tDCS they lost less weight and at uh six months they start the gaining weight and at 12 months they regain uh three percent higher comparing to baseline this was very interesting and then when we start looking at the genetic uh variation associated with this result then is what we saw like our striking i guess this is our striking result of our clinical trial because we know that there is uh evidence that the effect of neuromodulation is affected by dopamine and you know that dopamine is related to food reward and feeding and body weight and so what we did we investigated a variation in the gene comt which encodes an enzyme that's uh responsible for the degrading dopamine in the brain so it's related with the dopamine availability in our brain so what we did we we characterized our volunteers as carriers and non carriers of the net elite of the the comt gene because there is a single uh there's a polymer case we call it valine 158 metronim that uh affects enzymes so it uh makes it less effective so people with this variation they show they present higher uh dopamine availability so we classified our our volunteers based on carriers or not carriers of the metronim of the genicle okay and what we saw when started looking for the the active group we received the real um tDCS we saw that there was a subgroup of non-carriers that was responsible for this paradoxical effect this specific group of volunteers they represent the group that regain 19 19 of weight at 12 months follower and when we look at the appetite results of our trial it's very interesting during the interventions also saw a paradoxical effect so uh tDCS was the has beneficial effects for the met carriers of the gene comt so they showed reduced levels of appetite reduced levels of hunger desire to eat prospective consumption over time instead the non-carriers of met they showed higher levels of appetite so they present higher hunger and desire to eat showing a very clear paradoxical effect of the tDCS when you are looking for the variation regarding the genotype so so just to be clear the the carriers of this uh form of comt um have higher um synaptic dopamine levels we think because degradation is is impaired in these individuals is that right yes right so each video who has this variation of uh this volume of things they the enzyme that uh is related with the degradation of dopamine let's see what they call all material transfers it's less active so once so once they have an impairment they have like higher availability of dopamine right and in these individuals the neurostimulation seem to have a paradoxical effect in that it actually increased or or didn't or or had a didn't reduce appetite or relative to the control group or the group that doesn't have this form of comt does that right so the group that showed this polymer case with is related with the met carriers they show uh less levels of the appetite so they respond better right so how do we how do we understand that is that because they're already rewarding themselves so by having high dopamine levels or and and therefore you know they don't need to reward themselves with food or something what's what is it is there can we factor this into the sort of dopamine hypothesis perfect so this is related to the inverted u curve when you speak at the low and higher levels of dopamine so this seems to have to have a beneficial effect of these higher levels of uh dopamine and respond better to the tDCS intervention so the mechanism underlying these results is the one clear we i think more studies looking at mechanicists um mechanism studies also looking at um brain images that we can see like from our MRI that we could try to understand because the comt and a comt and in particular this uh this form of comt this is not the only context in which it has been implicated in in perhaps having a causal role or important behavioral differences is that is that correct what what kind of other sort of traits behavioral traits has has this been associated with yeah i mean we studied just um this genetic genetic polymorphism but we know that there are other uh genetic factors that can affect uh eating behavior so um i think we also need to explore and try to understand better which factors can affect uh neuromodulation tDCS but i think this is uh the first step that have been shown the response to the high variability between individuals and helps us to understand uh why some people respond to tDCS intervention and other people don't so this is what we see in the literature but we do not understand why so why it might be uh might may benefit some individuals or not for all the individuals right this i think it's the inside that we need to start looking at the genotype there are other factors neurotransmitter here we are talking just about dopamine but you know that there are others catecholamines also involved in yeah eating behavior control it eating behavior is very complex it involves integration of homeostatic and known homeostatic um regulatory pathways so and and in research we see with studies studying uh both mechanism but not integrating all these mechanisms i think we need to look at this integration to try to better understand this complexity and try to give answers to show who are people who can really benefit from this uh intervention because regarding any therapy we see that they might be not good for everybody so for example one diet can be good for one person that can be harmful for another so it really depends on the individual level i think we need to start looking at the individual level to try to answer okay who are the persons who tDCS could be of uh benefit so tDCS is a very attractive technique the brain activity i think it's fascinating but i think we need to try to uh look at these studies looking and uh at this uh field to try to give this answer and is better the mechanisms they're trying just to see for example we see that individuals with obesity they show a decreased activity in the dorsal in the prefrontal cortex but there's also other uh networks that we have in pairs so i think we need to try to understand the better to figure out the try the target that we are going to yeah yeah exactly which is the part which is the right protocol yeah and we met yeah which is the right protocol because we because one of the things i i've noticed is that we sort of glided over what sort of the the transcranial the exact form of stimulation is here and presumably um this is uh there's you know there are many many different ways that you could uh deliver this therapy i mean not just the the anatomical location you've mentioned the there's a dorsal lateral prefrontal cortex but that's a fairly large piece of neural tissue uh you could deliver it posteriorly anteriorly more laterally i presume are there different what's what's the kind of what's the kind of level of parameterization here are there are there really millions of different ways in which this could be delivered because i guess one possibility might be that you know someone could argue well well for certain uh with certain forms of comt this protocol that you followed is effective but actually if you've taken uh if you've taken another protocol it wouldn't have been effective for that group and then we would have seen the inverse with the other group so so all we're really seeing here is not that one group is uh gets effective treatment from neurostimulation but it gets effective treatment for neuro stimulation according to this protocol exactly Jonathan i think this this is how we need to think and then how we need to plan the future instead is to try to give these answers and then to safely and effectively prescribe tDCS to the right person using the right protocol so nowadays we see protocols varying from the time of the the current so varying from 20 to 40 minutes so apply 30 minutes of tDCS some studies are are looking for doing a anodo or catodo tDCS over the f3 or f4 looking at the 1020 international system um so yeah there's not like a pattern we see different protocols during the research so this is also difficult to do a meta-analysis and also to try to to analyze are there any prospects for doing something sort of adaptive transcranial stimulation is that something that's being explored is there a way that we can sort of feed back and update that the way that the stimulation is being delivered much as you're probably familiar in adaptive deep brain stimulation there's a new generation of of stimulators that are also sensing and one of the hopes um although we've yet to see whether or not it's true is that we can use the the local field potentials as a feedback signal in order to optimize the parameters i mean particular for more complex as it were diseases like neuropsychiatric conditions which don't seem to be amenable to treatment with simple protocols that we found were successful in parkinson's disease or essential tremor is something like that happening in in non-invasive transcranial stimulation yeah there are a few studies uh looking at also tms and most like non-invasive neuromodulation that show to uh improve symptoms also they are looking at the dorsolateral prefrontal cortex so yes we're still like trying to understand which is the better non-invasive um strategy and uh also trying to figure out the best protocol to see this result um so there is a very interesting study published in 2015 that they uh they also use the tDCS looking at the left dorsolateral prefrontal cortex so the volunteers there was admitted in an inpatient setting and then they was exposed to a vending machine okay so we have unlimited access to food 23 hours 23.5 hours a day and so they look at after three sections just of tDCS the researchers could see that the volunteer that the patients in the in the in this in patients setting they um have a significant revolution of body weight over a week and also consume it less fat and less soda and also fewer calories so it seems to be uh a very uh interesting strategy so i think you just need to look at like instead is looking at more long time stages so definitely look at this long-term steps also looking at different uh group ages so for example different groups related with age and also different classes of bmi and also gender uh most of the studies are conducted with women or i think yeah generate this to the population is also to investigate other subgroups of population but also considering the variability there is a meta anlysis that says that we do not have enough evidence also of course because tDCS is a very well known uh technique there is very study techniques that have been shown uh that results to depression and neuropsychiatric disorders but in the field of obesity the investigation of tDCS individual visits is more recent when i started my postdoc studying uh tDCS and neuromodulation in 2016 there was just 10 published studies in the world so i think yeah i think it's a very experimental but i see uh a potential of the technique they're just needing to continue studying and trying to give these answers regarding mechanisms and regarding long-term effects to try to figure out who are the patients who can really benefit of this okay one of the things i was wondering when i was reading this was it was you know i guess the the the sort of paradoxical result that you've got is is much more interesting than just a negative result right and and one of the contexts i was thinking of was well this is a study looking in particular to obese people but what about people that are under eating and have eating disorders i mean is there is there a prospect for applying this kind of technique to people that are suffering from anorexia or bulimia yeah yeah they don't they're already a few studies published with anorexia showing good results and also because it is related also with uh impairments of behavior yes related to food control so yes we have a a study of anorexia using tms shown in potential results and also with bulimia uh working with tDCS so yeah there are just one uh study published last year also investigating people with severe obesity higher levels of bmi up to 40 and now we are planning to conduct a study also investigating those uh subgroup of people with higher levels of bmi because this patients has fewer options of treatment comparing with other classes of bmi so we are starting looking at um unpack that for me a bit why have they got fewer options people with a very high bmi yes because our patients for example with bmi uh 60 70 they for example surgical is not an intervention right okay yeah okay so that's why i think and also it's really more challenging for them exercising makes sense when you think about it yeah exactly usually lifestyle motivation is even more challenging for this group with very high levels of appetite and they have studies with constitutional modeling supporting the use of standard tDCS do closing and parameters for people with higher levels of bmi that's why you start thinking about studying these patients yeah and are there any downsides to this i mean we're sort of trying to work out how we make it work is there any suggestion what are the possible what are the possible negative effects of this do we know of any is there a prospect of any is there even a theoretical for the reason for believing that there would be sort of deleterious side effects negative side effects for tDCS? yeah no actually says it's very safe uh it's it actually has a lot of adventures it's very safe and uh portable it's easy to apply we are thinking about a low-cost therapy really could be uh new therapy for the treatment of obesity is we're talking about something that's very affordable uh and also i think that the most adverse effect is skin readiness this is what we really see when we apply it to tDCS but this could this could potentially be a sort of consumer device that people can buy from the chemist maybe even without a prescription ultimately in terms of its potential yeah we need to take care about this this is a very important topic because we years we have seen like devices being developed like a cap that people could put in like at home so i think yeah we need to supervise we need to take care and actually also for example this is showing this paradoxical effect show that it can be harmful for some yeah for the wrong people exactly it can be uh benefit but also could be harmful for certain subgroups of people that we still need to investigate and try to give this answer i think this is the first inside but i guess we are in the way of figuring out for the next years brilliant all right Priscila i'm afraid we've reached the end of our allotted time but it has been fascinating to hear about this uh research and you've also mentioned some other studies that i'll certainly be looking up um and some other applications to this this technology and we look forward to seeing what your next uh contribution to this expanding field is and so yeah thank you very much and and all the best thanks Jonathan
2021-03-22 00:35
