Neuromodulation for Eating Control in Women

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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

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