 Good afternoon. On behalf of the McLean Center and the Glowsham Institute for Neuroscience, quantitative biology and human behavior, I'm delighted to welcome you back to the 2050 and 60 lecture series on ethical issues in neuroethics. This lecture series, as I've told you before, was organized by John Wansel, who's here with us. I'm Peggy Mason from neurobiology. My dad's so lazy from the McLean Center. I have been housed today before we start. Today's session by Dr. Warnke will be the first session in the winter quarter. We are not meeting next week, so the session that was scheduled for January 20th has been postponed. And so we will resume these lectures for the rest of the quarter, two weeks from today on January 27th with Professor Jason Bridges talking about mind, brain, and thinking. But it's important. We'll try to send out an email notice also on this point, but no meeting next week. Today we're delighted to welcome Dr. Peter Warnke, who's a professor of surgery and urology, and the director of the stereotactic and functional neurosurgery here at the University. Peter is an internationally renowned neurosurgeon who's performed, listen to these numbers, more than 3,000 stereotactic surgeries and more than 1,000 brain tumor surgeries. Dr. Warnke is one of the few neurosurgeons in the United States who has experience with opening, transporter imaging, and is studying the use of such imaging to predict responses to deep brain stimulation in Parkinson's disease. Dr. Warnke also is researching the development of biological and minimally invasive treatments for epilepsy, movement disorders, brain tumors, and is studying the tumor physiology of many of the blastomas in pediatric brain tumors. Dr. Warnke is the associate editor of the general neurology, neurosurgery and psychiatry, a journal which has one of the highest impact factors among neurosurgery journals. Today, Dr. Warnke will talk to us on the talk entitled Behavioural Change in Deep Brain Stimulation. Please join me in giving a warm welcome to Dr. Peter Warnke. Thank you very much for this very, if not overly kind introduction. And I'd like to structure the talk in predominantly three parts. Number one, I'll take you a little bit through the clinical aspects and the actual technique of deep brain stimulation which was developed originally for movement disorders but is spreading out to different diseases now. So you get a feel for the intricacies. Based on that, I'll then show you some data on the actual biological effects including the network activation that we achieved with deep brain stimulation of very tiny little structures in the brain which will answer the question that is behind the title. There should actually be a question mark because all of papers in the early 90s came out questioning whether actually there was a behavioral change induced by deep brain stimulation of deep subcortical structures and I hope the data will show you how overly naive that question actually was and the third part actually will then focus on deep brain stimulation intended to change behavior i.e. in psychiatric diseases, predominantly depression and OCD. And in all three aspects, I'd like to view this from two angles, the patient's perspective and the surgical neurologist's perspective who actually does perform the deep brain stimulation and you'll see this perspective is entirely different and in the end, hopefully we can then discuss whether and to what extent the brain stimulation in what structures really does change behavior and bear in mind and I'll elaborate on that everything changes behavior walking the sacred halls of the University of Chicago certainly does, I can tell you that but all these patients take different drugs video games, change behavior, etc. so we have to put this into the right perspective these are my disclosures just for the sake so there's nothing new about deep brain stimulation or any kind of neurosurgery there's this wonderful book some of you might have read this and the neurologist knew this since decades when the air hits the brain and the title of the book continues life is never going to be the same again it's the memoir of a Philadelphia neurosurgeon and that is true, any intervention we perform in the brain introducing a little pneumocephalus by a craniotomy will have some behavioral change the point is, do we change behavior where we actually harm the patient this is why I put this very fashionable book title next to it or is this a totally tolerable side effect and the other point about this book of course, do no harm is very easy if you don't do surgery you don't harm but you also have to be efficacious as well and that balance is the delicate one that we have to strike so to start back, deep brain stimulation was actually brought to clinical applications by the Grenoble group of neurosurgeons and neurologists who used it to treat one symptom of a disease which is tremor and they first started to target the thalamus then the globus pallidus and then the subthalamic nucleus and the reason for that was the old DeLonge model from Emory showing these circuits which actually, just to step ahead tells you already, as this is a circuit and each component is of course creating a network and contributing to a network if you manipulate one of them you will manipulate the others so you can see the circuit between the subthalamic nucleus, the thalamus and the globus pallidum and that is of course extremely important for motor coordination and you see the difference in a normal person versus a Parkinson person and the difference stems from the degeneration of the substantia nigra and the depletion of the dopamine stores but it tells you already there is a connection of these deep basal ganglia structures to the cortex at that point in time which was in 85-86 nobody thought that this would ever change behavior the ability of decision making including moral decisions etc because this was all subcortical and the idea was we are all very rational cortical human beings far from so I can tell you but so this is the idea and it then evolved through different randomized controlled trials from the thalamus being effective to the globus pallidus to the subthalamic nucleus being the most effective to treat tremor but also bradykinesia and the side effects of the dopaminergic medication which is adopa-induced dyskinesias so the subthalamic nucleus has really been crystallizing out as the most effective target interesting aspect of all of this is in all treatments neurosurgery has to offer deep brain stimulation is the only one that has pure evidence class 1 it's really in multiple international randomized controlled trials the only other disease that has class 1 evidence is epilepsy and that actually is limited to temporal lobectomy for temporal epilepsy that's where we have crystal clear data so it is very efficacious and we know it lasts the other problem was when this was started that you would have the same problem with deep brain stimulation like you would have with dopaminergic medication after years you would run out the effect would go down that's not the case even 20 years and we are now more than 20 years out in the European centers the effect on the motor symptoms is still there and it's actually not diminished but it is only treating the symptoms not treating the neurodegenerative process the substantia niga degenerates they're very good studies from the max plant group in Cologne on longitudinal studies on actually adopa-pet showing that the adopa-pet content goes down continuously in an almost linear fashion so we're not treating the neurodegenerative process we're treating the symptoms and we can do this I've talked about this very effectively but you have to be extremely precise and I'd like to look at this little 5 millimeter bar so this little structure the sub-thonomic nucleus that we are targeting has roughly the size of a squashed P very very deep inside the brain so you have to hit this with ultimate precision and actually it's not the STN we are stimulating that crystal clear from the study so far it's actually the dorsal third of the STN which is the motor part of the STN which leads up to the interesting question of behavioral change because there are also other parts particularly the anterior parts of the sub-thonomic nucleus which are intrinsically related to actually behavior and even decision analysis so this is where we put our electrodes and in order to do that you need, as I said, precision so the patient is totally immobilized in a stereotactic frame you have to use multiple image modalities MRI and CT and this is a fused hybrid image it looks very odd for those who know CTs and MRIs it's half CT, half MRI scan so we fused those images and then you can see the trajectories we designed and the blue actually is a digital atlas the Schaltenbrand atlas that shows the brain that is reformatted to the individual patient's brain and only if you have precisely targeted that area then we proceed with surgery so that's the technique we use in this day and age and this is all done in the patient completely awake because we are testing the patient which is interesting because you could also say with all these super precise imaging you have an imaging target you know exactly where to put this and you can do direct targeting and you can see the sub-thalamic nucleus or you can do indirect targeting just using the mantricular configuration of the patient but images can still be misleading we do this in an awake patient and test the patient so we see exactly when we hit these structures whether the tremor appears or doesn't appear and furthermore when that's just relying on clinical testing we use micro electrodes inserted micro electrodes which are so small you can basically not really see them with your naked eye which allow us to do single cell recordings so we record from these structures particularly from the sub-thalamic nucleus and from the thalamus from single cells and can identify the number we are putting actually micro electrodes in parallel down there the tremor cells so you can see a cell firing synchronous to the tremor of the patient and if you hit those cell populations that's really where you know your electrode has to go so this is treating very basic physiology not an image or not a volume but the actual area where the tremor is generated and that pertains to Parkinson's disease dystonia, MS-related tremor all kinds of movement disorders and then actually that's one of the advantages here at the University of China we actually still want to make absolutely sure that we are where we want to be we have an intro of CT scanner so we do a scan during the surgery and make sure that our electrodes are really where we calculated them to be so that's the whole procedure and if by now you haven't realized this is a day's job so this takes a whole day and it's very stressful for the patient because the patient has to be fully awake for the whole procedure for hours immobilized in a stereotactic frame where he can't move his head and on top of that we make it even more stressful for the patient number one the patient is not one of us it's a Parkinson's patient who has already ready kinesia is immobilized and to have a very clean slate to test the patient on we take them off all their medication which they need to control their movement disorder so they are off medication and if they have a lot of ready kinesia rigidity it's very uncomfortable for the patient they are very stiff and you have to operate as fast as you can but still get the answers you need to achieve the precise targeting so this is what you can do then we can do this very precisely and reproducibly we've done several hundred of these procedures but the question and that brings us back to the talk is what are we really doing we are of course stopping the tremor and that's for the medical students in the OR and even the residents that's the most fantastic thing you see the patient shaking wildly on the table to the point that's sometimes hard to insert precisely your electrodes and as soon as you turn it on and it takes about one, two volts through a tiny electrode the tremor stops immediately completely and the patient usually that's the first behavioral change you induce with DBS gets completely euphoric but then you turn it off and the tremor reappears within a second basically so that's nice and this is what everybody focused on in the late 80s, early 90s that we can stop tremors we can relieve pericinesia we can reduce the medication for these patients but are we not also doing this rewiring the brain because we are stimulating the subthalamic nucleus and by that with all the external connection we must have an effect on at least the supplementary motor area on other cortices etc plus other bisoganglia structure and actually the outflow of the subthalamic nucleus goes straight into the pallidome so that some people actually wanted to rename subthalamic nucleus stimulation in just doing a smart pallidotomy and the interesting thing is we were actually interested not so much in the behavioral aspects or the cognitive we were interested in the effects of deep brain stimulation on metabolism and physiology from a different angle from the angle of how can we predict the response to deep brain stimulation if we do intraoperative PET scans or CT scans and see how the patient metabolic re-response because 85% of the patients with a tremor respond fantastically with almost a complete abolition of the tremor but 15% and although you have super precise targeting do not really respond which might have to do with a couple of things either we didn't hit the right target or Parkinson's disease is not one disease for which the evidence is growing by the hour it is a variety of different diseases probably clearly with different molecular genetics underlying it and different phenotypes some people have tremor we have a lot of Parkinson's patients that have no tremor at all solely bradykinesia this must be a different disease et cetera so this was our angle when we started to study these patients in terms of effects generally on metabolism and physiology and this is one of the very early studies where we did FTG PETs and what you can see already and that shows you how naive the question is does it change behavior of course it does because it changes the network you get an overall this has been repeated by numerous investigators overall increase in glucose utilization if you stimulate the tiny area of the subthalamic nucleus and we are really talking about like 170,000 neurons out of a billion that we stimulate and can reach with the tiny electrodes we implant and the little current we give so we get an overall network effect which is quite dramatic and can be quantified very easily this then led us to a different study where we actually looked at Parkinson's patients treated with different types of interventions in the basal ganglia lesions like a paladotomy purely tremor related stimulations in the VIM ventral intermediate nucleus of the thalamus and the subthalamic nucleus and we did this under very rigid conditions off seven days post-surgery we repeated the study and we looked at dopamine transporter molecules, metabolism glucose utilization and blood flow and used the UPDRS rating scale still again under the idea that we could use this to predict and therefore stratify patients being good candidates for the brain stimulation versus alternative treatments and the interesting thing is what we found is that if you look at the responders and the effect of deep brain stimulation on the glucose utilization you see sort of a staircase phenomenon and these three bars signify three different things the red is pre-stimulation before we did any surgery the yellow one is which has been neglected in the literature for almost 10 years is the so-called micro subthalamotomy effect we didn't stimulate we just put the electrode in that creates a tiny micro lesion which already and a lot of patients stops the tremor in the OR immediately it does come back because the brain can compensate that and then the greenish bar is on top of that the stimulation turned on and you see this is not just in the thalamus not even only in the supplementary motor area also in the frontal cortex you see this metabolism and there's actually a recent study from last week from Günter Deuschel's group and Kiel was one of the pioneers of this who actually showed if you do not have this pattern which we see in responders they don't respond very well we've shown that but he actually looked at the cortical thickness of those parkens in patients and about 40 patients and predicted based on that which is a biomarker of the cortical integrity in these PDE patients that if your cortical integrity was impaired you would not have a good response so it's not as simple as people thought that it's just stopping the tremor cells in the STN you need to influence the whole network and the network needs to be in a shape to be influenced which is interesting and if you look at the non-responders non-responders means they didn't get a 50% improvement in the unified Parkinson's disease rating scale which is the UPDRS you see in the frontal cortex still sort of staircase phenomenon but it's much much milder and not the same thing in the SMA and the thalamus so these patients behave metabolically differently have a different response to deep brain stimulation which is quite interesting and then and there was a reason and there's a link to behavior and cognitive effects we looked at the actual really interesting thing because Parkinson's is a dopamine disease it's a dopamine depletion disease because of the degeneration of the substantia nigra and one of the theories was that actually stimulating the STN the outflow to the striatum and that's where the actual dopamine depletion becomes effective for the Parkinson's patient would sort of energize the striatum and get more dopamine there and a little bit of a simplistic approach but we wanted to look at this we did this quite some time ago with a marker which binds specifically a radioligin to the dopamine transporter protein in the striatum which wasn't available until four years ago in the US so we had to do this in Europe and this was our protocol and the interesting thing is that if you look at 12 hours everybody was studied off medication because I can modulate these images by the dopamine level in the brain easily so you have to have very rigid conditions 12 hours off medication you can see what happens it's almost like with the glucose utilization except the other way around you see just putting the electrode in without turning it on reduces the expression of the debt protein and then stimulation reduces it further and first we were actually a little bit puzzled what does it mean because if you have less dopamine expression dopamine transporter expression that's a although it's upregulated very quickly in the brain within a couple of hours that would be the opposite of what we want we want actually more dopamine but of course this is a ligand competing with the dopamine that's occurring so you see less binding if you actually have more dopamine coming in as well that's another explanation so we're still working on quantifying these data so I can't give you the definitive answer but the important thing is weird and that leads us to the interesting question if the brain stimulation can modify dopamine binding whatever the mechanism is dopamine is one of the most powerful drugs to change behavior and cognition as we know of course it will change behavior and this is actually the numerical data you can see pre electrode in and then stimulation a significant drop for the debt binding capacity so this is all nice and good and we know that we can modulate networks we can change this and does that actually change the patient's behavior, mood, decisional capacity, etc and the patient quite rightly comes at us you are putting electrodes into my brain allegedly very deep not in the cortex we're not in the cortex like an epilepsy patient but does that really make me a different person which is a very legitimate question but it's actually very very difficult to answer because it brings us back to very ancient philosophically what is the person and personality but that's the question we are usually faced with which is very interesting and I would like you to bear all these questions in mind because that's the patient's perspective and the doctors view this completely differently and one of the things is will I lose my free will and that's a very good question because one of the hallmarks the cognitive hallmarks of Parkinson's disease is impulse disorder a lot of these patients particularly in high doses of dopamine become very impulsive to the point that you have to stop them going to the casino every day and lose all their money which actually very it's not frequent but it happens at about 3 to 5% of patients which is a serious problem interestingly this is linked to the dopamine level and the dopamine medication you need but one of the effects of subsatomic nuclear stimulation is you can turn down their dopamine a couple of patients had no impulse disorder got STN implants they were turned on and then developed impulse disorder which is quite interesting and that's of course a major behavioral change so which leads to the question will I lose my free will a legitimate question we'll come to that but what you can also see is yes subthalamic nucleus deep brain stimulation does change things but these patients are already sick so they have a new generative process that is changing their personality to begin with they are on excessively high doses of dopamine which changes their personality dramatically so the other thing is and I have a lot of sympathy with that is that patients realize they completely rely on the impulse generator which is a battery implanted in their chest to run these deep brain stimulators so they will depend in their mobility but also in their ability to reduce their dopamine etc on a battery implanted in their chest and that battery is pretty sensitive if you have an MRI scan it turns it off and all of a sudden all your symptoms come back but you don't have the dopamine to cover it etc so a couple of patients are very afraid to become dependent on a battery very reasonable and the point is indeed when the battery drains which we try to prevent by checking them regularly and when we see that the battery comes to the end of its life we bring them in and change the battery but what happens if the battery drains and you are on a vacation in Hawaii we can't just get a new battery immediately that's a legitimate reason of fear and then the interesting question is and again there are some preliminary reports on patients already is continuous stimulation of the subthalamic nucleus not changing my brain the actual physical brain what we can tell you is exactly for some patients who unfortunately died for different reasons when the brain was examined about 3 months, 6 months even 18 months after deep brain stimulation you get a gliotic scar of course surrounding it and you get widespread in some patients we don't know which ones are the ones you get the gliosis surrounding this almost tumor like so you do change the actual anatomical environment in a very small way but you do do this so those are the patients perspectives rightly so the surgical neurologist sees this completely differently so actually the disease makes you already a different person I mean 90% of my patients have already a reactive depression if you have Parkinson's disease you cannot move you have this embarrassing tremor you can't go to a restaurant build your food, all that that already makes you a different person the disease per se and on top of that we put them on a gram of dopamine and more sometimes and that changes your personal behavior dramatically as well so the contribution of DBS might be almost negligible compared to what the disease does to your brain that's the doctor's perspective and interestingly the recent paper from the Grenoble group of all that actually looked in the population of artists they had in their Parkinson's patients painters predominantly and looked at their level of creativity and after deep brain stimulation their creativity went down and they couldn't really correlate this very well until they looked at the actual dopamine so the whole point is to take the dopamine-ergic medication down and a lot of these painters lost their creativity because their dopamine-ergic medication was taken away from them which led them to the slightly over-exaggerated thesis of creativity it's all dopamine take dopamine you'll become an artist not quite but anyway the question of the patient will I rely on the impulse generator will it change? Yeah, well you do but actually your brain doesn't work so the impulse generator just restores your normal brain function and what happens when the battery drains your disease will take over and of course we are talking about a brain disease and it's not as particular as of course not just the disease of the substantia nigra there are other systems involved as well so we would actually wish if we could change your brain with the deep brain stimulation because it needs change because it is actually literally dying in front of you and the symptoms are proof of that so very different perspective from the patient's perspective and that has to be born in mind so and then you can take the hardcore view I love that so this brings me back to my original remark you can change this dramatically your level of certain and dopamine and you can change it by the environment you put people in Sacred Halls of University of Chicago watch violent movies all of these changes things so whatever you do will change the question is to what extent and how is this seen in the overarching view of the disease you are suffering from and what are you buying so and the interesting thing is as I said the disease itself changes the brain so dramatically this is from one of David Adelbert's from New York famous papers which follow along the lines that he wanted to establish with finding patients with a specific disease pattern which allows us to determine that they will respond to the brain stimulation and he found in Parkinson's patients two different metabolic patterns you can see if you have an optimal response and this is to pallidotomy actually the pallidom is hyperactive over using glucose and that's causing actually the symptoms the same patient clinically phenotypically the same patient but not an overactive pallidom you can do pallidotomy and you don't have a big effect on the movement so patients are already neurologically and neurophysiologically different which is very important to bear in mind then of course the neuropsychologists kicked in because by then in 2005 and from then on so in the last years we had so many patients upgraded that we created a wonderful population to study and this is one of the first case reports published in JNMP of all journals where they found to be able to induce manic behavior immediately when they turned on the deep brain stimulator and actually the first response of the neurosurgical community was well you probably put it in the wrong place actually they didn't it is exactly in the right place and you got a little bit of substantia nigra stimulation which you inevitably have to get we are talking about a millimeter or two distance between the sub-thonomic and the sub-thonomic nigra actually we deliver it over with our microelectrode into the substantia nigra to find the specific and know exactly where it physiologically is so that came a little bit as a shocking surprise that you can change behavior the big problem is it is very very difficult to disentangle behavioral changes induced by deep brain stimulation unless you look at immediate changes because if you look at a patient test neuropsychologically before deep brain stimulation and then three months later with the stimulation on you don't know what you're looking at because by then you have changed the medication dramatically and that it has a big impact on behavioral aspects you have changed the symptoms and the patient becomes euphoric because of that patient become mobile more outgoing etc so you can only really in a clean experimental setting look at changes almost interoperatively and that is a totally artificial situation you have a patient whose off medication head is fixed in the frame we don't know whether this really has anything to do with real life changes and then we've talked about that already hold your horses so it's very interesting if you look at impulsivity and deep brain stimulation because it is so closely linked to the dopamine levels so unless you have a very clean experimental paradigm where you keep your dopamine stable or test them in the off you don't really know what you're doing but clearly there are cases which have been reported to induce impulsivity with constant dopaminergic medication by deep brain stimulation and to be fair we have no metabolic, physiological or molecular marker to identify these patients upfront there's a tragic component to that as well and that is that you can also increase negative impulsivity in these patients and these patients as I said are reactively clinically depressed a lot of them because of their symptoms and there have been reports that have shown that after deep brain stimulation patients became suicidal and some actually unfortunately did commit suicide so that is something you have to bear in mind in order of course to reduce that risk as much as we can but deep brain stimulation has to undergo neuropsychological testing and actually depression on the test scores is a contraindication of deep brain stimulation because you could potentially kick them over the edge so no doubt we can change behavior whether that relates to change in personality is a different aspect and I'll come to that in a second interestingly this is a wonderful paper not the highest impact factor general I agree ethical safety of deep brain stimulation and they did a study on moral decision making in Parkinson's disease so they actually countered them with moral paradigms and it doesn't change the moral coordinate system so I'm almost intended to say you cannot convert the general Trump supporter to a Hillary Clinton supporter with that although some would wish but it doesn't really seem to change the deeply ingrained moral opinions people have but that's a different thing from changing behavior being more impulsive more outgoing things like that so the next question is sorry as you see we're now switching from the adult Parkinson's patient to the pediatric population and I'm doing this because we're talking about personality change the again very well evidence based studies showing that pediatric patients with generalized dystonia which is a dreadful disease and it usually doesn't occur isolated but in combination with cerebral palsy and dystonia and either the palsy or the dystonia can be the predominant feature but these patients basically respond very very poorly if at all to any medication but again pioneered by the group in Montpellier from France if you early on implant deep brain stimulus in the pallidum you can dramatically improve these patients and it's actually from this paper and the pharma, dystonia rating scale can come down in the lower your value the better is the patient all but this is something in a developing juvenile brain we're implanting the brain stimulators and how that relates to cognitive development we have no idea there's no data and certainly it's not done for such a long period that we know how these patients are and how different they could be from adults deep brain stimulation versus not treated patients but then again how do you want to disentangle that if you don't treat the patient or give them best medical treatment as the control group these patients will cognitive changes based on their dreadful dystonia so again it's the price you're willing to pay for symptom improvement but it's dramatic these patients and the big fight we have we're one of the very few centers in the US that do pediatric dystonia treatment because you have to have a pediatric neurosurgeon as well and unfortunately I was forced to become one and take the training to do that so we're doing this here but the earlier you intervene the better is the outcome that is pretty sure but the FDA allows us only to treat patients 7 years and older which and a lot of these patients is at a stage where the dystonia has progressed so far that it's very very hard to revert that and this is actually showing you how we do this and this again shows you this is a prospective control trial this was published in 2009 Lancet Neurology again just to corroborate my point this is not just neurosurgeons trying something this is real class 1 evidence finally I'd like to focus a little bit on the areas of deep brain stimulation where we really want to change behavior which has the wonderful title psychosurgery which has a very bad reputation for very good reasons because it was abused brutally all over the world predominantly in the UK with leucotomies etc so we stayed away for decades from psychosurgery but that was of course the other extreme it is very clear that non-refractory depression which means you have failed all drugs all psychotherapy and you have also failed electroconvulsive therapy there is nothing left for you is still a disease that is very malignant a lot of these patients successfully commit suicide so the idea to study this disease and find potentially a target to intervene not an ablative target but a modulation target for deep brain stimulation was intriguing and a Canadian neurologist Helen Mayberg who was in Toronto now at Emory actually studied these patients very thoroughly with functional imaging and found that in this area there subgeniculate CG-25 these people with refractory depression fulfilling those criteria had hyperactive CG-25 areas so there was a biological target for deep brain stimulation which of course neurosurgeons who think in images and targets they jumped on and said fine we can target that, that's no big deal and see what happens and so there was a biological rationale to do this but as I said psychosurgery has a very bad reputation and it's very interesting because when the neurosurgeons and the I call them the Mayberg scholars jumped on this they were warned by some psychiatrists but depression is such a complex disease to reduce this to a pea-sized CG-25 target is a terrible simplification number one number two depression is probably not one disease even if you take this subgroup of completely refractory patients so you're oversimplifying on the other hand these patients were mostly suicidal you have nothing else and deep brain stimulation that's something I should mention as well has an extremely low morbidity mortality profile so then this went further you can throw very expensive things at these patients which unfortunately we can't do at the University of Chicago 015 PET but once we have the cyclotron we can do this you can look at the metabolic and blood flow activation and look at the connectivity with these techniques very nicely the reason why most people use PET instead of MRI once you have the electrodes in you cannot do MRI scans properly number one you're changing the impulse generator but number two you get artifacts from these electrodes which if you want to measure things very close to this it gets difficult we'll get around this hopefully very soon because we've now developed some techniques to actually mathematically take this artifact away so this then went further and the next thing that was sort of the response to the psychiatrist's critique of stimulating a small area is no no no no we actually stimulate networks we just take sort of points where all these fibers which we can nicely see on the MRI scan this is diffuse and tensor imaging come together so the big grand central station that's where we put the electrodes and then influence networks great idea but of course it's you don't know what the networks effects are and the other thing is this is a DTI image I can change the color of this with a switch of a button and this is a theoretically statistically derived image that is not really the representation of the fibers and we recently had Ron Kikini here from The Brigham with whom we work now who has shown very nicely depending on what algorithm you use you can change this dramatically so has to be seen critically as well and then people went ahead and did a trial to put the brain stimulators into the CG-25 and if you see this the medical therapy, whether it's neurostimulation and you look at the PDQ-94 score and other things wonderful effect these very very sick patients had a significant response to the D-brain stimulation but this was a non-randomized uncontrolled trial that's important to bear in mind and the quality of life increased published in the American Journal of Psychiatry and this then of course got the people with money interested the companies because we are talking about millions of patients with refractory depression in the US way more important than the few 100,000 patients with brain tumors or aneurysms this is a giant population and then metronic and the people that make these stimulators got interested and said this is what we want this is a huge profit source and then they did a phase 3 randomized controlled trial which was actually then to go right to the bottom stopped by the FDA so in a randomized controlled setting reproducing exactly the same surgery that was done in the uncontrolled trial there was no effect basically so the concept was too simple the problem with this is that actually the one of the editors of the stereotactic journal of the American Society of Stereotactic Functional Journal is we had to write a letter to the NIH because these things then kill the field for a decade it does all this really means is that CG 25 is an oversimplified approach and that might not be the right target but what the NIH of course concluded is depression is nonsense doesn't work so if you want to do more research it's kind of very very hard so we had to rectify this a little bit that I think to revisit this in a very clear and scientific fashion and not jump to things because metronic wants to make money so and for another disease where actually the brain stimulation is effective and is actually FDA approved we still do an NIH trial on this is OCD and this we would propose is the way to go forward the trial is almost finished now and the reason why we actually did not participate in the depression trial were the ones I mentioned I think that from the psychiatry community OCD is a very different disease it is a very circumscribed behavioral disease to the point that if you watch these very very sick patients it is actually a continuous spectrum of parts of Gio de la Tourette syndrome where you almost wonder whether this is a real psychiatric disease or basal ganglia disease so bridging movement is always anyway it's a very circumscribed disease we were very lucky to recruit John Grant from Minnesota who is an OCD expert to work with us here and so this is what we're doing right now we actually implant these patients and then we do sham DBS active DBS we look with FDG pads at the network activation and see what the effects really are and I think for any kind of psychosurgery to jump to non-controlled trials is not the right way we prefer to do it this way and actually this is what we do coming back to the Grand Central Station we're not looking at just one tiny little target we use wide spaced electrodes go to the ventral striatum and then we have these four contacts and we can stimulate monopolar bipolar can differentially activate large areas and hopefully by that large networks the other thing with all these approaches looking at functional MRI which again we're looking at a 2-3% statistical signal with functional MRI over the baseline which is the bold effect we don't even know whether it's over activation or under activation we're looking at etc so we don't know this so this is for example a patient with a left hand tremor and tremor is a nice symptom you can objectively diagnose it you can do accelerometry and quantify it get alphanumeric data we don't really know so you see over and under activation and actually you see in the frontal cortex so we are stimulating the STN and stop just the tremor cells maybe we should stop target the left frontal cortex and actually transcrinial magnetic stimulation there are some very good trials showing that if you do this which you can do on a daily basis in Parkinson's patients you can make them asymptomatic almost take the bradykinesia away just stimulate the motor cortex done it basically so we're not really knowing what biologically we're really targeting here and the other thing is a lot of people now are totally focused and there's another depression trial going on in Europe to stimulate the medial forebrain bundle unfortunately at my old institution and Fiber people completely rely on DTI images and use this to target and stimulate fiber tracks although these are statistically derived images of fiber tracks and we don't know how accurate they are so whether you stimulate function or anatomy is again one of the critical questions and then even if we would have the right target or the right fiber track or the right network then and we've shown this even very simple Parkinson's patients with Tau Z from our group then you can change the parameters high frequency versus low frequency stimulation we don't know which one is better yet so there's a lot to be done in that area and we have no idea how low frequency versus high frequency changes behavioral changes, network activation etc and then of course I apologize for the German Scribbings but this is I got this from the Lightness Institute then of course we are still talking about the past the future is we will now have 7 Tesla 9.4 Tesla MR images which will show us things so this is the peripedunculine nucleus the brainstem nucleus which you cannot see on any of our regular MRI but you can see it nicely on these 7 Tesla you can actually see each small little arterioles and vanuels going into the brainstem so you get a precision imaging which is unbelievable and then the other thing is we have been talking all the time about 1 or maybe 2 bilateral deep brain implants you can put multiple electrodes and stimulate simultaneously multiple networks we have no idea how this works interestingly this is the spatial resolution for DTI images these little spaghetti fibers you can almost go down to single fiber levels with these super high Tesla MRI scanners and then modulate where you put your electrodes so you can then selectively stimulate fibers and if you know where the fibers go and what they activate you have a much much better grip on what you're really doing so that's part of the future and then you can model exactly where your current goes what volume you activate and then correlate that to the behavioral changes to the symptomatic changes you want to induce and that is the only way to really strike the balance between symptom improvement which you want and at least behavioral mood decision or capacity change you will induce as a side effect of your treatment so deep brain simulation and neuroethics from all we know from the evidence we have so far it really doesn't change your biographical personality and your moral or judgmental capacity but it certainly can change your behavior and your mood but the important thing is risk benefit so does the disease I mean Parkinson's patients are severely cognitively changed as well as a matter of fact as I said it's not a disease of the substantial nigra a lot of Parkinson's patients also have dementia and will develop this later in the course of the disease on top of that and this is Parkinson's, Huntington's, dystonia all these patients are on medications with a lot of psychotropic side effects and the other thing is this concept we think with our cortex we are all rational we make decisions and this is what distinguishes us from other mammals actually some interesting studies and that outside of behavior have actually recorded from the substantial nigra and the subthalamic nucleus in patients with essential tremor who don't have any real neurodegeneration whilst they were asked to make economic decisions buying stocks for example selling stocks and you would be amazed what neuronal patterns you see from the substantial nigra and the STN how that influences the decision making which partly explains the walled street crash but anyway so we are limbic people and if the frontal cortex does anything it probably modulates and controls our limbic system a little bit but a lot of decisions are totally subcortical so we're not as cortical as we think and when we think it's mostly subcortical but that has to be born in mind so I didn't give you an answer whether it changes behavior I mean it does deep brain stimulation changes behavior it changes mood can make you more aggressive, more impulsive any of this but so does the disease so does our medical treatment and it has to be weight and that's the important thing and this is a wonderful book from who was the chairman of psychology here for a decade or so and he's now the director of the Max Planck Institute of Psychology in Berlin and I think this is and that doesn't only apply to DBS it applies to all kinds of medical decisions is really we have to weigh and first assess and quantify the risk that is associated with any procedure and then inform the patient and the best is not to give him probabilities most doctors don't even understand probabilities but to give them real number scenarios one in a thousand that's something people can get much better so that's I think where we stand right now and of course when we do psychosurgery psychiatrists think we are crazy when we do psychosurgery neurosurgeons think psychiatrists are a little bit loopy anyway so it depends on where you come from which angle you use which is very important to bear in mind as well but one thing is for sure functional neurosurgery is going to move dramatically and this is actually a Lancet paper from 1998 so in the past we've been dealing with brain tumors and aneurysms these are butterfly diseases on the spectrum of real healthcare problems we have so the incidence of brain tumors is 7 per 100,000 and for aneurysms it's around the same whether we stop treating brain tumors or not will not change the life expectancy of the American population for example diabetes, lung cancer diseases we're a very small exotic group but if we start looking at neurodegenerative diseases stroke, trauma, neuromodulation and the big stuff we're talking about long unit different paper populations and this is where we are moving now we have worldwide more than 300,000 patients with deep brain stimulators running around and we now have implanted the first electrodes loop epilepsy systems where we put electrodes into the epileptic focus connected to a mini PC in the skull that records automatically the EEG and once it finds an interrectoral pattern that predicts a seizure then starts a stimulation to stop the seizure so this is coming we have when I came in 2010 there was zero DBS and now we are doing 60 to 70 a year and every year we increase our volume by 40-50% so it's a big paradigm change in neurosurgery but the important thing is last excel who invented the gamma knife in one of the stereotactic frames these things can also be abused and if you don't know what you're doing you can have the most sophisticated 7 tesla MRI scanner you can do a lot of harm of course and I think this is the summary it's all about risk and benefit and you need to have the informed consented patient but it's not DBS only treats motor symptoms or it completely changes your personality none of that to a varying degree probably different in each patient thank you that's about if you follow the literature it's about 1 in 100 so roughly 1% and the whole effort we do is to try to pick these patients up front to tell them that this could happen etc test them with neuropsychological tests to see is there already a hint of personality disorder that will lead up to that so we want to exclude those patients but it's about 1% but of course there is probably a little bit higher because there are patients who deliberately come because of my gray hair and say I don't want deep brain simulation but I want the old procedure we did functional neurosurgery way before deep brain simulation which is a lesion you can lesion the thalamus and make the tremor go away to the contralateral side the problem is you can only do it unilaterally so the patient will have symptoms on the other side there are some patients who actually are willing to have the tremor remaining on the non-dominant side in order to avoid deep brain simulation thank you to answer the first but I couldn't agree more there is a conflict of interest and as you might know actually the group that advocated CG25 actually and I have no idea how this was possible certainly in Europe wouldn't be patented that as a target so you cannot do it unless you pay fees royalties to that group they found it actually a company to do that I think that's the biggest conflict of interest I could imagine and the other thing is of course I didn't touch on this until this year we had a major problem that is one single company in the US that actually makes deep brain simulators which is metronic so it's a complete monopoly it's changing now because St. Jude's and Boston Scientific have systems as well which hopefully evade things better but if you look at the papers on deep brain simulation 90% and more if you look at the conflict of interest show partly sponsored by metronic etc except for the big RCT's which strangely were run in Europe but that's because it was developed in Europe there's no company involved in there they're all published in New England Journal etc but I see this is a big conflict the only thing to do is it takes a lot of effort to do this non-company sponsored this is why we insisted the OCD trial is totally company independent NIH sponsored and you can only do it as an RCT particularly in psychiatric disease which is open to that many interpretations company involvement is a no-go and you have to use public money and the second part of the question was whether it's being done in depression we're not doing any depression trials we're trying to form a consortium plus right now CG25 is a dead target I think we have to look at different things one of the things is actually I think looking at fMRI a little bit too simplistic we need more electrophysiological information so one of the things is MEG for example but an OCD has been FDA approved OCD is approved actually not only for deep brain stimulation but also for lesioning in the internal capsule in the ventral straight and gamma knife radiofrequency because that has been shown also in prospective control as being effective thank you so how often is cooperation in the capacity of the patient a barrier to having surgery since they have to participate as an individual for me as a neurosurgeon rarely because I exclude all these patients so if the patient is cognitively impaired or even demented with a significant proportion of Parkinson's patients they are excluded from surgery I need a fully cooperative patient because what we do is we test the patient during the surgery clinically so he has to perform task movement, task cognitive tasks etc so I think those are all filtered out already but I would easily guess from our movement disorder board meetings that we have that 25% of patients are not candidates just because of that yeah who is telling me about it that was wonderful I wonder what percentage of patients are studying therapy for instance yeah, Parkinson's patients are we have our own MJ Fox funded trial but that pertains only to midline symptoms it's a small subgroup so 90% are just clinical indications for psychosurgery everybody is on a study I have a follow-up question about treatment and depression yeah so the first aspect so patients with Parkinson's who really don't have a good symptomatic relief that's a very very small that's about 10% it's not that they have no effect but we consider effective at least a 50% improvement on the trimer rating scale etc the interesting thing is we can still reduce their dopamine medication a lot of the side effects from dopamine trouble the patients so it's very rare that they get more depressed after the surgery even if we don't get the effect we want to see number one, number two because we can reduce the dopaminergic medication we can then put them on other medications which in combination wouldn't have been possible and then did you say it's no longer you the the actual morbidity is infection which in the national average is about 6-8% because actually it's not so much infection in the brain it's infection of the hardware the big batteries etc to remove those is extremely easy it's not risky at all yeah even in the brain just follow up that question one of the differences between deep brain stimulation and the much condemned psychosurgery in the past seems to be the reversibility of this that you can extract the wire you can turn off the current you can go back to the well I guess my question is can you go back to the prior state having tried the deep brain stimulation is it the same state or is it different no you can go back and actually that's the ultimate thing if the patient coming back to your question really has no good effect gets depressed you don't even have to remove the wires you just turn the system off leave everything don't no more surgeries involved you can do this remotely turn it off and the patient will go back to his pre-state no further questions I want to thank you so much Peter my pleasure