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Part 2: Selected Presentations from Brain Stimulation for Movement Disorders, OCD, and Epilepsy
Drs. R. Mark Richardson, Robert Hudak, Robert Howland, and Alexandra Popescu each present from Brain Stimulation for Movement Disorders, OCD, and Epilepsy Symposium.
Upon completion of this activity, participants should be able to:
- Discuss diagnosis, epidemiology, and use of DBS for OCDReview the usage of DBS for the treatment of depression
- Describe the use of neurostimulation in the treatment of epilepsy
- Discuss the future of DBS, including ongoing research
- Dougherty DD, Baer L, Cosgrove GR, Cassem EH, Price BH, Nierenberg AA, Jenike MA, Rauch SL. Prospective long-term follow-up of 44 patients who received cingulotomy for treatment-refractory obsessive-compulsive disorder. Am J Psychiatry 2002; 159:269-275.
- McGrath PJ et al. AmJ Psych. 2006;163:1531-1541.
- Trivedi MH et al. N Engl J Med. 2006;354:1243-1252.
- Morris GL III and Mueller WM. Neurology. 1999;53:1731-1735.
- Husain MM, et al. Ann Gen Psychiatry. 2005;4:16.
- Suthana N, et. al. Memory Enhancement and Deep Brain Stimulation of the Entorhinal Area. NEJM 2012;366;502-10.
Drs. Richardson, Hudak, and Popescu have reported no relevant relationships with proprietary entities producing health care goods or services.
Dr. Howland has financial interests with the following proprietary entity or entities producing health care goods or services as indicated below:
- Grant/Research Support: Cyberonics, Medtronic,NeoSync, Shire
The University of Pittsburgh School of Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.
The University of Pittsburgh School of Medicine designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credits™. Each physician should only claim credit commensurate with the extent of their participation in the activity. Other health care professionals are awarded (0.15) continuing education units (CEU) which are equivalent to 1.5 contact hour.
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Release Date: 6/10/2015 | Last Modified On: 6/10/2015 | Expires: 6/10/2016
Transcript - Hudak
As Dr. Richardson said my name is Bob Hudak and I'm the Medical Director of the OCD-IOP and I want to go over today some of the research that is behind OCD and deep brain stimulation.
Okay, so first off today I want to give you some background about OCD and how we came to use DBS in OCD. First off OCD is a little bit of an interesting diagnosis in psychiatry in that it's a dimensional and not a categorical diagnosis. And by that I mean that most of the diagnoses we make in psychiatry are categorical such as major depression, most people here know that to meet the criteria for that you have to meet 5 out of 9 criteria. You know you have 9 symptoms and once you meet 5 you have a diagnosis.
Now OCD is not that way, OCD is a dimensional category, which means that basically we sit and interview you and decide you either have it or you don't. And you are somewhere along that dimension. And as a result on one hand it makes OCD one of the easiest diagnoses to make in psychiatry because you simply have to have either obsessions or compulsions, and that's it. And if you have obsessions or compulsions and they are recognized by the patient as excessive and if they cause some marked distress with the person you are diagnosed with OCD and that's pretty much it.
DSM-IV and DSM-5, by the way DSM-III did not do this, but DSM-IV and 5 does say you can have either obsessions or compulsions, I will tell you that in clinical practice virtually everybody has either - has both obsessions and compulsions I should say. I don't know that I've ever seen anybody that's had obsessions only without compulsions or compulsions only with obsessions. There are a large group of patients on the internet, they talk about having pure obsessions, they call themselves pure O, they are kind of an internet subcategory of people. I've seen many people who have considered themselves to be pure O and again they almost always have compulsions associated with their obsessions.
Okay, so what is an obsession? And while OCD is technically an easy diagnosis to make it's confusing for a lot of medical professionals and even - excuse me, and for a lot of mental health professionals because of language issues actually and you know what is an obsession. I have a lot of pet peeves, I have a current list going, I think I'm up to 528. I added a new one in the last 2 weeks, so I was at 527, I'm at 528 now. If you've been watching ESPN at all over the last 2 to 3 weeks they've been talking about football being the national obsession. What they say is well if baseball is the national pass time football is the national obsession. That just sets my teeth on edge because of course football is not an obsession, it's not a national obsession. It may be a national preoccupation or a national fixation, but an obsession it is not. So an obsession is very different than a preoccupation or a fixation because obsessions are recurrent and persistent unwanted thoughts, urges or images that are inappropriate. So what is an obsession, obsession is something that actually people don't like. It's a thought that makes them feel very uncomfortable. So by definition football would never be an obsession because people like watching football.
Sometimes people mix up obsessions and addictions or compulsions and addictions because they think that the need to use a drug over and over again is a compulsion. It is not a compulsion because again there is nothing recurrent or persistent unwanted, there is no unwanted nature about that thought. So that's just a brief what an obsession is and the obsession is not a worry that the person has, so the obsession is different than an average worry. So if you worry about something all the time that's very different than what an obsession is. And this actually comes into play later on when I show you some functional MRI research that's been done. Obsessions feel as if they are imposed on from without, they almost feel alien in some way, but the person recognizes it's coming from their own mind and there is always an attempt to try and suppress the thought in some way.
So a compulsion is just simply the repetitive behavior, a mental act that the person must perform. So when a person gets an obsession they attempt to suppress that obsession in some way, and the way it's suppressed is with a compulsion. And it's important to note that the compulsion and the obsession do not always match each other. So for example someone may have an obsession about germs and may think that their hands are not clean. And most of you here might say okay well then their compulsion must be that they are going to wash their hands, and that's not always the case. Their compulsion may be if they feel their hands are dirty that they will pray the germs away off their hand, perhaps they'll chant, they'll just there and say I am clean, I am clean, I am clean to get rid of the germs, okay. So the compulsion and the obsession do not always match. And in the short term the compulsion makes them feel better, of course the catch is that the compulsion always comes back and it comes back even worse. The obsession comes back even worse, I'm sorry.
So OCD was originally thought to be a very rare diagnosis, now we know it affects about 1 in 40 people and it's equally common in adult males as it is in adult females. It's a little more common in the pediatric population in males actually, but by the time they get to adulthood the rates are normal and that's one way that OCD is very different than any other, than other psychiatric disorders is that most psychiatric disorders seem to favor females, this one is equal.
One of the important things about OCD is that even with adequate medication and cognitive behavioral treatment many patients are treatment resistant and the treatment resistance rate in OCD is incredibly high. We don't have a real consistent definition of what treatment resistance is in OCD unfortunately, but depending on how you want to calculate it maybe 40% of people with OCD do not respond to convention treatments. So what do we do at that point? We need to do something additional and some very aggressive treatments are often needed. This can be a very debilitating illness and it's one of the most debilitating conditions in the world. The World Health Organization actually ranks OCD as one of the top 10 to 20 reasons for chronic disability in the world, and that's not psychiatric disability, that's all medical disability. So again this is a very severe illness.
Just to give you an idea of what the typical flow chart would do, a typical algorithm for treatment. What we do with people with OCD if they are mild we usually give them cognitive behavioral therapy, we don't even bother with medications with mild people. If they are more moderate to severe we try SSRIs. And as I said a number of people, maybe up to 40% of people, will not get a response and what we do is we put them on a second SSRI. We will switch one for another. If that doesn't work what we consider is augmentation with Clomipramine, and if Clomipramine does not work we'll try to go fully with Clomipramine, we will take them off the SSRIs altogether and use only Clomipramine. And then again if none of this works we consider augmentation, and with augmentation we have medications like antipsychotics or Memantine, which is also known by the trade name of Namenda. It doesn't work real well with dementia which is what it's approved for but works much better for OCD than it does for dementia. And again if that doesn't work we consider trying different antipsychotics. There are other medications to try such as Ondansetron which is an antinausea medication called Zofran. And again if there is no response to that there is other agents we try as well. There is other second line agents, second line antipsychotics, there is a whole raft of other antipsychotics and treatments that we may try.. Suppose all of this is tried and none of this works what do we do? Well then we go to treatment refractory patients and then we try the more experimental treatments such as neurosurgery at that point.
Now once upon a time there was a secret cabal of psychiatrists and neurologists and they all got together in a room somewhere and they said okay just kind of arbitrarily said psychiatrists you take these illnesses, and neurologists you take these illnesses over here and we'll pretend like they are completely different. As someone said in the back earlier in the morning session talked about depression having an organic cause and we know that many of these psychiatric illnesses do have a medical cause to them. And what is important about OCD is that OCD probably has the most well defined neurological basis of all the psychiatric illnesses. And I think if that secret cabal of psychiatrists were to meet again today neurologists could actually make a good case that no, we are going to take OCD away from all of you shrinks here and we are going to treat it ourselves because this is really a neurological condition.
So there are some implicated regions in OCD, we have the orbitofrontal cortex, the anterior cingulate cortex and the caudate nucleus. There have been neutral state studies, hyperactivity at baseline. So in other words you put someone with OCD in a PET scan or an FMRI scanner and these areas of the brain right here are more active than they are with someone without OCD at rest. And what they've done is pre and post-treatment studies, they are attenuated with treatment. So in other words when you treat someone with OCD the hyperactivity in these areas goes away. This actually was a big deal. I was a resident when the studies were first published in UCLA that showed that therapy and I mean cognitive behavioral therapy had the same neurochemical changes that SSRIs did in the brain. And that was a big deal at the time. That was the first time that anyone ever showed that therapy could do the same thing as medications in treating neurological biochemical changes.
And then later on what they followed this up with some symptom provocation studies and this is a little bit of some of the cruelty that researchers often have. My wife is a researcher so I don't like to make fun of them, but so what they did is - what they would take OCD patients and they would put them in the scanner, take a look at their brain and they'd say okay now we want you to worry about your marriage, worry about your job. And guess what, those regions of the brain don't light up. And then they would, and then they would try to symptom provoke their OCD and usually what they'd do is give them a dirty rag. So then they are in the MRI scanner and they throw in a dirty rag. One thing that will bother an OCD patient virtually more than anything else is a dirty rag. So give them a dirty rag and those areas of the brain light up. So just normal worry doesn't do it but an actual obsession does. And one of the nice things about these studies where people really acted as their own controls then at that point.
And so what areas of the brain were lighting up? Right here, see the orbitofrontal cortex and you know the caudate, thalamus, globus pallidus right here. So these and this was the - it's called the frontostriatal thalamo-frontal loop and this loop is the proposed circuit that is underlying OCD. I'm a little bit more of a schematic kind of guy so here this is in more anatomical but still schematic version, so the orbitofrontal cortex and then the thalamus and the caudate nucleus and what I'm most comfortable with is fully schematic drawings. Okay, so with this drawing here really illustrates is the loops that we hypothesize right now are affective with OCD and what the DBS target is.
So right her we have the orbitofrontal cortex and the thalamus and the striatum and what is really thought to be going on is that the cortical thalamic loop right here seems to be hyperactive in people with OCD and/or this loop right here between the orbitofrontal cortex, the striatum and the thalamus, this loop is underactive. And this is actually an inhibitory loop so when this loop here is active it damps down that part of the equation there. So you either have this is too hyperactive or this isn't active enough, maybe a little bit of both. And what the DPS target is, the DBS target is right here in this part of the loop to try and calm down the hyperactivity in this part of the brain.
Early on ablative limbic system surgeries were typically used for OCD in the most treatment resistant of cases. Okay, so what are the criteria? I'm going to go over the criteria for OCD neurosurgery and this includes both ablative surgery as well as DBS. So what we have to do before we do surgery with someone we have to do three adequate trials of SSRIs. One of the trials has to be of Clomipramine, you had to have tried augmentation with both an antipsychotic and a benzodiazepine. I think I know that I've gotten away form that, I don't consider that really to be a criteria. I think it's still officially centers use it but there isn't any evidence to show that benzodiazepines do anything for augmentation. Augmentation with a glutamatergic agent such Namenda, and they also have to have an adequate trial of exposure with response prevention, that is the therapy that and the only therapy that's been scientifically shown evidence based to work for OCD. And they have to have a YBOCS of 28. The YBOCS is a scale to measure the severity of OCD, it goes from 0 to 40 and so you have to have a 28 or above, and that's considered to be a very severe level of OCD. Another statement to make about YBOCS is that people with the YBOCS it is not a - it's not a diagnostic study, it is something only used to measure the severity of OCD, so in other words it's not like - there is no minimum criteria for OCD to have a YBOCS. in other words if you have a YBOCS of 0 or 1 that doesn't mean you don't have OCD. That isn't the way it works. All right.
So I just wanted to briefly show you some of the targets that have been looked at for neurosurgery in OCD and ablative surgery. And anterior capsulotomy, that's right here, the anterior cingulotomy and the subcaudate tractotomy and these are three surgeries that have been. These surgeries were don either with thermo-capsulotomy where they put the electrode in the brain and essentially heat it up to kill the brain cells, or now what's commonly used is gamma knife surgery which involves radiation, they don't even need to cut the brain open. And again this is a more representational, the cingulotomy, capsulotomy and subcaudate tractotomy. One of the most common surgeries that is performed nowadays when they do do this is a surgery called the limbic leucotomy and the limbic leucotomy is just a cingulotomy plus a subcaudate tractotomy, and I have a neurosurgeon here in the front row looking at me if I get it wrong he's going to yell at me and I'm not seeing any dirty looks on his face so I assume I got it right. And I just wanted to throw up some more pictures here, and these are pictures of what an MRI of the brain after you have an anterior cingulotomy. And this is the sagittal section. Okay.
So effectiveness of cingulotomy for OCD and they took a look at 44 patients and they had 32% responders and 14% partial. And the mean improvement in their YBOCS is 28% with minimal adverse effects. This was published in 2002. That mean improvement in YBOCS of 28% is important because if you figure that someone has a YBOCS let's say of 35, a 28% improvement is an improvement of maybe 8 to 10 points. At that point they still have a YBOCS of 15, 16, 17 so even with fairly robust improvement a YBOCS of 15, 16 or 17 is severe enough to land you as moderate OCD and enough to land you into most research studies. Just to let you know that even though these treatments work patients are still left with a fairly robust and clinical amount of illness. However it's interesting that people with OCD can often - will say that even with that 25 to 30% drop they really get a significant difference with their quality of life, they really can do a lot that they couldn't do before in spite of the fact that they sill have fairly significant levels of illness.
Okay, so I'm going to talk about some of the deep brain stimulation data. And this is just a nice picture I've thrown so people know what the - what it looks like. And I threw in this picture here as well which just shows you from pictures this is from the 2006 study which I'll be referring to and these are patients and these are what MRI - their MRI scans look like with the electrodes in place. And you don't need to be a radiologist to be able to determine hey here are the electrodes.
So deep brain stimulation for OCD was first used in 1999 and obviously I think that the reason for using it was because unlike ablative limbic surgery you can actually do DBS without killing brain cells and I think that's why it was originally tried. The original target was the anterior limb of the internal capsule and now they use the ventral capsule, ventral striatum. This was after a 2006 study which demonstrated greater improvements when they moved the site more posterior. So it's interesting in the review studies what they show is that one of the positive factors for improvement with OCD DBS is that you had your surgery later rather than earlier on in the case series because our siting is improved since then. There is a large multicenter trial underway that is double blind and includes sham control to determine the efficacy of DBS. And the trial is still ongoing and they are actually still recruiting patients at this point. And as I said here originally the anterior location was based on internal capsulotomy lesions and they started using more posterior sites and right now they are at the VCV, VC/VS.
So let me talk about one of the early studies. This was 10 subjects from Mass General Grown and the Cleveland Clinic Foundation. If you take a look at the original study my - I have a patient who is Cleveland Clinic No. 5 on the study. I still see him for follow-up every few months and he doesn’t have a neurosurgeon, actually we'll contact you because he - we will need to meet with him together at some point. So they used the same inclusion criteria for - as for the cortical stimulation as the anterior cingulotomy. So this very, very strict criteria I talked about, they did the same thing for the DBS. They did all the ratings and they implanted the device and they do stimulation 2 weeks later. I'm not sure why the difference is for among the Parkinson's is what I heard earlier, but they do 2 weeks.
And here you take a look at the OCD severity. So the OCD severity dropped quite a bit after between 6 and 12 months of implantation. They got a really nice improvement with their YBOCS scores. So of the 10 patients they were able to follow-up 8 of them over a 36 month period and 6 of the 8 subjects experienced a 25% reduction in the YBOCS at 36 months, 4 of 8 a 35% reduction. That's a huge difference in improvement. Depression and anxiety improved at 3 months. We went over adverse effects earlier today so I did not include the medical adverse effects but some of the psychiatric adverse effects, people did have transient elevated mood. We got a nice description earlier of the super man syndrome, I really like that, but that's one of the side effects of this. And there is various bodily sensations and one person had an asymptomatic hemorrhage.
As I said my patient was one of these 8 patients here. Now he was one of the sickest ones in the study. I believe his YBOCS was a 39 and that's a 39 out of 40. Now his YBOCS nowadays is a 30, and that's a 30% improvement. And that's a dramatic improvement. A YBOCS of 30 however is still sick enough to be able to get you to be eligible for the study again. And that's how sick he remains at this point. But yet the difference in his life is tremendous. Before the surgery he was unable to leave the house or do virtually anything at all. He only would leave the house maybe once a month, and when he did leave the house it was, it was very difficult for him, he would try to get back in as quick as possible. Unfortunately one of the things he could not do in his house was use his bathroom. And so he couldn't leave the apartment, but at the same time he couldn't use the bathroom in the apartment. What he had to do was go in containers in the house. So he just had containers filled with - because he wasn't able to do use the bathroom, not able to go into the shower. He would go for years at a time without being able to take a shower.
So I see this patient now, he leaves his apartment, he is able to get the energy to get out of the apartment 3 or 4 times a week. It takes him a couple of hours to get ready to leave. So he has to have the energy and that's why he can only leave a few days a week, it takes so much energy to leave the apartment he can't really muster that every day. But given 2 hours he can leave the apartment, he goes out and he goes shopping, he has some friends that he visits, some friends in the same apartment building. He's able to use his bathroom in his own apartment now, so he can use his bathroom and he does a shower occasionally. Now not very often but I do think he showers a few times a year now. So while this sounds like someone who is very impaired, and again he is, compared to how he was before the changes are dramatic, just absolutely dramatic.
And so this is from a recent metaanalysis, the average initial YBOCS of people given DBS is about 32, the YBOCS decreases about 8 1/2 points. Again this is a pretty significant improvement, they get improvements in GAF and HAM-D scores. Again the most common side effects are hypomania, that's that superman syndrome; anxiety; some paresthesias; dyskinesias; impulsivity; facial symmetry and some dysarthria, dysphagia and walking difficulties. And again interestingly later implantation seems to improve outcome.
So basically what you get is symptom reduction and functional improvement in about 2/3 of the patients. And like our Parkinson's patients who we were talking earlier, thank you all for that by the way, they still have to take their medications. People who have DBS for OCD still need their medications, still need to do therapy. They still have clinically significant patients remain in most patients. Many of the side effects can be managed with the adjustments and depression worsens very quickly with stimulation interruption. So if you stop the stimulation they do get worse again, and they get worse again fairly quickly. Depression seems to get worse before the OCD gets worse.
Transcript - Howland
These are my disclosures.
As Dr. Richardson mentioned we do have experience with a variety of neurostimulation therapies for depression. The question that comes up though is why do we even need brain stimulation for depression? Dr. Hudak mentioned that OCD is in about 2% of the population depression, the prevalence at least lifetime prevalence is probably 10 times that. But it's only a very small percentage of patients with depression that would be considered chronic and treatment resistant. There are now 27 drugs that are marketed in the U.S. that are considered antidepressants, there is also a range of other psychotropic medications including some that would be considered medical medications and not psychiatric per se that are used as either alternatives or in combination for treating depression.
This is a representative study STAR D, the largest study ever conducted in depression. What I want to illustrate is the fact that each time a person is treated and does not respond to treatment the next treatment is less likely to be successful. And generally the cutoff is about 4 treatment failures where we really begin to look at a group of individuals that are chronically depressed and then classify them as treatment resistant. So this is a much smaller percentage of individuals suffering from significant clinical depression.
And the group of individuals that would have failed at least 4 different types of treatments, either mono therapies or combination therapies including psychotherapies are the types of patients that would be treated with a variety of brain stimulation therapies. ECT is most commonly done for treatment resistant depression, it has long historical use. Surprisingly there are really no controlled studies but there is really no reason to think that it's not successful in treatment depression. But there is now a number of invasive and non-invasive brain stimulation approaches. ECT would be considered FDA approved because of the devices that are used. TMS is now available and is marketed for treating a limited form of treatment resistant depression. Vagus nerve stimulation is also FDA approved. That was originally done using an invasive approach that can now be applied noninvasively although that has not been as well studied in treating depression. And then the invasive approaches: cortical stimulation which we did a small pilot study here and also deep brain stimulation. I'm going to focus on DBS.
And this is a review of DBS for depression at least around 2012 when I looked at in detail at the studies. And these were all open label studies and there were at least 3 main targets that were included, the subgenual cingulate cortex, the ventral capsule, ventral striatum which is the same site that Dr. Hudak talked about for treating OCD and also the nucleus accumbens. And some of these are U.S. based trials, others have been done in Europe and also Canada. The number of subjects in these studies is actually very small so a total of 84 subjects that were treated and followed for up to 6 years. These were all open label so it did not involve sham control or double blind. And the response rates as you can see were fairly impressive, 29 to 90%, and also the remission rates, 33 to 58%. And keeping in mind these are not patients that would have been eligible for FDA trials for a new investigational drug. This is a patient population that would have been at the far end of the scale, so these are chronically depressed, they've failed multiple therapies, they are considered dirty in terms of clinical trial material. So these are very sick patients.
And similar to the experience in movement disorders the safety profile of DBS for depression is fairly similar, there is no real difference in terms of adverse effects, surgical effects, long term complications or cognitive effects. We are dealing with a depressed population so either suicide attempts or completed suicide would not be unexpected, and in these studies it's not at all clear that DBS itself was a precipitating or triggering factor for suicide.
Now the particular target that I'm going to focus on is the ventral capsule, ventral striatum and this is the target location. This was one of the studies that was done as a pilot that I had showed you earlier, a collaborative study focused on patients with chronic treatment resistant depression. The reason that this study was done was the observation in the OCD trial that those patients with their stimulation their mood and anxiety symptoms got better so that led to an interest in studying DBS for this particular site but focusing on patients not with OCD but were suffering from major depression. And as you can see that these subjects who were severely ill at baseline were depressed for a long time and they had failed about 12 different types of antidepressant therapies or combination therapies during their course of their illness showed fairly significant degrees of improvement over a period of time.
And this particular study then led to the first randomized sham controlled trial of DBS for treatment resistant depression. We participated in this study, the other sites are as listed. This study has not yet been published although it's now being reviewed for possible publication. I'm going to go through the results of this study. So again this is a randomized study, double blind, sham controlled, so all of these subjects had non-psychotic, non-bipolar depression. We had specific inclusion, exclusion criteria in terms of their treatment resistance. They had to be chronically ill, all of then had to have received a course of psychotherapy. We didn't necessarily specify that they had to receive ECT but all but one of the subjects in the study had received ECT in the past.
So these subjects were screened and they had to maintain the same medications at the same doses during the screening period up to the time of implant. And then there was the 4 weeks postsurgery for stabilization and then subjects at that point in time were randomized. All of them had the implant but they were randomized to a sham control which is they went through the same programming procedure but did not receive active stimulation or the group that was actively stimulated. And the procedures for maintaining the double blind involved a programmer who would do assessments of side effects but had nothing to do with any of the clinical ratings. And then the clinical raters were blind to the treatment assignment.
And then patients were treated under those conditions for 4 months, 16 weeks, so that's a longer trial than would be considered typical for treating major depression. And part of the difficulty in doing a study like this is how long ethically can you maintain a sham controlled condition, especially since it involves an invasive surgical procedure. And at the end of the 16 weeks of the double blind phase all of the subjects were treated openly with active DBS and they went through an additional year of continuation treatment and then have been followed up long term. So we currently have 3 subjects that are still receiving DBS during long term stimulation.
And this shows the study flow. So 46 subjects were screened and 30 were randomized into the double blind phase. And all 30 of the subjects completed the double blind phase but one of the subjects became disinhibited and their stimulation was turned off so they were not counted in terms of an efficacy assessment but they were maintained for safety assessments. And then all of the 29 subjects went through an additional year of continuation treatment and thereafter 3 subjects had discontinued not for safety reasons but for lack of efficacy.
And here are some of the characteristics of the patients at baseline. Somewhat unusual for a depression trial is a preponderance of male subjects. Most clinical trials in depression about 2/3 of the subjects are females and depression is more common in women than men; this is a point that I'll go back to a little bit later. But the average age of this group was similar to most clinical trials, more severely ill than most clinical trials in depression and also the duration of their illness, more than a decade in their current major depressive episode.
And this is some of the treatment characteristics, all but one had received ECT, some of the subjects had received vagus nerve stimulation or TMS. Three of these subjects had received an investigational type of cortical stimulation which was one of the pilot studies that we did here and two of our subjects actually had received cortical stimulation, another invasive procedure, and that was explanted and they were eligible for the DBS trial. And this demonstrates the number of trials and the current episode and lifetime of these subjects. So again they were depressed for an average of 11 years and had received a large number of mono therapies and combination therapies as well as psychotherapy without an adequate response to their treatment making them eligible for this trial. And here is the primary end point.
And the trial had failed, it did not show a significant benefit during the double blind phase for DBS versus the control. There is a numerical difference favoring the active treatment but it was not statistically significant. And the percentage change in the MADRS score at the end of 16 weeks was not significantly different either. And this shows graphically during the course of the 16 weeks how the two, the active treatment group and the control group, fared.
And this also shows the individual subjects. So 3 of the subjects in the active group were considered responders which is a 50% or greater response, or decrease in the MADRS score from baseline to endpoint and 2 of the control subjects. What you see is kind of a curious spread of the control subjects during the course of 16 weeks. With the active treatment there is kind of clustering that they didn't really show much of a change at all, and that was a curious finding given the fact that by the end of the treatment period there was no average difference in outcome between the two groups.
And this is long term follow-up and it's focusing on the percent change in the MADRS. So baseline, the end of blinded phase, and then at that point in time all of the subjects received active open label DBS. Now during this phase their programming can change and their medications could change, so you really can't draw any conclusion in terms of absolute effectiveness of DBS simply because it was uncontrolled. But we did find that there is a change over time suggesting long term benefit in the subjects that were receiving active DBS. And again keeping in mind that they were chronically depressed and had failed a variety of antidepressant therapies including ECT. So these changes, about a 40% drop in the MADRS score over a period of 2 years for this type of patient population is actually significant and clinically meaningful as well.
And this again is showing graphically by subject how they fared. Here is the double blind phase and then year 1 and year 2. The dark circles are patients that would be considered remission where they actually had very low level depression symptoms and that's ideal. And so patients in remission are a subgroup of individuals that are responders. So again you do see a trend downward is that there is a spread of individuals over time most of whom show no significant change, but there is a group of individuals that again having been depressed for an average of 11 years and have failed a lot of therapies is meaningful for them in terms of the drop in their depression scores.
Safety, this is during the blinded phase. In general the type of surgical side effects, adverse effects that you see in the movement disorders literature is really no different for depression and the same thing for OCD. What was curious was some of the acute effects that occurred only in the active group, hypomania, mania, the mention of the superman syndrome probably is a mood elevation. One subject became disinhibited, very impulsive and this individual had the DBS not explanted but the device was deactivated. And again this suggests that there was something that was happening in the brain even though at the time the data were collected that they were blinded to the treatment group but did suggest that there was a small clinical signal.
And then looking at safety during all of the phases of the trial, again the types of problems and adverse effects really are not significantly different for patients in this depression study compared to the movement disorder literature and the OCD trials.
So to summarize the pilot study seemed to suggest that focusing on the ventral capsule, ventral striatum may be a beneficial antidepressant therapy. Controlled study which is the first one that's been conducted for depression, treatment resistant depression did not support that although there was some hint for long term benefits. And this is one of the difficulties in doing device studies in chronic psychiatric illness is being able to do a controlled study for a longer period of time in an ethical fashion. And although we've emphasized, Dr. Hudak emphasized for OCD, the chronicity and the treatment resistance, the same thing for depression one cannot necessarily exclude the possibility of a placebo effect. Placebo effects occur in the movement disorders literature. So this is one of the difficulties is being able to find a study in terms of demonstrating benefit beyond a double versus showing something that involves an invasive procedure over a period of time.
It is possible that simply the VC/VS is not an effective target for DBS for depression based on this study but the long term data would suggest that it probably should not be something to give up on. It's also possible that the treatment effects couldn't be detected. This was a 30 subject study so it was not highly powered, and the study was actually designed initially to be the introduction feasibility study of a larger pivotal study involving a larger number of subjects. But at the end of this phase in breaking the blind and really not finding any significant benefit the decision was not to move further to enrolling further subjects.
The other possibility is an alternative study design. Again if you think about doing an implant and being able to determine under a sham controlled condition how do you actually design the study, so in this particular study patients had the implant and then at the beginning were randomized to active treatment or sham. An alternative would be to use DBS actively in all individuals for a defined period of time, 4 months or 6 months, and then to plan a randomized double blind discontinuation of active stimulation. And that's something that has been considered in other particular studies as being used as an alternative study design, again focusing on a determination is the device effective under a sham controlled condition.
And just to put this in perspective, this is the study that I just talked about, this is the Pilot Study in the same target. The MADRS group focusing on the said subgenual cingulate cortex has gotten a lot of PR and press and they have an ongoing study, a double blind sham controlled study but no definitive results have been presented. But their outcomes are the ones that have been publicized and then VNS and TMS is to look at some of the characteristics. For example the average number of failed trials for our trial was much higher than what was seen in the VNS studies and the TMS studies for treatment resistant depression.
I had mentioned earlier the proportion of patients in the study that were males is actually greater than would be typical in most clinical trials but also with the exception of TMS for the other device studies. And we don't really understand whether there may be gender differences in terms of treatment effectiveness. There is some evidence from the pharmacologic literature in depression, so this I think may be an issue to look at in additional studies. The other factor too is the length of depression was considerably longer in the other device studies. So even though this is a treatment resistant patient population the clinical characteristics were not exactly the same. So putting it into context the results from this particular double blind study with what's been done in the literature I think is important.
DBS is still going on despite the negative results from this trial, there are other targets to consider, and if you look at clinicaltrials.gov there are a number of open label studies and also sham controlled studies that are either still actively recruiting individuals with treatment resistant depression or ongoing in terms of assessment but have not yet published their outcome findings. And one of these trials is focused on bipolar depression because most of these other studies have been with unipolar or non-bipolar, nonpsychotic depression. Thank you very much.
Transcript - Popescu
So a few interrogatory points here about epilepsy, the third most common neurological disorder, worldwide burden, similar with breast cancer in women and lung cancer in men. Risk of epilepsy up to age 20 is 1% and lifetime it's 3%. Now we are not talking about seizures, that's 10%. And 3 million people in the U.S. have active epilepsy.
Epilepsy treatment right now we have antiepileptic medications, seizure surgery, neurostimulation, dietary therapy immunomodulation. Now we are going to talk today mostly about neurostimulation. And first we have to try drugs. Whatever physician sees the patient first has this 51 chance that the drug will work if it's well tolerated. The second drug 7% response and then the third, fourth are polytherapies really are low response. 35% will have resistant epilepsy. They will not respond to the medications.
Now in 2010 they came with a definition, epilepsy n which seizures persist and seizure freedom is very unlikely to be attained with further manipulation of antiepileptic drug therapy. What you have to do is two tolerated and appropriately chosen antiepileptic medications. If you fail the first two your chances are really low. The patient should be referred early for surgery. Now I'm not talking about neurostimulation, I'm talking about executive surgery because this remains the only cure.
So today we are going to talk about neurostimulation. Now what do we know about focal seizures? And when I talk about neurostimulation we are mostly going to talk about focal epilepsies and not the generalized epilepsies. Even untreated seizures are brief, self limited events. Seizures are characterized by transient increased network synchrony. Seizures from a single focus in a given patient have similar dynamics, particularly at seizure onset. The seizure usually starts at the same spot in the same frequency band. Seizure termination can be abrupt and synchronous over a broad region. Most seizure terminations are abrupt, but we do see in our patients that sometimes the seizure spreads and then you continue the seizure on the other side but that's not the rule. Seizure termination may not require inhibition, we just need to desynchronize the network. Termination of seizures may represent the synchronization or diminished activity.
Now brain stimulation, there are two types from my point of view as an epilepsy doctor: chronic stimulation which may disrupt reduced baseline network synchronization and acute stimulation which may disrupt abnormal activity during seizures altering seizure dynamics and reducing seizure duration. Inhibition may not be necessary for seizure termination and we only need a small current. Now we are not defibrillating the brain, we are not applying large currents. And when we talk about synchrony yes we do need synchrony in the brain otherwise you are in a coma or you are dead, but we are talking about seizures having I shouldn't say but it's almost like a hyper synchrony.
Neurostimulation to treat epilepsy. Avoid additional toxic cognitive, any side effects from medications, and patients are typically unaware of intracranial stimulation. There were some early unsuccessful trials of neurostimulation and that was in 1978 and 1992 they tried cerebellar stimulation which kind of was the wrong way to go because they are firing continuously. And then they tried a centromedian thalamic stimulation. Those were not successful for epilepsy.
Now in 2004 what we have FDA approved as devices, we have the VNS and it has been approved from the '90s, we'll go back to that and we have enough experience with VNS. It's constant intermittent stimulation and then placement is external, it's on the left side in the chest. Also we have more recently in 2013 the RNS, the responsive neurostimulation approved which we are considering a closed loop will detect your seizure and stimulus is delivered in response to seizure activity. The stimulator is intra - it's not intracranial, it's like really in the bone and then the electrodes are intracranial. Devices awaiting FDA approval, we have anterior thalamic stimulator which is a constant intermittent stimulation, almost like the VHS. We have intracranial probes but for this DBS, our DBS for epilepsy it's also an external device in the chest.
And devices undergoing trials we have trigeminal nerve stimulation which is constant intermittent stimulation and placement of stimulation is extracranial. In fact you have this band which patients are wearing it on the forehead and you have to keep it like 12 hours every night. These hours not so good for now. And then transcranial magnetic stimulation which is also discrete treatment periods, extracranial stimulation. I'm not going to talk about them.
Back to the types of brain stimulation. Chronic stimulation, the open loop, like the VNS like the DBS you have - not continuous but regular periodic stimulation independent of seizure occurrence, like the VNS used you stimulate, you are off, you stimulate, you are off. We have option for patient activation at seizures with a magnet for the VNS. And then you have the closed loop which is the responsive stimulator designed to stimulate brain at seizure onset. The goal is to terminate seizure or significantly reduce seizure duration. We can hopefully top a seizure at the electrographic or aura phase. It does require sophisticated seizure detection algorithms.
VNS, the one that has been in use for a long time, so this is the one that's implanted, this is the magnet. This is our device. Right now it looks more like a laptop, they changed it. This is the wand that's connected to your device. This is not the wireless device. And then the patient in the chest on the left side has this little device implanted. There is kind of going into a wire and we'll show it soon what it does. And just loops around the vagal nerve, and it is on the left because of the less side effects, cardiac side effects.
VNS mechanism of action, it's unknown. Antiseizure and antiepileptic properties in animal models they did the studies in cats may be mediated by enhanced noradrenergic activity, locus ceruleus, and some think can be neuromodulator and might alter plasticity.
A VNS therapy, this is 3 years and we are talking about the patients that responded and we had a 42% of patients that were responders, that means they achieved more than 50% seizure reduction. Data, longer data at 12 years show that the patients - the reduction numbers were higher and higher in time. They went into the high 40s for the number of patients responding and for each individual patient that responded they got better and better seizure reduction, so more than the 50%. Based on the studies FDA approval was in 1997 and 1994 for Europe and was indicated for use as an adjunctive therapy in reducing the frequency of seizures in patients over 12 years of age. It was initially for partial onset seizures but now we know we use it in generalized epilepsies as well. The evidence based guideline that came in 2013. VNS is associated with a 50% seizure reduction in 55% of the patients. So 55% of the patients had 50% seizure reduction.
We know the safety profile, we had it for a while. We did not see any increase in SUDEP. In animal studies. In animal studies it was okay to use with no harm to the fetus and no problems in infertility, and then I have some patients that are pregnant and they didn't - I have some patients that already delivered, we have not seen any problems with the VNS in the mother or in the fetus.
So this is what we have, this is our baseline, this is what we have for epilepsy, this is what we had for a long time. But right now they came up with you know the RNS, and we'll talk about it. But quickly just one page about this trigeminal stimulation. So earlier studies reported responder rate of 40%, so 40% of patients had more than 50% reduction. But then when they did a recent double blinded controlled studies they only had 50 patients, they looked in this drug resistant epilepsies and there was no significant difference between the responder rate in treatment group versus the active control group. The device does not have approval here in the U.S. but has been approved in Europe and Canada.
Now the intracranial stimulation. So the intracranial stimulation we have two devices. One is our DBS that's not approved and one is the RNS that is approved. I'll touch base on both of them.
Patients with medical intractable focal epilepsy and seizures that significantly affects quality of life you are not going to put this in any patient that's controlled with medications even in polypharmacy. Patients that are not good surgical candidates if you can do resection that remains the only cure. Patients who have failed seizure surgery you can try the device.
The first one that's not FDA approved is the stimulation of the anterior nucleus of the thalamus. And I'm sure there was a lot of DBS being presented but the device is external, you have two leads going in. After the implantation they see this decrease in seizure frequency in active and in controls in the first month. Now when you go down that's good, that's a seizure reduction. The control actually started picking up by 3 months and the only one that continued having seizure reduction was the active stimulation.
Now there were 110 patients in the SANTE trial, the stimulation of the anterior nucleus, and they seen at the 3 months blinded period they seen a 38 reduction compared to the 14.5 on placebo. Now by the end of the couple of years they only had 87 patients in the study. And out of these 87 patients they seen that the patients that responded slowly increased. There were some patients that were seizure free in the study, 6 patients. But again the median, so 56% of the patients had over 50% reduction of seizures.
Now in the DBS study it worked better for the temporal lobe, and everything we have actually worked better for the temporal lobe. Our surgeries work better too, and did not work as good in frontal parietal and occipital epilepsies. Treatment work after surgery or after vagal nerve stimulator, they might have had a VNS for years. Higher incidence of spontaneous reported depression and memory problems and anxiety in the active group, but that was not confirmed by objective testing. So this is what we had and it was not approved. Now for the numbers so at the end of the 2 years we had 56 responder rate with a over 50% reduction in seizures. I'm not so sure how much difference was with the VNS even if we were intracranially on the device. But it is possible that in time we are going to see better reduction. That was just at 2 years what I presented, while for the VNS we already have like 12 year studies.
So now this is the one we are very excited about the responsive stimulator, the closed loop. And why we are excited is because this is a smart device. It's continuously monitoring brain electrical activity, it has 1 to 2 electrodes. Now this 1 to 2 electrodes you can place them in a single region, both of them, you can cover like more superficial if you have like - yeah a more superficial seizure focus or seizure network, you can put one of the subdural or you can go with a deep like a depth electrode if it's like you know periventricular area or kind of a hippocampus or anything different than temporal lobe. So you are monitoring the device, it's acquiring the data and it's storing the data. Now the data storage is temporary.
In a phase II you are going to program the device to recognize seizures. You are going to see what the seizure signature is, you are going to program the device to recognize this. And when it recognizes to deliver a very small current. Your hope is to stop the seizures. So FDA approval, individual 18 years of age or older with partial onset seizures, what we call focal seizures with alteration of awareness, diagnostic testing that localizes no more than two epileptogenic foci, you cannot have a multifocal patient here, a refractory to 2 or more antiepileptic medications. It's used in conjunction with medications. Currently have frequent and disabling seizures either the motor partial, the complex partial, some secondary generalized seizures, not just auras.
How does it function all this? So you implanted the device in the skull, you are recording through those two other depths or subdurals. The patient almost every day, sometimes every 2 days will have to with this wand kind of wirelessly transfer the data and the data goes into the database. You can access the database by yourself if you have time or whenever you are sitting with the patient in the clinic. You have to be able to read electronic cartography, you have to be able to read - to identify seizures intracranially. And after probably one month in which you are just acquiring the data you see how many seizures onset you are recognizing you are going to start programming.
So you've identified big spikes happening, you identified this kind of frequency building up sometimes and then you have to - you detect, you will deliver, you will deliver - I mean not you, the device will deliver a little buzz. Probably you have to adjust at each visit, you are not done. So you are going to see that in some seizures, that you are stimulated too late, that you recognize the seizure set 3 seconds and maybe if you are delivering at 2, at 1 second and every - or maybe you missed some seizures, maybe in the first month only one of the clusters was or firing and the second one was not. So you are going to - in time you are going to learn what seizures you missed, you are going to learn that maybe you missed them because you haven't seen them before or because you stimulated too late and the seizure continued. And you are going to improve.
So in the studies they had 230 studies, 230 patients. They seem the same as we see in the DBS, we seem to see improvement in the seizure reduction before you even started stimulating, but then once you turned on stimulation the seizure reduction continued while the other ones that were not stimulated kind of almost returned to their baseline.
Two-year responder rate for over 50% seizure reduction was 55%, somewhere over there. And you can see how the device, not the device but the patients are actually slowly in time getting better. There were some side effects, some of them related to the implantation site, they seen some deaths, most of them were not related to the device. We do have SUDEP epilepsy and the rates of SUDEP were not larger than in our chronic intractable epilepsy population.
The side effects we see no side effects on cognition, no adverse effects on mood, patient was unaware of therapy. It takes months to be properly adjusted both seizure detection and programming, Optimal stimulation parameters are unknown and we are still working through this. Intracranial surgery is mainly for implantation and the battery change was a problem. Initially they were expecting 5 to 7 years on the batter life, but then they seen that in 2 years your battery was running out. So they were wondering why. And under detection they seen it was expected to be you know whatever 10, 20 seizures and patients can have it a day, some patients you know are per months, but then they were seeing 500 detections and they were seeing 500, and the detections were not false detections. So they were seeing detection of abnormal epileptiform kind of electrical activity. And that's why the battery was running so fast. Now there is another question, is it possible that not only you have the closed loop so you've seen the seizure onset, you've recognized it and the device already buzzed that seizure and stopped the seizure but on top of that with the 500 seizures, seizure activity today you have also a chronic stimulation going on almost like in the other VNS and the DBS for epilepsy.
So who should get RNS? Disabling drug resistant focal onset epilepsies, we are not talking about patients that have generalized epilepsies. We are not talking about (inaudible) patients that are multifocal. Not good candidates for execute surgery, remember that remains the only cure for epilepsy. One or two seizure foci, not multifocal. Relative localization of seizure onset zone and intracranial monitoring is not required. We really don't know how close we need to be to the seizure focus, we don't know. We think that the closest we are the faster we are going to be seeing the seizure. We are not going to see a seizure spread in the network, we are actually going to see the real seizure onset so we should be as close as possible because that will allow us to identify the seizure and deliver the current much faster. But we don't know how close we need to be. You should be somewhere in the network for sure.
Very good candidates are the bitemporal epilepsies. We've been frustrated for years because we couldn't offer them anything. You have seizures coming bilateral hippocampus and this is a device that we expect that will work really nicely on our seizure focus in our eloquent cortex, so you were intracranial, you identified the seizure onset, you are really happy, the single seizure onset, it's a really small area, it's really good for eviction but you can't because you are in the motor area, you are in the language area, you really can't take that out. So this will be something also to be strongly considered.
Now as a conclusion, we had pivotal trials with responder rate 38% during blinded phase and rising over 50% in open label period. Just as a reminder, we don't know the stimulation parameters and we don't know how close to the seizure focus stimulation needs to be. And not knowing this we still got over 50% responders. The better we are going to become I expect the numbers are going to improve. And as I said with typically tuned detection algorithms RNS delivers therapy more than 500 times a day. And that's a lot of -
Transcript - Richardson
We'll talk about future directions in brain stimulation. So this is a kind of fun talk just at the end and please feel free, just raise your hand and interrupt me if you have a question, you know don't mind at all.
So I want to talk about a couple of things that Dr. Homayoun brought up and this is going to really show you the whole spectrum of kind of what is easier to do but still difficult that would be new in DBS and then kind of what is very futuristic. So there is a problem with primary freezing of gait in Parkinson's disease and maybe also as its own entity and for this specific problem simulation of the pedunculopontine nucleus has been you know suggested and tested in patients and the pedunculopontine nucleus is one of the outflow targets of the basal ganglia, it's lower down in the brain in an area called the locomotor region, brain stem locomotor region, and has direct outputs to the spinal cord. It also does have projections back up into the striatum. And it's been stimulated just one side, it's been stimulated on both sides, it's been stimulated with STN, it's been stimulated with GPi, it's been stimulated with this region above the STN called the zona incerta. And the long and short of it is that this hasn't happened in a controlled fashion and we are still not sure how well it works, but it's definitely worked well enough in some patients that it's an option. But this kind of highlights one of these things that is just kind of outside of our reach right now for instance in how to expand you know indications in movement disorder surgery, how to treat some of the effects that aren't well treated by our standard targets in movement disorders. And it's really only from kind of the larger academic centers that can receive these referrals and receive enough over time and to really study this in a systemic way and think carefully about this in terms of applying new targets in doing dual target stimulation that we can start to get some answers for this.
Okay, so in terms of targets and indications if you go to clinicaltrials.gov and you look up DBS trials you'll find that they are ongoing and by the way you don't have to be in the United States to list your study on clinicaltrials.gov, so this is kind of the worldwide experience right now. There is a one to one trial in addiction, there are - is a one to one trial on Alzheimer's disease, anorexia, bipolar disorder as has been mentioned, depression, epilepsy, OCD, post-combat PTSD, schizophrenia, Tourette's. So if you can think about it chances are someone else is already thinking about it for DBS and a lot of these indications are currently under investigation.
This is a good table by one of the longstanding English groups doing DBS so these are just the targets that have been used for Tourette's, OCD and depression and you can see the list is very long. In a lot of cases they overlap. But it speaks to one of the slides that was presented earlier in terms of functional basal ganglia thalamocortical loops and how these nodes are functioning abnormally in different disorders that have overlapping symptoms. /And one thing that's very - let me just I'll get there in a second, I don't want to forget that - in terms of thinking of targets one thing I did mention is that kind of in contrast to what the history of movement disorders where we are targeting gray matter structures and the subcortical structures the efficacy in OCD seems to in a large part be related to stimulation of the internal limb of the internal capsule which sits right above the nucleus accumbens which is also known as the ventral striatum. So if you can think of an MRI where you are used to seeing the caudate and let's say a coronal view the caudate and the putamen separated by the capsule if you go down deep enough they actually meet. So that's the ventral striatum also known as the nucleus accumbens and right above that is the internal capsule. And so the electrode is actually in the anterior limb.
The group at Emory and Toronto in conjunction with a very good imager at Case Western have - are really leading the field in terms of looking at white matter tractography, so these are anatomic studies that I have to tell you are really subjective, so if you see publications or you see pictures of tractography and it looks very pretty these are really subjective. But this group has done some very nice work with DTI tractography and looking at areas of activation, so there are models that can estimate how much tissue is activated by a different current delivered in different electrode combinations and they basically have shown a difference between, between responders over here and nonresponders here. Actually this was a contact in which the patient reported you know a clear benefit in terms of symptoms, this is a depression patient, and this was a contact where this was the estimated tractography was affected. And here this was the estimated tractography.
So you can see here where you are affecting more of the network you know the overall loop, and here you are just not making it there. So one of the reasons why the most recent depression trial probably failed is that some people's you know electrodes were creating a picture of stimulation like this and other people were like this. And that's one of the issues is that when trials go to these large multicenter trials before we understand things like this they are likely to fail and it's actually a real problem in the field now because these are expensive trials and if industry doesn't fund them it's a question of how are they going to get funded. And so these are going to have to be funding kind of at individual institution level with a number of different kind of creative mechanisms for doing that.
Okay, Dr. Popescu mentioned this idea of closed loop stimulation and actually I didn't really go into this further or earlier in contrast to open loop stimulation, or open stimulation. So that you know we set the device in our movement disorder patients and it's on and it goes. And then that has an effect over time and then there may be side effects or other adjustments need to be made for improving efficacy and we modulate that, we you know turn it up or we do some kind of experimentation in the clinic with the patient. But then when they leave they have a setting and that's the setting. And then maybe with the patient programmer they have a B setting too, so in some people maybe they can make a little switch or they can go up and down.
But what the RNS system does as has been mentioned is record all the time and then deliver stimulation based on instructions that are given by a clinician through a programmer. But that can be modulated. Now that still requires recording analysis and modulation by the clinician. Eventually these devices are going to have the ability to learn and that is going to require instruction but machine learning is eventually going to play a role in these devices such that they can learn different patterns and modulate their activity based on dynamically. Of course in response to programming by humans.
And I think this is what the future looks like for closed stimulation. So we have very crude electrodes now in both the systems that have been talked about today, and you know these are very large contacts and they stimulate large populations of neurons and actually this slide is really out of order. So Dr. Homayoun mentioned this idea of current steering so here are current electrodes and you get a big sphere and you can kind of stretch this sphere a little bit you know if you turn this one on or maybe you can turn on two of these, or you can kind of change how they stimulate but you can't do a whole lot with this. You could create the same sphere of activation with a bunch of electrodes but you could also shape the charge distribution and you could think about fitting it within your structure of - your desired structure whether it's a gray matter structure or a white matter structure. So this idea is called current steering, you can think of it as shaping the area that's affected by DBS.
Let me just go up here again and show you why I put this on here. These are microelectrodes. Someone asked before about you know what's the difference between these recording electrodes and the stimulating electrodes, so you can see here is a microwire bundle, so these would be very thin, I mean a hair - less than hair thin microwires that would extend into the brain and these can kind of go in a bundle. They can come off in a ray that would sit on the cortex and have like 100 penetrating electrodes and these have been used in brain computer interfaces for instance in patients that are paralyzed from spinal cord injury in order to control the prosthetic devices. And these are actively under development and one of the - just looking at the clock here - this I'm showing you this paper because it really, it wasn't the only paper but it was - it's a kind of well known paper that kind of has moved the field forward in a number of ways. So in patients that underwent intracranial monitoring in order to detect a seizure focus this group at UCLA did some stimulation studies specifically related to memory function. And they reported and there may be a follow-up paper that says something similar but still I think they are really the only ones that have shown the kind of strong affect that they did and improvement essentially in memory function. And this is very interesting and it's interesting related to the RNS device because it may be even if we can't stop seizures that we can somehow shift the network dynamics to affect cognition patients so that someone who is having epilepsy isn't affected as much by their seizures, or by a baseline network dysfunction that number one predisposes them to seizures, and number two is responsible for cognitive impairment.
So in light of this, the Defense Advance Research Projects Agency, also known as DARPA, just awarded about $80 million for these two projects, primarily to just 4 institutions working on conjunction with NeuroPace is one company, Medtronic is another and some of the other device firms that are working on micro stimulation. And I tell you that because this is, so this is part of the Brain Initiative. You know it's interesting, this is kind of an aside then we are running out of time. But you know Obama said well we are going to have $100 million for brain research which is basically nothing you know going into this NIH. But DARPA which has a different kind of funding mechanism just gave you know 80 million bucks away to several different places.
But just I want you to read these if you don't mind if you don't like reading slides, but number one is called restoring active memory and so the point is to develop and test a wireless fully implantable interface that's a neuroprosthetic and the idea is to improve someone's ability to encode new memories or retrieve old ones. Okay, no one knows how to do this, not even close. However the point is there is going to be a lot of exciting stuff happening in this field and it's driven by some of the work in our epilepsy patients that have implanted electrodes and we have ongoing studies in our own epilepsy monitoring unit, it's also driven by data we can collect when patients are awake in the operating room undergoing DBS and we have studies related to that as well.
Here is the other one, the SUBNETS, reduce the severity of neuropsychological illness of course in service members, veterans, basically with the same type of technology, sensing enabled technology that detects biomarkers for instance of depression or of anxiety or of posttraumatic stress disorder and then stimulates desired brain regions. And the group at MGH was involved in one of these studies and this is the schematic of what this would look like and it's similar to the picture I showed you before. There are different types of electrodes, they are implanted in different parts of the brain and there is an interface and you know very smart computer system essentially that is going to modulate the detection and stimulation.
So I really do think that's the future of brain stimulation. It's going to take us a while to get there but these things are popping up in the news now, so just to give you an idea we are very, very far away from even doing these in patients because a lot of this funding is going to go to device development. The devices to do just some of the general ideas that have been proposed literally do not exist so they have to be developed.
Okay, so in conclusion, this is really kind of conclusions from the course, DBS is the gold standard of treatment for Parkinson's, essential tremor and primary dystonia when symptoms are not controlled with medical management and when patients otherwise meet surgical criteria. And there are multiple efforts underway to expand what we've learned in movement disorders in terms of brain stimulation to other circuit diseases of the brain, and we've kind of given you an overview of that today.