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Part 1: Selected Presentations from Brain Stimulation for Movement Disorders, OCD, and Epilepsy
Drs. R. Mark Richardson, Houman Homayoun and Jamie Pardini each present from Brain Stimulation for Movement Disorders, OCD, and Epilepsy Symposium.
Upon completion of this activity, participants should be able to:
- Review scientific background of DBS for Parkinsons Disease
- Describe the use of a neuropsychological assessment with respect to DBS candidates
- Discuss indications and outcomes for DBS in Parkinsons Disease
- Kringelbach et al., Eur J Neurosci, 2010.
- Engel et al., Nature Reviews Neuroscience, 2005.
- Schuepbach WM, Rau J, Knudsen K, Volkmann J, Krack P, Timmermann L, Hälbig TD, Hesekamp H, Navarro SM, Meier N, Falk D, Mehdorn M, Paschen S, Maarouf M, Barbe MT, Fink GR, Kupsch A, Gruber D, Schneider GH, Seigneuret E, Kistner A, Chaynes P, Ory-Magne F, Brefel Courbon C, Vesper J, Schnitzler A, Wojtecki L, Houeto JL, Bataille B, Maltête D, Damier P, Raoul S, Sixel-Doering F, Hellwig D, Gharabaghi A, Krüger R, Pinsker MO, Amtage F, Régis JM, Witjas T, Thobois S, Mertens P, Kloss M, Hartmann A, Oertel WH, Post B, Speelman H, Agid Y, Schade-Brittinger C, Deuschl G; EARLYSTIM Study Group. Neurostimulation for Parkinson's disease with early motor complications. N Engl J Med. 2013 Feb 14;368(7):610-22.
Drs. Richardson, Homayoun, and Pardini have reported no relevant relationships with proprietary entities producing health care goods or services.
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 1.75 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 (0.175) continuing education units (CEU) which are equivalent to 1.75 contact hour.
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Release Date: 6/10/2015 | Last Modified On: 5/10/2015 | Expires: 6/10/2016
Transcript - Richardson
Okay, so I'm going to talk, I’m going to try to stay on time here and look at my watch and give an overview of the course and a general overview of brain stimulation. So we really are going to talk mostly about deep brain stimulation today, even though the closed loop device for epilepsy for which there will be a talk by Dr. Popescu later in the afternoon is not thought of in the same way as traditional DBS is thought of because it can also stimulate the cortical surface. So most of the time when we are talking about deep brain stimulation we are talking about stimulating subcortical structures and most of the experience with that is in movement disorders as you can tell from the program it's highly movement disorder oriented.
So DBS is not the only type of brain stimulation. I mentioned responsive neurostimulation which is a closed loop device for epilepsy, can stimulate cortical and subcortical structures. Here is an example of those two devices. So when we talk about DBS and please no question is - the point of this course is to orient you in this technology and basic indications and surgical techniques and outcomes. So please if you have any basic questions write them down on the cards we have to address those, so that's why we are here today.
So it's cut off from the picture but the actual stimulator is the pulse generator that's implanted in the chest. I have a picture of that again later. But the business end in terms of the brain surgery part is in the brain. This would be for instance a movement disorders patient who has an electrode planted deep in the brain, there is a 14 mm opening in the skull, typically there is one on each side through which a DBS electrode is placed. We'll talk about how that's done later. There is a plastic base for a locking cap so there are two locking components that keep the electrode secured in place on the skull. And this is typically done in one surgery and then in a second surgery we open up another incision here, find the other end of the DBS lead and connect that to an extender wire that then goes down to another incision that's open in the chest where we place the pulse generator.
That's in contrast to this other stimulation system which is the Neuropath system. In that system the pulse generator is actually implanted in the skull. So one makes a pocket in the skull for the device. There is a holder that's secured and the device is placed there. There can be a deep stimulating electrode, typically these will go in the temporal lobe but they don't have to they could go anywhere a seizure focus has been detected. And then there is another electrode that could also be a deep - in a deep structure or could be on the cortical surface and these electrodes can both record and stimulate and so we'll have some more information about that later.
Now there are - so there are types of brain stimulation that are not invasive. We are going to talk about invasive brain stimulation today but transcranial magnetic stimulation actually has an FDA approval for some use in depression as well as migraine headache. The efficacy studies however are not great, a lot of insurance companies do not cover this therapy. DBS has a much longer history of efficacy but we should mention that there is TMS and there is also transcranial direct current stimulation, so the TDCS some of this is voodoo that you kind of see out there, these little devices that people make and they you know put it on You Tube and sell them out of their garage. And then there are some real studies in transcranial direct current stimulation that are interesting. But that is not FDA approved and not really in clinical use.
Okay, so what is DBS? We've talked about this. So a little bit about deep brain stimulation. Here is a picture of that pulse generator and this is true relative size. So I tell patients that it's not as big as a hockey puck but it's pretty close. It does protrude from the chest, there is a visible you know incision that is going to heal pretty well but you know always someone is going to notice that if you are at the beach. For ladies we do try to make the incision so that if they are wearing a deep V shirt it sticks off to the side so it's not as apparent. But it is certainly visible and patients can feel this under the skin. Typically they get used to it, acclimate to it pretty well but there is a range of how long that takes. And we can hear from the patients later about that in particular.
What our neurologists and physician assistants do in the clinic with programming the patients is done through this telemetry device. So this is a telemetry head that's placed over the pulse generator, it's connected to a wire, by wire to this handheld computer and using this computer one can program different characteristics of stimulation. And I would like to point out that we'll see in a second this therapy is not experimental, at least not for primary movement disorders and some of you may have seen that the Lasker Prize was recently awarded to a neurosurgeon and a neurologist jointly for their work in deep brain stimulation for Parkinson's disease. So this is an important point about the nature of this treatment and its use and it really does require a team approach between neurologists and you'll also see psychiatrists for other indications outside of movement disorders where these two subspecialties really need to work together to both identify patients and to treat them and maintain treatment with the therapy. Dr. Benabid was the first neurosurgeon, he is French, to implant the DBS system. He did that in 1987 and this is Mahlon DeLong who is a movement disorder neurologist at Emory University in Atlanta.
Okay, so DBS is not new. Here is the proof of that. First implant in 1987, that is basically with the same technology that we are using today by the way. The European Union has always been ahead of the United States for approving both devices and pharmaceutical treatments so you can see they were a couple of years ahead but DBS has been FDA approved for use in the United States since 1997, so this is you know over 15 years now and there is a lot of good safety and efficacy data. It was 2002 when the FDA approved this for treatment of Parkinson's disease although it was being used off label for some before that in the United States so there is actually a much longer history than just 2002.
A humanitarian device exemption was granted for dystonia in 2003, so that's actually a pretty longstanding history of treatment of dystonia now over a decade, and then in 2099 also a humanitarian device exemption was granted for the treatment of obsessive compulsive disorder and we'll have a talk about obsessive compulsive disorder in the afternoon. So humanitarian device exemption is granted for indications where it's felt that there will not be enough patients to generate multicenter large randomized controlled trial data.
Quickly to wrap up, how does DBS work? These are the electrodes that are available to us. These are the two that are typically used in movement disorders, so the electrodes themselves are 1 1/2 mm long with either a half mm gap or a 1 1/2 mm gap. This is the electrode that's approved for obsessive compulsive disorder because it stimulates over a longer region in the brain and also is used to stimulate some white matter pathways. And each of these can be programmed independently and you can program 3 different parameters so one is the amount of charge or the amplitude, one is the rate so how often you get pulses of electrical stimulation and then you can set the duration of each of those pulses. So these settings have different effects on improving symptoms and they also have different effects on creating side effects that may be unwanted. So these are things that we can tinker with in terms of getting the stimulation correct.
Okay, so how does DBS work? Well it's essentially based on this concept of loops, segregated loops, functional loops within the brain and we think of these as basal ganglia which is the target for most of our indications for DBS, thalamocortical basal ganglia loops. And these are - have a little bit of an overlap but for the most part they are segregated into a motor system, a limbic or kind of emotional system, and an associative or executive system that maybe is more important for kind of putting information together and decision making. So for instance this is why we can put a DBS electrode within the motor circuit and not affect we hope these other regions. When we do get side effects that may be associative or limbic it's because of spread of electrical current or in some cases the electrode could be not in the optimal position. But 99% of the time we put it in the right place and get a nice benefit with motor symptoms.
So just to summarize, a lot of neurologic and neuropsychiatric diseases are known to be associated with different problems in some of these individual nodes. And Dr. Homayoun who is going to talk next will talk to you about how that happens in Parkinson's disease. But essentially any diseases that we are trying to treat with brain stimulation we are trying to alter a network and there is a specific part of that network that's known to be affected. So when that happens communication that's important for the initiation of movement and also important for sitting still is thrown off and electrical stimulation in the way the DBS is delivered in some way resets abnormal communication in the brain and generally speaking I think Dr. Homayoun is going to talk about this too, there are different bands of oscillatory activity and neurons fire signals at different rates and communicate with each other in that fashion.
Transcript - Homayoun
So I'm gong to talk briefly about use of deep brain stimulation in Parkinson's disease and I'm going to cover more of the scientific background, some of the efficacy data and then my colleague Dr. Berman is going to talk about the practical aspect of patient selection.
So I'm going to talk about the targets we use, mechanisms of action, efficacy and a very brief discussion of what would be next. So the size of the - probe of the DBS which we put in the brain and where it's located that gets the name of deep brain simulation, it's basically a revolutionary type of treatment. If you think about the ability to modulate the activity of the brain really for the first time to get clinical results, and I think you know as we talk about the mechanisms and our understanding this - you know the idea I think from a neurological perspective is this is still a kind of a crude technology despite all we can achieve with it. And if we an fine tine it we probably can do better.
So as Mark talked about this we are talking about this idea of the circuits, the loops between cortex, basal ganglia and thalamus. And these parallel loops as far as it goes with the motor cortex, motor system they go through these loops the information that is required for performance of motor actions. The role of basal ganglia is thought to be more of a modulatory role, fine tuning of movements, certain aspects like scaling of movements, sequencing initiation and the type of thing we see affected in diseases. There is a parallel processing and there is also a topographical organization which is very important which part of the body is affected and how the system works.
So the idea of these parallel loops as was mentioned, the other parts including ocular motor, reward or limbic system which involves the cingulate cortex or the prefrontal cortex, the prefrontal or called associative or executive loops and these loops work in parallel. All of them share this pattern and the ability to stimulate one circuit separate from the other ones allows us to make a modulation without affecting those other functions.
Now going a little bit into what was the contribution from Dr. Delong, which was mentioned, and his colleagues in terms of this box circuit idea of basal ganglia which still kind of derives our major way of thinking, so the initial you know model would indicate you know we have the cortex sending signals to the striatum, that's where the dopamine is working. And we have a different role between D1 and D2 receptors. The direct pathways which go to the output of the basal ganglia, GPi and then send the signals out to thalamus, back to cortex. When we think about the direct pathway mostly as let go for a motor to be exerted and an indirect pathway which involves the subthalamic nucleus and as a final outcome it's like a brake on the movement. Now in reality the circuit has become much more complicated but still we think about these two main ideas of let the movement go and stop is holding true. One of the key features that we now think about is this pathway form cortex to subthalamic nucleus which is now called a hyper-direct pathway and is a direct excitation through the indirect pathway. We can think about a way for our cortical control to stop an unwanted movement and there seems to be some of the possible involvement of how DBS works may go to that hyper-direct pathway.
So what happens in Parkinson's is substantially nigral neurons degenerate, we have a lack of dopamine in the striatum and therefore this normal dynamic is supposed to change. So the change happens in the direction of weakening the direct pathway, strengthening the inhibitory in direct pathways and that is thought to be translating into more difficulty with initiation and exertion of movement, the slowness that we see in classic Parkinsonism. And what we think about why the levodopa is helpful is because it allows the brain to make the dopamine or allows the dopamine act on the striatum in the case of dopamine agonists and we were able to reverse some of the motor deficits of Parkinsonism. So the idea of DBS is are we able to change anywhere else in this pathway with you know electrical stimulation to replicate the effect that we can pharmacologically see from dopamine and we know we can do that.
Now how can we do that with putting the electrodes in a specific part of the brain to get to that result? Again, now we think it's because we really are going to modulate the circuit. The initial idea came from you know observation that when they were using the stimulation in operating rooms to do lesioning and for which was you know kind of established treatment for some of the movement disorders, a high frequency stimulation could replicate and effect of an ablation. So as a thought about you know deep brain stimulation primarily have an ablative or functional lesioning in that part of the brain, but you know the benefit of being reversible, you turn the switch off and then the lesion goes away. Now why you know this was the basic idea of how it works. In reality we do recordings from subthalamic nucleus during this period of stimulation some of these neurons stop firing, but there are some other neurons in this area that increase their firing, that don't change their firing. So it's a more complex picture and that kind of drove the thinking that it's not just the rate of firing of neurons, there's more into it.
So what happens when the deep brain stimulation is affecting, you know sending the electricity towards a neuronal environment around the tip of this electrode, so we have the neurons. We think the primary effect on the soma of the neurons, the body of the neurons which are close to the electrode is an inhibition but the pathways, the axons that are leaving could be excited primarily and then they have affects on other components. They can also have an effect of stimulation on adjacent or passing by tract fibers. And now we think that's also a part of why it works. It's not just the subthalamic nucleus, some of it is just the fibers that move next to subthalamic nucleus.
And now what is he evidence that we are doing more than modulating the rate? Now we know for example that when we use the DBS the pattern of firing of neurons changes, so here is high frequency stimulation of subthalamic nucleus recording from GPi neurons, they become very rhythmic. The same thing happens in thalamus, they become rhythmic. So with high frequency stimulation we basically change the pattern of firing of the neurons so it's not just changing the rate of their firing. And the bigger idea is we try to normalize the abnormal pattern of activity in this part of the brain.
And a step forward in terms of what we think about it these days, this idea of oscillatory activity that Mark referred to, so we have now evidence that there is abnormal oscillatory activity in key output areas of basal ganglia as well as in subthalamic nucleus in Parkinson's disease, which we don't see in other subjects. And these are based on direct recording from patients with PD. And one of the ideas here is we have the neurons that are firing, the recordings from local (inaudible) potentials and there is an oscillatory activity which this firing of neurons are locked to that. We can see there is a peak of frequency that usually falls in the beta range, and that's why this is called the beta band oscillatory activity. And now this has been shown in a number of studies. So it's the recordings from individual patients with Parkinson's you see they have a peak of beta activity. Some of them interestingly may have two peaks of beta and this is not - this is a fixed frequency for each patient but it's not the same in all the patients. So it's very individualized. And in some of the recordings that are 2 recordings from bilateral sides they are synchronized to each other. So these patients carry an abnormal hyper oscillatory activity in the beta band frequency and now there is evidence that it also is related to their abnormal movements and ability to move fluently.
So some of these works come from comparison here between the on and off state with the medication. The red line is during the off state when there is no medication and the beta frequency is there. With an on state where their symptoms improve the beta frequency is suppressed. In fact there is some higher frequency in the gamma range that become active in some studies, but this is the most consistent. So the idea is you have some frequencies that are anti-kinetic, the beta frequency between cortex and basal ganglia, and then some pro-kinetic frequency. And this is one of the key things that we are trying to treat. There is also an idea that tremor frequency which is not present in all patients is also very individualized is another type of oscillatory activity. So this beta frequency is more timed to bradykinesia, the core motor deficit, the tremor frequency individualized in patients who have tremor and we know DBS treats well for this and so the idea is that it disrupts that oscillatory activity, and that's how it normalizes the activity in the system. So there is some evidence clearly that - this is again recording patients with Parkinson's, there is a difference when they perform a task if go or no go, so the difference is for a task to be exerted they need to really suppress the beta oscillation or beta synchrony, and there is less suppression when they don't do it. So basically you need to suppress your beta synchrony to exert the task. This is whether it is a stimulus induced task, it correlates with reaction times, the earlier you suppress the beta, the earlier you do the reaction time its activities in the beta range that changes on levodopa becomes a faster high frequency but you don't see that beta frequency on the spectrum, you see the beta suppressed, you may get some on the gamma range. And this suppression clinically interestingly correlates with the motor improvement, I think it's one of the more convincing evidence that it's causative here. Another example that on a self paced movement in patients with Parkinson's this deep dark blue area is the area of beta synchrony, beta oscillatory activity. It gets suppressed when they are on levodopa, you get some of this you can call it a good or prokinetic oscillation but this anti-kinetic oscillation goes away.
And now what happens with DBS? Now recordings from patients in operating rooms recording this beta synchrony when the DBS is working and then they turn it off after a longer period of stimulation like a 5 minute stimulation and for a period of time, up to a minute, you still have this suppression of beta synchrony. It's kind of time dependent. If you do like a shorter period you get a little, and then it goes away. And that's during the period that they still have the benefit even when the system is off and then the benefit goes away. So now we have direct evidence that the same thing that levodopa does the DBS can do in terms of changing the synchrony. So this seems to be one of the key functions of how it works. And also brings the door open to the idea of okay if we can tap into this abnormal synchrony in an individualized way, because it's different for each patient, maybe we will have a better way of controlling symptoms if we can you know promote the DBS technology to the next generation.
Now on top of it we talked about the network and we know these changes affect the whole network. So the whole idea of these targets which we us STN and GPi as a standard target are that they are working but the idea is if you can tap into this network in any other place that you get the same result without interfering with the normal function you should be able to get the same results because it's a network effect. So some way of looking into it which has been the idea that we have this resting state activity which you can look with FMRI, and this is abnormal in patients with Parkinson's disease. So there is some now evidence that in patients with Parkinson's disease there is a change in the coupling between these areas in terms of how the two areas connect to each other. Maybe shown better here. So it's thought to be an end result of when we put electrode in STN we exert a modulatory activity on a number of areas in this network, there is a positive modulation of thalamocortical pathway allows the movement to happen. There is also some inhibition of this hyper direct pathway which is kind of decreasing the activity of subthalamic nucleus so - and that's partly because of these adjacent fiber tracts which go through it. I think that's part of the reason why it works.
And finally in terms of how DBS works, keep in mind that there is - if you turn the DBS device on and off you have some immediate benefits which go away. Like tremor for example appears right away, but there are some effects of the DBS which may last for minutes or even in hours. So some of the rigidity and some of the axial benefits may take hours to wear off. So we know there are different types of mechanisms, it's not just a single mechanism that delivers the effect of DBS because these symptoms wear off at different pace. Then we have some other conditions not Parkinson's but most notably dystonia that we have a much more delayed way of acting of DBS in patients with dystonia turning on and off the device doesn't do anything. They have to be adjusted and be on those settings for months at least to get the benefits. So then we think it's some affecting of the same network but to a mechanism that involves neuroplasticity. So arguably there may be some of this involving Parkinson's as well, but in terms of motor symptoms we think about the shorter period of time.
Now what's the evidence for clinical efficacy geared to our brief summary of - now we know this is working and you know that's why we are clinically using it. It's an aggregate of some of the major studies with Parkinson's showing the percentage just for you know improvement in major parameters. So motor score during the worst time off medication there is improvement in that; motor score during the best on time even gets better. Activities of daily living give more of a quality measure off time which is decreased in off time, the dyskinesia gets better and they are able to cut back on meds. So like major factors that we would consider as an indication for Parkinson's disease, there are multiple major studies that confirm the efficacy. And there is a list of those.
The big idea, the more common situation we would use it is this idea of the patients to get into fluctuations. They have benefit from levodopa and then they fluctuate. They have periods of time that they may very low on their dopamine level and as a result they lose that benefit of levodopa, it's a turn off, and then there we have this peaks that are associated with abnormal involuntary movements which usually develop after a few years as a result of sensitization of the (inaudible) receptors and other mechanisms. So these patients the goal for us is to decrease the dyskinesia and to decrease this off time and that's what it tries to do, to give them more a stable baseline, the medication still gives some benefit but even if there is no medication there is a much better baseline compared to when the device is off. And that's you know that's the way we look at this.
Now again this was like one of the major earlier studies, the different stimulation study group that showed we can achieve a better improvement of on time without dyskinesia when we use the EBS. Another major study was when directly comparing the DBS effect to the best medical therapy and again the major change was that you may get with DBS an improvement in the mobile time without dyskinesia. So you can improve the good on time and you know in some of the studies this translates to maybe 4 or 4 1/2 hours of better on time a day, which makes a significant difference for patients. And there is also evidence that this directly correlates to the quality of life because that's the big message here of when we consider DBS.
Now there is a more recent study and it's kind of a comparison. The patients who underwent DBS at a more advanced level, and patients who understand at an early level. This is kind of a new you know incentive that is driven again by Europeans and they said okay we start to implant a DBS early in the process when they still can be managed well with mediations, does it going to happen to help with the quality of life? And it was, I mean there is an improvement when you turn the DBS system on whether they are more advanced or even in the early phase you would get an improvement, in this case as kind of a Hoehn and Yahr Stage which is a measure of their mobility and there is also the same improvements in the quality of life measures.
Now there is also the comparisons, there is like big studies that was done, one of them was a VA initiative, and a couple of previous ones to compare the two targets we have, STN and GPi and basically I mean there is not a huge difference in terms of their motor efficacy so we kind of consider them equivalent, the big difference is in terms of if there is side effects, for example that one may deal better with, the ability to cut back on medication maybe a little superior. So the motor benefits are very comparable going back to the same idea that we are modulating the network so whether you do it at STN or at the output point of GPi you get the same results.
In terms of the ability to cut back on medications STN has been doing better and that also can be kind of consistent in most of the studies I would say. This is a cartoon in terms of overall they are maybe considered a draw. We tend to use STN a little bit more and it's like a little bit more in a smaller area, easier to manage. One of the you know advantages is in terms of ability to reduce medication, STN is superior. In certain patients for dyskinesia suppression GPi may be better although we a lot of times can do it here as well. There is also this concern that sometimes when there is significant problems with psychiatry issues or cognitive issues or very severe speech problems there may be some advantage to place it in the GPi, once again it goes to the discussion of patient selections.
And finally and very briefly talking about what's next. So we basically use these electrodes that Mark showed to chose how to do the stimulation. Now there is a field of stimulation, that's the area where we deliver the electricity and that's where we would get the results from. We can change this field of stimulation by choosing you know where we do the stimulation. If it's a larger field or we use a higher voltage we can get the bigger field of activation. We can change that pulse with duration of the pulse with stimulation, that translates into the neural elements that are involved so if you get the same area of stimulation you may partially involve the elements or you may completely involve the elements and get a different type of results.
Now why do we want a bigger field of stimulation? To get you know stronger results but why do we want to limit it? To prevent the side effects because when the electricity goes to the adjacent areas we would get to the side effects, the tingling, to the sensory pathways, pooling or weakness or dysarthria when we get to the internal capsule pathways, so we want to keep it focused.
Now we have limitations with current technologies and you know thus again why we get the problem because in STN we try to be in the dorsal STN and you are not close to the internal capsule pathways where we get most contractions and so forth, so ideal is we stimulate the area we want and avoid the area we don't want but remember here with our current technology we have a circular like a round shaped field of stimulation. So one of the you know ideas if you can change the shape of this, because we don't go send electricity in all directions, so how can we do that? A big idea here is what is called current steering. This is our current type of electrodes and this is what is you know the next level of the electrodes, have a more number of smaller electrodes and the idea is then you are going to be able to send the stimulation in a directed way so this is what we get. You have to put at the center, the red area is the area of stimulation and if you get here and you go outside you are going to get side effects, but if you have the ability to do the steering with this more advanced type of electrodes we will be able to get stimulation in the area we want and avoid the area we don't want. And this is really one of the most important practical problems we have when we do the programming. So I think that's one of the things that makes the programming harder because even with 4 contacts it's very difficult to do programming, have a lot of parameters. Now imagine you have a lot more to do, but it's going to give you a lot more ability to do. So it's an interesting challenge. And these thing have been already made, been already showing efficacy in small. They are not ready yet for primetime, but this technology is kind of very close. And this is again the idea, instead of going through the whole round area you define where you want to do the stimulation to kind of you know custom make it, and that really would be interesting.
The other idea in terms of what we do is this idea for closed loop, we talk about this responsive neurostimulation, the idea is you get the signal from the brain, give it back to it. So just briefly and Dr. Richardson is going to mention that too, I mentioned this oscillatory activity and you know one of the signals now we say this beta band synchrony is an abnormal signal and it's kind of individual as to the patients. How if we can record this signal in real time to the electrode in the brain and then disrupt it when it comes, and maybe even disrupted in a frequency specific way. So that's what the idea of a closed loop circuit targeting and signal that you know is abnormal. And we are learning more about the brain and what are the nature of these abnormal signals in the brain which a lot of them in the psychiatric disorders we may be able to this I think would I think a huge applicability.
You know this is again some major studies were published in the primaries, the system, the ability of doing this already exists and the ideas is you can basically pickup the abnormal signal or you can pickup you know the feedback signal from the cortex and deliver the signal to the basal ganglia and get an improvement in the experimental Parkinsonism.
So pedunculopontine nucleus has been suggested as an area that is involved in axial control of gait, it has a cholinergic component to them. We know it's one of the things that in Parkinson's it's not under well control is the problem with freezing of gait and aspects of the you know fluidity of gait that is not levodopa responsive and there are some preliminary you know data to suggest with the DBS in this area that can improve freezing of gait that is not responding to levodopa. It's a very deep area in the brain so Dr. Richardson should go really deep there, but I mean it's apparently feasible to do, especially with MRI guidance.
And another idea of this kind of abnormal oscillatory signal which I think is an interesting study was they for the first time in the patients who have Parkinson's they put these electrodes that do the recording. They recorded patients when they have walking and they have freezing of gait. This is really interesting data, we don't have a lot like that. And what we saw is there is an oscillatory activity that correlates with the freezing of gait in these patients, and that was interestingly in the alpha band, not in the beta band. And it was in a specific part of PPN, this was more a caudal part of the PPN that this signal was there. And they then did the stimulation, this was a small case series that could improve the freezing of gait in these patients and the best results were gained where they did the stimulation at the area that had the highest alpha frequency. So to kind of break this alpha oscillatory activity that correlates with the gait.
Now there is a caveat here, all of the talk is about high frequency signal which we think about to disrupt the activity, and in this case the idea with the alpha synchrony was it was actually something which was beneficial to gait, if they had the alpha they were doing better. And it is a low frequency signal, which we usually think is stimulatory. So this is very primitive of course and that's it for now.
Transcript - Pardini
I'm going to talk to you about a specific part of our candidacy determination which is neuropsychological assessment. And whenever I talk about what I do to people who aren't psychologists or neuropsychologists it's always important to first answer the question what is neuropsychology because many medical providers don't have a good idea about what it is that we do. And basically what we are are PhD trained psychologists who have been sub-specialized in assessment of the brain behavior relationship. So we are trained to understand how psychology and neurology interact to produce difficulty with thinking, behavior and so forth.
And in my opinion we are best utilized in a team setting. So you know the Movement Disorders Group is an excellent example of how people of various expertises can get together and really work in the best interests of the patient because we communicate regularly and we communicate often. So we are independent providers, meaning that we are licensed independently in addition to earning the PhDs and we do postdoctoral training which is typically 2 years after you receive your degree.
What happens during a neuropsychological evaluation which is a particularly important thing to understand when you tell a patient that that's what they are going to go do because it again sounds like a very mysterious thing. There are essentially four main parts that constitute what we do. First is obtaining a history both from the records, the other providers and the patient. And this history is often different and in addition to what's collected during a typical medical history. We want to know about a lot of premorbid factors so what was their education like, did they have any developmental problems growing up? Did they have any history of learning or attention disorders that might affect the testing at this point in a different way than how the disease or injury might affect the testing? We certainly want to know about past psychological history and then of course as we interact with people then we accumulate behavioral observations. So how do people respond to success and failure on testing? Are they particularly guarded or defensive or are they so anxious that testing is difficult to complete? So all of those things are important in interpreting the other information which you get from the assessment.
Our assessment tends to come from a wide variety of tests that are typically commercially available to people who are deemed qualified to give them. They most often in traditional neuropsychology occur in a pencil and paper format, meaning you and I sit across the table from each other and I administer a memory list to you. So I read you a list of words and you say them back and see how many you can come up with. Then I do it again. We do this several times to get a learning curve. Then we do a bunch of other stuff, and then we come back later and I say hey remember that list of words that I read to you? So it's a very interactive process where we assess not just memory which is an example but multiple domains of cognitive function which I'll talk about a little bit later.
And then of course this all gets assimilated - assembled into a report and having worked with medical doctors and particularly surgeons now the constant that we hear about our reports as psychologists is this is really long and it seems like so you know we are trained in graduate school for some reason to write 10 to 12 pages of a report, which is very useless in the real world setting. So hopefully what you get as a physician from a psychologist or a neuropsychologist who is trying to answer this specific question for you is a 2 to 3 page report. And then if you just read the summary you can kind of know what we are trying to convey. That makes it more useful for the patient and the physician and any other rehab providers if that becomes the case moving forward. So if you work with a neuropsychologist and you don't get that then it's always useful to say hey, you know this is what I - this is what else I would like to see in the report or you know can you make sure that the summary makes sense to you, both the patient if they pick it up and answers the questions that I've asked of you even in that concluding paragraph.
And then we do a follow-up consultation and of course the patient's physicians will - you know I'm just a small part of the process so they'll follow-up with their other medical providers but I do get feedback about to the patient and their family if the patient chooses to have the family present about their test results as well because you know one important questions is you know are you cognitive, are you cognitively okay to undergo surgery but also it's very important for you as the person who just went through 2 to 5 hours of testing what does that mean to me? And what are my testing patterns like and if there is an area of difficulty is there a way that I can improve that or are there things I can do in my life to work around that or compensate for any deficits. So the follow-up consultation is very important with the patient and it's also very important with the medical providers because working together as a group to figure out what may improve quality of life over and above surgery you know those are important components as well.
So in order to assess cognitive function what we really want to do is look at a wide array of cognitive function, and that's because even if this thing that you are concerned about is memory there are a lot of different things that can affect memory. If you cannot pay attention it's going to be very difficult for you to even encode the information to begin with. So there are people who have difficulty with memory because they have an attention deficit. There are also people who seem to learn information just fine in the initial phases but then 20 minutes later may not remember that we've even gone over a list together. So there is different ways that these cognitive functions can kind of come forth if you do good detailed testing.
Language we test in a variety of ways as well. There is kind of the language that sticks with you almost despite any sort of illness or injury like reading and vocabulary which gives you a good idea of what along with someone's education and occupation gives you a good idea of what their pre-injury, pre-illness, premorbid function is like. And then there are other language measures such as naming that can be a little more fluid if someone develops some sort of cognitive disorder.
Executive function as Dr. Richardson has already referred to are one of the functions that are vulnerable in Parkinson's so we try to do a good detailed assessment of the those to track over time and those are your higher level cognitive functions, and they really incorporate a wide variety like decision making, judgment, planning, there are so many executive functions, inhibition, impulses, impulsivity.
Attention is our basic attentional functions. We look at kind of simple attention, so hearing something briefly and being able to say it back immediately. We look at complex attention for the ability to hold information in your head, manipulate it and then present it back.
Visuospatial function, so ow people process visual information. So can they integrate separate things into a unit and get a gestalt of a picture based upon its parts? Can they see something and perceive it well enough to draw it or copy it well?
Motor functions, we look at fine motor speed as well as gross motor activity.
And then of course we look at mood and mood in general you know we tend to see most for anxiety and depression because they are the most common, but certainly if there are other mood disorders present or a suggestion of other mood disorders then we certainly screen for those as well. And in the corner you can see what it might look like to sit across from a psychologist and do some of these tests.
Like I said there are a lot of tests and this is certainly just a sampling of what is sitting in the bookshelves waiting for the next patient in my office, but I just wanted to show this to you to illustrate that you know some tests are talking, some tests involve manipulation or stimuli, some tests involve both of those things. So we really do have a wide variety of ways to assess different cognitive abilities, so if there is something that is a specific concern it may deviate from our standard battery in terms of what we do for DBS screening but we always can incorporate that in if a physician or a patient has a specific concern.
And now as many of the physicians have already alluded to in their talks there certainly are cognitive effects that can be directly attributed to the progression of Parkinson's. And a lot of those that are seen early on typically are the executive or frontal functions are the most well known and similar to that you can see difficulties with working memory or complex attention. Verbal fluency deficits can emerge relatively early and then some studies have shown less consistently difficulties with visual perception or memory. And you know we've mentioned this circuit over and over again but although the exact mechanism are unknown it's believed to be related to changes in that circuit.
There are many ways to perform a neuropsychological assessment as a screening tool for DBS candidacy and so when we thought about you know what are the best tests to choose for this one of the things to be mindful of is that you know neuropsych assessment in the traditional setting can be 6 to 8 hours, which is unreasonable for a patient who has a lot of fatigue, a lot of movement problems, who is going to be on and off throughout the day. So we wanted to try to capture a breadth of information that was number 1, able to assist us in understanding the patient's memory difficulties and cognitive problems and also able to give us a good idea about where patients are across multiple domains so that we then can track progress over time.
So this is the battery that I settled on which so far I think has worked pretty well for us. We do the mini-mental just as a basic screening mostly for orientation and just to kind of get a good idea upfront about where people are in a very basic sense. Same thing for the clock drawing which gives you a very basic understanding of planning and organization potential for detecting more significant problems as we move down the battery.
So Wechsler Test of Adult Reading provides in just a sample where you read and pronounce words, and that's one of those tests again that's relatively static that can give you a good idea of someone's premorbid functioning. So where would we expect them to fall prior to the development of disease or injury.
Trailmaking Test provides - the simplest version provides a good idea of psychomotor speed, attention, a little visual scanning. 'the second part adds in an executive function, so set switching, and this is where they move from basically connecting the dots from 1A. 2B, 3C, 4D. So not only do you have to have speed, attention, monitoring of responses you also have to understand where you are in the set so that you can continue to execute that switching correctly.
And then I use a screening measure called the R Band, which is used in - if you've read neuropsych research it's a screening test that's used relatively often. Number 1 because it's not - it doesn’t take a really long time to administer and you get to capture a lot of basic information about cognitive function, you get memory, visual perception, fluency, 4 digit spans, so simple attention, a little bit of naming and some processing speeds all within about 45 minutes and the other thing is that it's a battery that has really good, it has really established norms for a dementia population and so one of the things that you've already heard a lot of providers mention so far is that dementia is a risk factor for having poor outcomes following DBS surgery. So not only can we look at the pattern of people's responses but we can also look at whether or not the norms are more similar to a dementia population or more similar to the general population. So it just gives us a little more objective information as we talk about cognitive functioning of patients.
I do the FAS test which is another fluency test, it gives us (inaudible) unique verbal fluency. We do a digits backwards, digits sequencing so I say a string of numbers, you say them in backward order. I say a string of numbers, you say them in sequential order. They start really short and they get longer and longer and longer. The more you can do the longer we can go. And that gives us a good idea of working memory, complex attention.
The color word test is pretty much the same as the Stroop Test for anyone who has read any sort of psychology literature from way back. You get basically two speed baseline tests and then you get key word executive test and this is even available in popular literature in the sense that you've seen the word red printed in yellow and blue printed in red and green printed in orange and you have to ignore what the word says and instead name the color of the test. And that provides an ability called inhibition. So what is your brain's ability to inhibit the dominant response and instead follow the given rules, which is an executive function.
And then the DKEFS, this one that we give also has a cognitive switching task where in addition - where on the final part of this sometimes we have to inhibit and say the color, but sometimes yo have to read the word. So you have to hold onto that rule and be able to effectively switch.
The Boston Naming Test is a classic well known and well normed, reasonably well normed naming test. So again naming, decline in naming is something that we see in dementias like Alzheimer's which the really low naming can give us a good cue about basic cognitive functions.
Picture Completion gives us visual attention, visual processing and then these three tests here number 1 can give us - vocabulary can give us a premorbid estimate or a pre-injury estimate whereas these two are abstract verbal and nonverbal reasoning, so that' sone of those executive type tasks that we can follow over time. And then we do screening for depression and anxiety as well, because depression and anxiety can also have effects on cognitive function. So there are people who go to their physician or bring their loved one to their physician with concerns for dementia and what we may learn sometimes is they don't have dementia, they are really depressed because the patterns of the testing can look very different. So assessing mood and talking about mood is always important.
What we do here at UPMC is typically a presurgical assessment so as well as a 6 month postsurgical assessment. In the literature scant as it is you at least see follow-ups that range from 3 to 6 to 12., one with a 1 year follow-up. We chose 6 because 5, 6 months we should see programing in general should be kind of on its way. And then we can also do it as needed. So if there are any major changes that are noted at any point postsurgery then we can go back and do some testing and really objectively document whether or not any changes have occurred and why those changes might have occurred.
So you know not everyone does presurgical neuropsychological evaluations at every site. We do them for everyone, but that's not - you know that's not 100% what happens across the country. the two main reasons to do it have been alluded to, particularly number one which is patient selection and/or exclusion. So we want to make sure that if there are risk factors for poorer outcomes that both the physicians and the patients are aware of that and can have a better discussion about how and if to proceed. And then it's also good to have a baseline for neurocognitive status so again later down the road we can get more information about how they responded cognitively and certainly as the disease progresses that also gives us a way to measure change over time.
So in addition to risk we can also more objectively explore any subjective - any subjectively reported difficulties by patients or by their families. So if there are memory complaints what are they like, are they amenable to treatment? And with all surgical procedure you may get a good surgical outcome but there still might be subtle changes that the patient notices and they want to have that quantified and they want to understand it and explore it. And maybe you can still go back to work and do your job and do your daily activities and interact with your family but you know if you were high average before and now you feel like you are only functioning at an average level that's still a great outcome but for you the person that can cause some distress and that's something that a lot of people like to explore. And the other thing that testing can provide is to help make some other postsurgical decisions and we'll talk about those in a little bit.
Now some of these exclusion criteria or potential exclusion criteria have already been eluded to. If you look across the literature these are kind of the main ones that emerge and these are things that we consider: advanced age again, there is no - as has been said before there is no cutoff, most of the literature has looked at 70 and above versus below 70; advanced disease stage, dementia, severe other cognitive dysfunction or severe mood disorder. The problem with listing all of those potential exclusion criteria is that the research isn't great. There are case reports, there are very small end studies, 5, 9, 13 patients. There are very strange ways that have been used to classify improvement or decline, which you know 1 for improvement, 0 for decline and it is really a wide range of how this has been classified and a few times you read it and like how did this get published? But what exists out there are very few controlled studies and very limited empirical data.
Now in terms of the second reason to do neurocognitive testing is to establish that baseline for a later comparison and you know the one thing you can say by reviewing the literature is that some people observe cognitive changes following surgery and the best way to monitor that change is to have something objective that happened prior to surgery so that you can compare it. Our subjective report of our experience can often be very different than what the actual numbers say. And that can occur for a variety of reasons. So when we do these comparisons you know it gives information to surgeons, to the neurologists, to the patient, to the family and it really helps with planning a little bit more because a lot of these problems could be amenable to some sort of therapy. So the sooner we know what the problem is and he more we know about what the problem is the better and more refined recommendation we can make, which hopefully will lead to improved quality of life. And then at some point we need to have data from multiple people that have collected in a systematic and objective way with good long term follow-up that we actually can understand better what specific inclusion, exclusion, red flag types of characteristics are because again it's not very clear just yet by reviewing the literature.
I made this one slide to summarize the literature because again with the neuropsych testing it's not fantastic. The literature has been divided into kind of location of placement of the stimulator and what we'll - what we talk about is obviously GPi and SPN and overall there seem to be - there is evidence of improvement in some tasks and certainly subjectively I see improvements in motor speed and those kinds of things. Some studies have shown improvement in attention, many studies have shown some improvement in subjective rating of mood. Typically it's subjective rating of anxiety, subjective rating of depression has been a little more kind of marginally significant. What you see throughout the literature most consistently as Dr. Berman alluded to is - are changes in verbal fluency but that certainly doesn't happen in everyone and one study actually looked at the relation of cognitive changes to the relation of quality of life. And even though this group of patients experienced a decline in verbal fluency they still had improved quality of life that was comparable to those patients who did not have that decline.
So these subtle losses when we talked, when Dr. Richardson and Dr. Susky and Berman and Homayoun talk to patients about the risks and benefits of surgery you know one of the big things is quality of life. You have to think about you know with a loss of verbal fluency what's the tradeoff for you know having better movement and those kinds of things. So in some ways these things kind of muddy the waters but the big, I think the big take home point across all of these studies is they are never - in these studies there has never been an observed decline in overall cognitive function. So if you look from pre to postsurgery and you look at those big measures of cognitive function there has never been a statistically significant observed decline. So we see these subtle, this one has attention memory, most have verbal fluency but nothing that's this kind of huge, meaningful cognitive decline.
In terms of the psychological effect if you look across studies of mood changes there is an incidence of 1% to 25% in terms of experiencing transient mood changes that are often depressive after a DBS. That doesn't mean a major depressive episode, it just means an increase in depressive symptoms. These are often transient and the thought is that that may be due to the withdrawal of some of the dosage of the dopaminergic medications. And as I said before on the one study we saw that quality of life stayed up even if some subtle declines in cognition occurred and that we do see some reduction in mood symptoms in group data following surgery.
And that's not to say that you know Dr. Berman referred to and Dr. Susky severe mood disorder, and that's a separate thing. If someone is so depressed that they cannot followthrough with appointments or the decision making process is unclear as to whether or not they are able to make a good informed decision because of mood, or the mood is severe enough that we actually think that they are more at risk for having worsening mood following surgery then that is a separate issue. But the typical types of mood problems you most often see don’t tend to change pre to postsurgery in a more than transient way.
The other thing that the report and assessment can be useful for is to make other types of recommendations. So sometimes it is helpful to know above and beyond what the physical symptoms are and what the patients think they are capable of in terms of are you ready to go back to work, are you ready to go back to driving? Is there any - and this is less so with DBS but with other surgical conditions is there any supervision that's required following surgery, and when people are returning to school those kinds of things and objective neurocognitive evaluation can help you as a physician make that decision.
And then other recommendations we can provide, the two most common postsurgical recommendations that I tend to provide along with the physician based on neuropsych testing is number one cognitive rehabilitation. So if for any reason a patient has a persisting presurgical or a postsurgical difficulty with memory, attention, executive function you can go to a speech therapist who is trained in cognitive rehabilitation to learn compensatory strategies for that difficulty. And certainly if psychotherapy is necessary you know at times as Dr. Susky mentioned if someone has some mood complaints we want to make sure that if they are eligible for surgery we also don't ignore the fact that mood complaints are there. So we want to make sure that they have a good social support system, maybe get involved with psychotherapy or someone to monitor them, or psychiatry, someone to monitor them over time. Surgery is a big deal so if you already have some vulnerabilities with mood changes it may be useful to have someone else to kind of help you process those changes. There is such as thing as you stress, so even when good things happen to us that can cause a change in our mental health function, I mean retirement, marriage and childbirth are all good things but they also can cause big life changes that can cause the changes in psychological functioning. So just because you know it's something positive it still doesn't mean that you don't need to monitor mood. And then these are other evaluations that may or may not be necessary. The top two being underlined just because they are the most common.
So in summary what the literature tells us is that if a patient has borderline cognitive psychological or both functions that we believe that they are at risk at least at in somewhat increased risk for difficulty, increased difficulty postoperatively so having an objective measure is one extra piece of data that the team can use to really make a good determination about someone's candidacy and to give the patient all of the information that they need to make an informed decision. Research does suggest again the research that exists does suggest that older patients are at greater risk for postoperative decline, there is some suggestion but again it's controversial and still up in the air that GPi might be a safer target in that situation. And then again I think that you know this is one part of a big team decision that really helps us understand what's going on with a patient before and after surgery; but certainly in reviewing all of the neuropsychological literature the one thing we do understand is that we need a lot more objective research with larger numbers of people to really understand more precisely these risk factors. Thank you very much.
Transcript - Richardson (DBS Surgery)
So I'm going to talk to you about the surgery itself, we'll quickly go through the targets and some of the outcome data just to be clear on that. And I'll show you some videos of what it's like in the operating room, and then specifically we are going to talk about the difference between awake microelectrode guided brain based surgery, stereotactic brain based surgery, which is the traditional way to do DBS, and then interventional MRI guided DBS which was FDA approved in 2010 and which we've been doing here for the past 2 1/2 years.
So let's go right into the risks. So really regardless of the brain target with some caveats and of course it depends on the patient's age and do they have a risk for coagulopathy and other things like that which are specific to the patient I basically quote everyone the same risks, and that's with the bilateral simultaneous implantation. So that's doing both sides at the same time. There is about a !% chance for a symptomatic stroke, so that's 1% per side of any bleeding, 1/2% chance that that's going to give a permanent neurologic deficit, so you put the two sides together you have a 1% change overall to serious stroke with simultaneous bilateral implantation. So it is a low risk but it's a real risk and we have very frank conversations with the patents about that to make sure that they understand that this a brain surgery and that bleeding in the brain is a potential risk.
I tell them the real risk though is one of infection. So there is about a 5% rate of infection if you look across published studies. Our rate is actually slightly lower than that but we do have infections every once in a while. Most of the time we can treat these with antibiotics and what we'll do is admit the patient for IV antibiotics if there is a problem with the wound, and occasionally we have to explant the whole system. Now that's rare but we have had to do that. The thing that we want to prevent is infection in the brain. The hardware can always be reimplanted if indicated, if the patient desires if they were to get an infection.
And Jamie gave really just such a nice summary of the literature and overall gestalt of that literature which is - and this is what I get out of it, there is about a 5% chance for a mood or cognitive change and for patients that are really concerned about that it can be difficult to discuss and that's why because this is the hardest thing to predict. We do this surgery to improve motor outcomes in our mood and disorder patients to improve motor outcomes and we are very interested in the non-motor effects because this is under study and that's why we have a database setup and then we monitor this very carefully with that 6 month follow-up.
All right let's briefly go through the targets because I think one thing that you should get out of this course is just a kind of a basic knowledge of okay what are the targets, what was that place again where they put the electrodes for Parkinson's disease. So this is a schematic and I think Dr. Homayoun already showed one or similar to this but let me grab a pointer. You know we don't put the electrode in our Parkinson's patients at the site of pathology which is the substantia nigra down here in the mid-brain that's sending these dopaminergic fibers up into the striatum that degenerate, we put them downstream in this basal ganglia circuit. The basal ganglia is not responsible for the initiation of movement but it has a large role in controlling what we call move making gain or different factors related to how movement occurs.
So there are two primary outflow pathways from the basal ganglia, one is the globus pallidus and the other is subthalamic nucleus and the target in Parkinson's disease is either of those for the reasons that have been discussed before, possibly neuropsychological reasons or the thought that patients who really need to reduce the amount of dopaminergic medication they are may benefit better from subthalamic nucleus stimulation for whatever reason. Why that happens is still not clear.
I do what to mention even though Dr. Berman mentioned this, that after this and Dr. Homayoun as well, after this 2009 study came out in JAMA which was the VA, Veteran's Administration, cooperative study, a big multicenter trial that showed actually two papers. The first paper showed that in comparison to best medical therapy, so this is groups of physicians deciding on the best way to treat patients medically, but in randomized controlled fashion patients who underwent deep brain stimulation did better. So there is clear class I evidence for that and that's why DBS again for the correctly selected patient is the gold standard for medically refractory disease. And the reasons are there is a gain in on time of about 4 1/2 hours compared to 0 gain in medical group in that study, 70% of patients had significant motor improvements compared to half that in the best medical therapy and as Dr. Pardini mentioned quality of life improvements from this surgery are actually huge in that none of these measures improved in the medication group in this trial and 7 out of 8 did in the Parkinson population.
The other very relevant study is this one that Dr. Berman mentioned in younger patients and similar changes. So quality of life improvement of essentially 26% on average in the DBS population compared to a 1% worsening in the best medical therapy group. And you can see the data there for the motor component of the UPDRS with significant benefit in the DBS group compared to best medical therapy. And some of that has to do with the fact that medication can decrease in patients who undergo DBS but as you would imagine in the medical therapy group on average it's going to keep going up with the complications that come along with that.
So again these two studies have really changed the way the field thinks about Parkinson's disease because we now have objective data that patients essentially do better with DBS therapy assuming they meet the criteria and they are appropriately selected. So that's why we are having this symposium. And then a lot of the lessons that have been learned from movement disorder surgery are now in the process of being applied to other patients that we are going to hear about this afternoon, obsessive compulsive disorder, depression and epilepsy. And we are further away in terms of the objective data there for sure but there is a lot of work being done.
Okay, this is moving on to essential tremor, you've already been told that the target is thalamus. What's the data here? There will never be a large randomized controlled trial with DBS for essential tremor because it works too well. So anyone who is at this stage and saying yes I'm ready to go for essential tremor would never agree to be randomized to a nonsurgical arm because they know that surgery is going to work. There are multiple studies of single institution, etc. that have shown on average an 80% improvement in upper extremity tremor. It's a myth that the head and voice tremor with essential tremor don't improve, they actually usually do it's just harder to predict the extent to which they will and when they will. But they actually usually do improve as well, it's just that tremors distally improve much more quickly and easier than those are proximal, voice being the hardest. And as some of the other speakers alluded to there can be a lot of reasons why a patient might have a voice tremor so these are very careful discussions that we have. But in relation to essential tremor these actually usually do improve.
Now dystonia, Dr. Susky talked to us about the target being globus pallidus, what's the data there? There are now - so smaller numbers of patients have been studied, there are a lot less patients with dystonia than there are with Parkinson's disease. So this is actually a real concern of patient support groups and maybe some of you maybe are involved with them in the dystonia population because they really feel overshadowed by the Parkinson's group. But we've still learned a lot about how to treat these patients. If you look at the worldwide literature it's over 300 patients now, it sounds small in comparison to Parkinson's disease but it is hard to publish these, these trials. So for generalized and segmental dystonia, so segmental dystonia is dystonia that combines two adjacent body parts. If you look across and actually these are not U.S. studies but there are two studies, European literature that show Class I data for 40 to 70% improvement. It's a broad range but I tell patients that we are shooting for about a 50% improvement in your symptoms.
The best response by far is with patients with a DYT1 mutation, so these are usually picked up in the pediatric population and this is a home run for DBS. These are kids, pretzel kids, that literally just unwind over the course of stimulation and GP1. So occasionally these are caught in the adult population. If you are a practitioner that treats a pediatric population with dystonia it's important to do genetic testing because that can stratify their potential benefit of brain stimulation.
There are actually similar results in cervical dystonia but there are even less of these patients, there is not randomized control data but if you look across the studies again I tell patients about a 50% improvement on average. Now there is some patients who still are not going to respond really very well. You have those patients and there are some that it can take 2 years but the head is perfectly midline at 2 years and they are essentially for practical purposes not very symptomatic.
Even smaller numbers of patients with Meige syndrome, so that's a little bit of a misnomer because this should really be called craniocervical dystonia specifically or a mandibular dystonia with blepharospasm is Meige syndrome. So we do treat these patients with DBS as well.
And Dr. Hudak who is going to talk to us about targets in OCD has some very nice slides so I'm not going to talk about that now.
Okay, so this is what traditional deep brain stimulator surgery looks like. So here is the surgeon and assistant, here is Dr. Crayman, a neurophysiologist, here is Danielle Wagner our physician assistant who also participates in the operating room and helps with intraoperative stimulation and this is a patient from Pittsburgh who has given her permission to have this picture used. A very nice lady who had a rigid akinetic Parkinson's so probably have this on a slide but in case I don't this is also another myth that it's only the patients with tremor that are really going to get a benefit from DBS. That's not true, rigid akinetic patients essentially respond just as well in terms of their UPDRS improvements. It's just not as dramatic to see.
So this is a lady who ended up doing very well and she opted for awake surgery so this is part of the stereotactic frame, it's covered by a sterile towel here and it's what patients call the halo, it's not a halo like we've used for someone who has a cervical spine injury but it is a frame, stereotactic frame, that's what it is called, that is bolted to the skull. We do this with the patient essentially under conscious sedation, also known as twilight anesthesia. So our patients and the awake cases are asleep, some of them snoring at the beginning and into the case, but we wake them up in the middle of the case for the deep brain mapping portion because that's how in the absence of being able to see in real time where the electrode is going, now that's how we know for sure where we are.
Now the stereotactic frame on average has an accuracy on the order of 2 to 5 mm, I mean few academic centers with large volumes have errors above 2 or 3 mm. But still when you saw (inaudible) very small, it's a structure that's 7 or 8 mm long. So 2 mm is a big deal. So because we can't see it we can use brain mapping to verify where we are. Okay, so how does that work? Let's see if I can play this movie.
Okay, so you are going to hear the sounds of the brain and this is a schematic of a trajectory, so this is a sideways view or sagittal view of the structures in the brain. Here is the thalamus, here is the subthalamic nucleus. Below that is part of the substantia nigra and all of these sound differently as you pass an electrode through there. So we are recording electric activity and then we are amplifying that on a speaker. And this is what it sounds like. (SOUND) That's a single cell. (SOUND) This one is two units. (SOUND) And I'm not sure if you can appreciate the difference there but that was a higher density and a more constant firing of neurons which indicates that we passed through the bottom of the subthalamic nucleus and into the substantia nigra.
So sometimes we do this one time and it makes perfect sense, and then we move on and implant the stimulating electrode which is the permanent DBS electrode. This is done with an even smaller electrode that is just used for recording because it can record from single neurons. But sometimes it doesn’t make sense, and so that's why we do this, we do a couple other tracks to verify where we are. So this is the critical part of the operation in awake cases and those sounds that you heard do not sound that good to patients asleep or under general anesthesia. Now it is possible to do this under general anesthesia and usually the localization is good enough, but the gold standard is to do this awake and even there is a difference between the patient's eyes open and closed in terms of the quality of the signals that we hear in the operating room.
Here is a video that's going to show you what this looks like in the OR. So this is a microelectrode guide that's attached to the stereotactic frames that's positioned above the patient's head and this is Dr. Kremens' computer in which we are watching action potentials in real time and then the audio is going to turn on in a minute so you can hear this. (SOUND)
Okay, I'm not sure if you could appreciate that at the end but at the final hand twist you could hear modulation of neural activity, you could hear a shhh, shhh, shhh and that's confirmation that we are in the motor sensory part of the given nucleus. Now we can find this in GPi, we can find this in STN. For our essential tremor cases because the target is so large we typically don't need to do microelectrode recording although that is still done in some centers, we don't do it here. So point being now think back to that slide at the beginning about different loops, circuitry loops in the brain and we want to make sure we are in the right loop. So in this case now we know we are in the motor territory so we've got a good spot and we can go on to implant the stimulating electrode.
Okay, let's talk about awake versus asleep DBS and let me just think about the time, so we've got plenty of time here I think. So awake surgery is traditional surgery with conscious sedation at the beginning and end, the patient awake in the middle, stereotactic frame based. it's microelectrode guided as I just showed you. There is the opportunity for intraoperative testing with the patient and it was FDA approved in 1997. So these are the points that we discuss with the patient when we are talking about different options, and patients can go online, we have videos online, we encourage them to you know read about former patients to read the information that we have online or the website and we want to make sure that they've seen pictures of what it's like to be in the operating room, and they have a good understanding of this.
And so patients tend to fall into two categories. The first category is oh wonderful, I'm going to be awake and you can, you know we can test this out and I'm anticipating surgery, this is going to be great, sign me up. And the other half says I would never have come to this office if I hadn't heard that you could do this asleep because I think that's insane. So what is asleep DBS? The way that we do it is in the MRI scanner, so we essentially turn the MRI scanner into an operating room. That allows the patient to be under general anesthesia because the way we are confirming that the electrode is in the right place is with serial MRI imaging. It's real time MRI guided, there is no intraoperative testing. Some people may see that as a downside because you lose the ability for physiologic confirmation if the electrode is in the right place. However it really should never be in the wrong place because we can see it. And we'll talk about how we know what the right place is based on the MRI in a minute, but I can safely tell you we have not had to reposition any of our electrodes. In our early data there doesn't appear to be any difference between using the MRI versus microelectrode recording. And this was FDA approved in 2010. So we have some patients that say oh this is the newer procedure, okay why don't you do it the way that it's been done for 25 years and we are quite happy to do that.
So this is what this looks like, literally we turn the MRI and we have a large bore MRI in which we can operate and I'm going to show you a video of what this looks like and this is one of our ones that's online so it's already narrated.
This video illustrates the basic steps involved in performing implantation of deep brain stimulating electrodes in an MRI scanner. The surgery occurs with the patient asleep under general anesthesia even before entering the MRI scanner. Surgery occurs at the head of the magnet and the anesthesiologists monitor the patient's condition from the foot of the scanner. Real time MRI scans are sent to a software program where the exact target for electrode placement is planned and the site of the skull opening is determined. Next an aiming device is mounted to the skull at the indicated location, a hand controller is attached and the patient is returned to the center of the MRI for a series of scans. Through obtaining these real time images the software generates instructions for lining up the aiming device until the predicted error for hitting the target is less than 1/2 a mm. When the actual trajectory matches the plan trajectory the DBS electrode is implanted. An additional MRI scan is then obtained to verify that the electrodes are located directly in the planned target. Both types of surgery are expected to achieve the same outcome for patients.
Okay, so both are expected to achieve the same outcome and I'll tell you essentially this is a skull mounted aiming device that is temporarily attached, making an incision in the MRI scanner, put it on as you saw, have the patient scanned, manipulate the aiming device according to instructions from the software, and then everything is removed at the end and at the end of the day they are exactly the same as the patients that underwent wake surgery. If you'd like to see this device the company that makes it is MRI Interventions has some models in the back, you can actually play with this yourself and have a look at it and get a better understanding.
So you know why would anyone ever develop this because a DBS works well anyway with the frame, so there is a category of patients that have anxiety about surgery specifically that's so severe that even if they've known that they've been candidates for DBS for 6, 7 years just won't do it, either won't go talk to neurosurgery about it, won't talk to their neurologist about it in a serious conversation or will see a number of physicians and just can't proceed. So I've seen a lot of these patients that show up and they say I'm so happy to realize that you have this because there is just no way I could do this awake but I know that this is going to help me. So it's nice that we have that option. We have some patients that would be perfectly fine mentally to undergo awake surgery but the tremor is so severe or dyskinesia that it just makes it much easier to do this in the MRI. We also have patients that are older and maybe some of our patients are already confined to a wheelchair because they are debilitated, it would be extremely uncomfortable in the operating room and those patients often choose to undergo MRI surgery.
And again just to bring up the pediatric population, there are small numbers of pediatric indications for DBS. These are rare cases, however in my mind there is really no doubt that the MRI is best suited assuming that you are using an MR - a visible target which you would for dystonia and GPi and again the reason that we can do this is because we can see these targets very well on the MRI and I'm just realizing I omitted a scan of an MRI to show you. But because of people doing this surgery now for a long time publishing results on which parts of the subthalamic nucleus and globus pallidus are the motor territory. What are the effects of stimulation in the operating room or the long term outcomes looking back at the location of electrodes on postoperative MRI scans we essentially know where the territories are in these structures and that's why we feel that we can place the electrodes there and still expect the same benefit.
And we are actually pretty close to on time. I want to show this one video of a patient talking about his DBS experience because I think it encompasses a lot of the issues that we've talked about so far today. So I'll just play this and then you can think about your questions and then we'll do a Q&A before lunch and then we'll have the break for lunch.
Well I was suffering primarily from tremors. My neurologist never hesitated to increase my prescription of Sinemet or add on Requip, just added on the medication. And then I found that my on and off times were growing every more compressed. I was becoming more off than on. My condition was deteriorating fairly quickly and I didn't think that medication could be the long term answer.
If I could tell you an amusing little story. Perhaps the most distressing thing of all was that I like to play a lot of golf and I could not tee up a golf ball. Finally one of my golfing partners or buddies would say oh here, let me tee it up for you, gee, you know. And it got that bad, I couldn't even put a ball on the tee.
Then Dr. Richardson came out to one of our support group meetings about 3 years ago or so, and I was very impressed with what he had to say and how his approach was different from what had been going on beforehand. I remember the day, October 7th of last year I had put in my month of waiting for any brain swelling to go down that naturally occurs with any kind of brain surgery. And Dr. Homayoun at the Kauffman Building in Oakland, a very expert neurologist programmer turned it on and immediately I became still, very still. My son Carl was over there in a chair and he says my God you are not shaking. Just like that. It's been that way ever - for just about a year now. I'm much more even tempered, I'm almost pleasant to be around again. I sleep much better at night. I can do activities again that I either couldn't do or didn't want to do when I had the Parkinson's prior to the DBS. And I engage much more in social activities again and I'm back to doing them again.
Okay, so you know I think that really speaks to the quality of life issue. Obviously this is a patient that did very well with essentially no complications at all so it's cherry picked, we didn't ask him to say the propaganda pieces. So I apologize for that. But you know I think he's a good example of it. This is a patient that we try to find. There was no question about his candidacy, he's someone who had known he was a candidate for some years and opted for the MRI procedure, that's what he's talking about in terms of the different approach.