04082014 B Cns Deviceinterventions

okay, lets go ahead and dive into wrap up our CNS work that we left incomplete at the end of last session. And we'll finish it up. And what we want to talk about is the interventions. What's the, currently available status of interventions in the Central Nervous System? Well, it's limited. There's not a lot we can do because we don't understand. The system enough because it's fragile. Our tools are inadequate. They span things like electroconvulsive therapy to Vagus Nerve Stimulation, Transcranial Magnetic Stimulation and Deep Brain Stimulation. Huge opportunities for bio engineers and all of these fronts. This you know, is commonly known as electroshock therapy. You might have heard about it. It's actively used around the world I myself have delivered more than 200 of these treatments. It remains the best treatment for refractory depression but it is astonishingly crude. I wish we understood more about how this works. The fact is we don't. But this is what happens. You take a patient. You put an electrode, surface electrode on either temple. You put them to sleep, and you actually paralyze them. You give them a muscle paralytic, so their body doesn't move. They can rest peacefully and you give them a seizure. You pass 100 to 500 millicoulombs from one electrode to the other, and there's a huge activation of everything in the brain. The parasympathetic nervous system is activated, then the sympathetic nervous system. You have a seizure that lasts for about a minute. Everything changes. There's sprouting of connections, there are. Neurotransmitters that appear in the cerebral spinal fluid. There's elevated metabolism. Everything happens. We don't know which of these is causal in giving rise to the anti depressing, anti depressant effects of electro convulsive therapy. Every time we try to make it more precise, more limited, more restricted to one part of the brain it is less effective, okay? So that, unfortunately is the state of things. Some of the hypothesis people thought maybe there's down regulation of neurotransmitter receptors maybe there's altered blood flow to the frontal lobe. There are some side effects, people are transiently confused, and some people complain of lasting retrograde amnesia. They'll say they can't remember a few months or a year or two of their lives and that's a serious issue. But it's life saving for many people. [COUGH] You can do it three times a week for eight to 12 total treatments. They'll still relapse like any psychiatric treatments, 50 to 80% will relapse within the first six months to a year. You can do what's called continuation ECT come, have them come by every week every month even. You can space it out to every three months to maintenance treatment. Again, we don't understand how any of this works. It's purely empirical. Now, there are more precise things people have tried, Vagus Nerve Stimulation is kind of interesting. The Vagus nerve is the tenth cranial nerve that runs down both sides of your neck it innervates your gut, your heart, but it also brings assurance back to the brain and those report on homeostasis of the abdomen and thorax. And you can put a little cuff around the Vagus nerve right here in the neck. As you can kind of access those afferents that are going back to the brain. You implant this little controller under the clavicle. And you can control that with a hand held wand. Radio frequency interrogator controller, much like a pacemaker. And I have a few patients in my clinic that I, I use this for. But again, we don't know how it works or why it works. It's actually not that effective, to be honest. What's nice about it is how it does let you access the brain without going directly into the brain so you avoid brain surgery by using this access route. The little surgery site in the neck barely visible and another little surgery site under the clavicle. Quantitatively what does it do, well it delivers a, a tiny current to the Vagus nerve. You pulse it at 20 to 30 Hz. Uh,leave it on for 30 seconds then it's off for five minutes then there's a duty cycle that's just free running around the clock its mostly off. And you elevate it to to about probably between two, it'll hit about two milliamps or until there are side effects, but what are the side effects? They're pretty substantial. This is. Kind of thing you can see, voice alteration that's very prominent. When it’s active, the voice sounds like they're being strangled. It's a very raspy, a strangled sort of sound. And so someone who has public speaking or in conversation as a normal part of their life, it's can be. You kind of cough, have neck pain, dyspnea is difficulty in breathing, dysphagia is difficulty in swallowing, all kinds of other things associated with the spread of the current around the neck. So you're you've got this current that's being delivered to the Vagus nerve that's affecting the [UNKNOWN] and [UNKNOWN] nerves and some of those side effects dampen out by nine to 12 months but some don't. But how effective is it? Well, it's pretty small. You've got depression rating scales that people use. You know, this goes down to 0, but just, it blew up to 30 to 45 region. The higher you are on this, the more depressed you are. And, you know, they didn't really do a side by side comparison. This was the pattern of the reduction in the depression score with the Vagus nerve stimulation. A little study, 205 patients. but, their comparison group also went down. It was statistically different. But this is not a huge effect. You know? The difference between 40 and 35 on, this depression scale. It's [UNKNOWN] look big, but it's really not that big. And. Clinically, it's, it's sort of unsatisfying to use. Many patients don't get better. All right, this is a more interesting one and that's it got, maybe, a bigger upside and more flexibility. This is transcranial magnetic stimulation. This is also FDA approved for depression. You put the patient in the chair and bring in a coil. That looks like this close up and you can tactically place it over particular parts of the brain. Still outside the brain over the skull, and the patient is awake and alert, you can do this in your office, as we have done a number of these at Stanford. Uses induction, uh,you have. Current that's in this, there are coils of wire, copper wire inside this little device that comes close to the brain. And what you do, is you pass current through it and that creates a magnetic field, and you pulse the current so it creates a rapidly changing magnetic field. And that, in turn, will induce. An electric current in the brain rapidly changing magnetic field will penetrate, and will change rapidly as that one is pulsing it in that one current of the brain. And so the quantitative parameters are pretty interesting here. You have enormous currents going around the coil, of thousands of amps, which is pretty remarkable. Magnetic fields that are generated on the order of Tesla, which is amazing for this small device, and you have rapidly changing e field, ball-induced currents. The spatial resolution is on the order of centimeters or so. You can't resolve smaller regions than that. But it's still been useful. People have used TMS to stimulate peripheral nerves first of all but you can also use it centrally. And you can compare motor output with a peripheral versus central intervention and that kind of lets you subtract them and see well is the patient has a problem in a signal getting from here to motor output is it more. The distal part, the peripheral part, or, is our central component as well. And so you can measure things like the delay, the threshold and amplitude of the peripheral response. It's not actually. I've done this myself. It's actually kind of interesting. You feel a little tapping sensation of tapping, and that's due to recruitment of the muscle, the scalp muscle. If you put it over motor cortex, you can get a, a twitch of the contralateral side. If you put it over occipital cortex you can see sometimes glowing lights and so that's kind of fun. For depression. >> [LAUGH]. >> We, we put it over the frontal part. This is actually kind of interesting though. So over motor cortex you get twitches. You put it over the whole frontal part of your brain which is involved in planning and, and motivation and hope. It's kind of interesting question to ask what do you experience when you're doing that? And the answer is nothing. So I've done it to myself I just, I cant, there's no, upon introspection there's no subjective sense at all. And yet that's the area we target for depression. Kind of interesting. again, we don't know enough to apply this, in an intelligent way. We don't know the right pulse pattern. We don't know the right location. We just generally apply it to this area, because we think that's involved in motivation. But a huge upside, if we understood, much about the brain. We could be much more precise about what we're doing. And you can recruit even though the, the magnetic field doesn't penetrate as deep as you'd like, it drops off with between a cube and a square while you actually of course everything in the rain is connected. So you can actually improve [INAUDIBLE] by recruiting surface structure. The final interventional technique to highlight is, deep brain stimulation, and this is where you just jam an electrode in the brain. So this is brain surgery. It's invasive. But it actually works. It works for Parkinsonism. About half the patients who have Parkinson's, deep brain stimulation to the subthalamic nucleus, is very powerful in, in solving. Aspects of tremor and bradykinesia or slow movement. It also works for depression, at least it's thought to. There was a report in 2005 which was buttressed by follow up work from Helen Mayberg and colleagues where they targeted the subgenual cingulate gyrus. That's a, its a frontal region but it's a slightly deep structure and they introduced an electrode. And just, this is the electrodes that are 1.2 mm in diameter electrodes, and they just brought them in bilaterally and just cored everything out on the way down, so it's pretty crude, and obviously you're only going to do this for pretty severely depressed patients who are treatment resistant. But they did it, they hit the set bilateral structure, the subgenual cingulate. And, it was exactly the region they wanted, in sergial section its this little, in the front and the patients had pronounced effects, they felt calmer, lighter, they had reduced sensation of emptiness or void. They felt more connected they had more planning, and motivated activity. And that helped for more than six months, and this was supported by, PET imaging studies. You remember our discussion of, PET, in Helen Mayber's earlier work, she had found that this subgenual cingulate structure was, hyperactive in depression at baseline. This is cerebral blood flow as measured by PET. All patients versus normal controls. And the regions that are increased are shown in red, and you can see that in the sagittal versus coronal sections, increased subgenual cingulate or CG25 activity. And then the patients who, responded at three months showed decreased activity there, and that was maintained at six months. So it's an interesting way to correlate a brain imaging with a [INAUDIBLE] response. Now it doesn't always work and so follow up studies have not been as promising as the first one but still shows the potential in deeper understand of the crucial. So that's our sort of central nervous system overflow from last time I just wanted to give you the state of the art in terms of [UNKNOWN]. Any questions on that or on Central Nervous System in general. Yep. >> [INAUDIBLE] >> Yeah, so any, any foreign object inserted into the brain will cause local Gliosis, which is a perforation of the glial cells, and it's effectively a scar. And it's thought that that is why deep brain stimulation stops working after about a year or so. But there are all kinds of tissue responses that might be therapeutic or helpful too. And we don't know which of those are helpful and which are not.