1 00:00:00,250 --> 00:00:01,800 The following content is provided 2 00:00:01,800 --> 00:00:04,040 under a Creative Commons license. 3 00:00:04,040 --> 00:00:06,890 Your support will help MIT OpenCourseWare continue 4 00:00:06,890 --> 00:00:10,740 to offer high quality educational resources for free. 5 00:00:10,740 --> 00:00:13,360 To make a donation or view additional materials 6 00:00:13,360 --> 00:00:17,241 from hundreds of MIT courses, visit MIT OpenCourseWare 7 00:00:17,241 --> 00:00:17,866 at ocw.mit.edu. 8 00:00:22,772 --> 00:00:23,700 PROFESSOR: OK. 9 00:00:23,700 --> 00:00:28,010 A little more about the normal striatum, 10 00:00:28,010 --> 00:00:30,840 but then we'll spend the rest of time talking 11 00:00:30,840 --> 00:00:38,806 about Parkinson's disease and treatment of Parkinson's and-- 12 00:00:38,806 --> 00:00:42,760 with methods that are to being explored 13 00:00:42,760 --> 00:00:47,810 not just for Parkinson's but other diseases as well. 14 00:00:47,810 --> 00:00:51,880 We ended on this rather difficult network diagram. 15 00:00:51,880 --> 00:00:56,680 The one thing that I note that's missing here 16 00:00:56,680 --> 00:01:02,080 besides the obvious things like I 17 00:01:02,080 --> 00:01:05,200 didn't put in the neocortical connections 18 00:01:05,200 --> 00:01:07,400 except the one from the thalamus because it 19 00:01:07,400 --> 00:01:12,100 receives a striatal connection. 20 00:01:12,100 --> 00:01:16,680 And actually the major output of the globus pallidus 21 00:01:16,680 --> 00:01:19,340 is to ventral thalamus. 22 00:01:22,550 --> 00:01:27,335 Where's does the VA of the thalamus project? 23 00:01:27,335 --> 00:01:31,100 Does anybody know? 24 00:01:31,100 --> 00:01:36,830 You know what the ventral posterior nucleus is. 25 00:01:36,830 --> 00:01:40,780 It gets the spinalthalamic tract and the medial meniscus 26 00:01:40,780 --> 00:01:42,780 pathway carrying some other sensory information. 27 00:01:42,780 --> 00:01:48,110 But that's caudal part of the ventral nucleus. 28 00:01:48,110 --> 00:01:50,930 The more anterior parts of the ventral nucleus 29 00:01:50,930 --> 00:01:54,250 are related to motor areas of the cortex. 30 00:01:54,250 --> 00:01:58,680 So the VL projects to the primary motor cortex. 31 00:01:58,680 --> 00:01:59,870 That's in the middle. 32 00:01:59,870 --> 00:02:04,730 And the VA projects the premotor cortex. 33 00:02:04,730 --> 00:02:11,795 Both can be considered motor cortex. 34 00:02:11,795 --> 00:02:15,550 The VA differs from the VL in that it's more concerned 35 00:02:15,550 --> 00:02:22,190 with movement patterns, whereas the motor cortex itself, when 36 00:02:22,190 --> 00:02:28,890 stimulated, moves individual muscle groups controlling 37 00:02:28,890 --> 00:02:30,610 a single finger, for example. 38 00:02:30,610 --> 00:02:33,530 A wrist or elbow or single joint. 39 00:02:33,530 --> 00:02:37,530 But what's missing from this that I wish I had more on 40 00:02:37,530 --> 00:02:40,590 was inputs to the subthalamic nucleus, 41 00:02:40,590 --> 00:02:43,700 especially because that nucleus is providing 42 00:02:43,700 --> 00:02:50,080 the major excitatory projections to the globus pallidus 43 00:02:50,080 --> 00:02:51,010 and to the nigra. 44 00:02:53,760 --> 00:02:56,075 Obviously very important. 45 00:02:56,075 --> 00:02:59,400 If you're missing that the whole system becomes 46 00:02:59,400 --> 00:03:02,220 unbalanced and you get some pretty striking movement 47 00:03:02,220 --> 00:03:05,830 pathologies in humans. 48 00:03:05,830 --> 00:03:10,620 The only thing I could find was there are projections coming 49 00:03:10,620 --> 00:03:16,490 in there, excitatory projections from somatosensory 50 00:03:16,490 --> 00:03:22,530 cortical areas and some more directly 51 00:03:22,530 --> 00:03:32,832 from somatosensory pathways coming from below. 52 00:03:32,832 --> 00:03:36,510 So what exactly that means, what I would like to see 53 00:03:36,510 --> 00:03:39,230 is a good computer model of this entire system 54 00:03:39,230 --> 00:03:41,475 because that's obviously pretty complex. 55 00:03:41,475 --> 00:03:45,490 And I think it would help us a lot in understand 56 00:03:45,490 --> 00:03:47,100 how this whole system works. 57 00:03:47,100 --> 00:03:50,990 But anyway, the kind of connections 58 00:03:50,990 --> 00:03:55,370 we have here with inhibitory pathways 59 00:03:55,370 --> 00:03:58,290 that are then connected to structures 60 00:03:58,290 --> 00:04:00,520 that inhibit further structures. 61 00:04:00,520 --> 00:04:04,810 So you have inhibition of inhibitory pathways. 62 00:04:04,810 --> 00:04:06,515 Obviously important in understanding 63 00:04:06,515 --> 00:04:12,180 the kind of things that go wrong with basil ganglia disorders. 64 00:04:12,180 --> 00:04:17,320 Parkinson's disease is the first example here. 65 00:04:17,320 --> 00:04:23,490 That's where you get cell loss here in the substantia nigra. 66 00:04:23,490 --> 00:04:27,940 And the cells that are being lost are in the Pars compacta 67 00:04:27,940 --> 00:04:31,520 here that provides that dopamine input putamen and cuadate. 68 00:04:31,520 --> 00:04:37,300 And it leads to-- that's one of the major things that happens 69 00:04:37,300 --> 00:04:39,660 in Parkinson's. 70 00:04:39,660 --> 00:04:43,730 And the striatum doesn't work well. 71 00:04:43,730 --> 00:04:46,523 You get-- the most obvious symptom 72 00:04:46,523 --> 00:04:49,600 is you get a tremor [? regressed ?]. 73 00:04:49,600 --> 00:04:51,610 And if they make an intentional movement, 74 00:04:51,610 --> 00:04:52,730 they'll stop the tremor. 75 00:04:52,730 --> 00:04:54,520 But if they're just sitting still, 76 00:04:54,520 --> 00:04:57,490 they'll show this kind of tremor. 77 00:04:57,490 --> 00:05:01,050 Very characteristic of Parkinson's disease. 78 00:05:01,050 --> 00:05:04,490 But as the disease progresses, you get an akinsesia. 79 00:05:04,490 --> 00:05:06,117 They move less and less. 80 00:05:06,117 --> 00:05:07,450 They have a characteristic gate. 81 00:05:07,450 --> 00:05:10,130 It's very recognizable. 82 00:05:10,130 --> 00:05:12,630 And then in the late stages of the disease, 83 00:05:12,630 --> 00:05:14,470 there are other things that happen too. 84 00:05:14,470 --> 00:05:20,350 Cognitive deficiencies show up. 85 00:05:20,350 --> 00:05:22,540 Other systems are clearly effected, not 86 00:05:22,540 --> 00:05:26,360 just the dopamine pathways and the nigra. 87 00:05:26,360 --> 00:05:30,240 But it is that nigral degeneration 88 00:05:30,240 --> 00:05:35,050 that accounts for the things that we 89 00:05:35,050 --> 00:05:41,960 see when Parkinson's disease is diagnosed. 90 00:05:41,960 --> 00:05:45,100 And other diseases like-- you get 91 00:05:45,100 --> 00:05:48,080 cell loss in the striatum in Huntington's disease, which 92 00:05:48,080 --> 00:06:01,575 is a genetic disease where it doesn't appear until adulthood. 93 00:06:01,575 --> 00:06:07,870 When people-- initially it looks like whenever 94 00:06:07,870 --> 00:06:10,150 they intend to move a limb, they, 95 00:06:10,150 --> 00:06:12,460 instead of moving the limb in a controlled way, 96 00:06:12,460 --> 00:06:15,550 they make a ballistic type movement. 97 00:06:15,550 --> 00:06:21,030 Have any of you ever seen people with these things? 98 00:06:21,030 --> 00:06:26,975 Parkinson's disease in aged people is more common. 99 00:06:29,980 --> 00:06:33,020 Whether that's really Parkinson's disease, 100 00:06:33,020 --> 00:06:35,710 they have Parkinson's like symptoms 101 00:06:35,710 --> 00:06:39,390 because they begin losing cells due to vascular 102 00:06:39,390 --> 00:06:41,960 insufficiencies. 103 00:06:41,960 --> 00:06:48,130 But anyway, in chorea, or especially in hemiballism-- 104 00:06:48,130 --> 00:06:51,300 in hemiballism they have a lesion 105 00:06:51,300 --> 00:06:53,974 of the subthalamic nucleus on one side. 106 00:06:53,974 --> 00:06:58,670 And when they make-- they intend to make a movement, 107 00:06:58,670 --> 00:07:03,340 they make a ballistic movement, that is, a flinging movement. 108 00:07:03,340 --> 00:07:07,300 The claim is that even these become involuntary. 109 00:07:07,300 --> 00:07:11,490 To what extent that's really true I'm not sure. 110 00:07:14,610 --> 00:07:17,520 But people say they didn't intend to doing that. 111 00:07:17,520 --> 00:07:19,630 But on the other hand, we're constantly 112 00:07:19,630 --> 00:07:22,470 making small movements. 113 00:07:22,470 --> 00:07:26,990 Basically, their habits now cause them problems 114 00:07:26,990 --> 00:07:29,610 because they can't-- they don't have normal control. 115 00:07:29,610 --> 00:07:35,100 Huntington's chorea, the genetic disease, 116 00:07:35,100 --> 00:07:37,430 they make writhing movements that 117 00:07:37,430 --> 00:07:41,180 was named the chorea or dance-like movement. 118 00:07:41,180 --> 00:07:43,740 But basically, they're involuntary movements. 119 00:07:43,740 --> 00:07:45,500 When people first getting it, they 120 00:07:45,500 --> 00:07:50,130 tend to hide it as if pretend they were doing something 121 00:07:50,130 --> 00:07:50,840 intentionally. 122 00:07:50,840 --> 00:07:52,740 But in fact, it gets worse and worse 123 00:07:52,740 --> 00:07:54,620 until it becomes very obvious that they 124 00:07:54,620 --> 00:07:55,825 don't have any control. 125 00:07:58,832 --> 00:08:08,270 So we think the double inhibition helps explain it 126 00:08:08,270 --> 00:08:12,150 because when you lose a lot of inhibition, 127 00:08:12,150 --> 00:08:15,395 cells tend to become hyperactive and produce 128 00:08:15,395 --> 00:08:19,880 abnormally increased movement instead of lack of movement. 129 00:08:19,880 --> 00:08:24,230 In Parkinson's disease, you get reduced movement except 130 00:08:24,230 --> 00:08:24,945 for the tremor. 131 00:08:24,945 --> 00:08:27,586 In these others, you get excessive movement. 132 00:08:35,980 --> 00:08:44,190 So let's go back to a more inclusive view of the striatum. 133 00:08:44,190 --> 00:08:47,710 Talk about-- integrate the limbic striatum with this. 134 00:08:52,520 --> 00:08:55,393 We went through that a little bit in the last part. 135 00:08:59,520 --> 00:09:02,430 The limbic structures are in here in the hemisphere. 136 00:09:02,430 --> 00:09:05,430 And we're talking now, in limbic striatum, 137 00:09:05,430 --> 00:09:08,890 the structures of the striatum, they 138 00:09:08,890 --> 00:09:13,800 give the output of these limbic system structures shown 139 00:09:13,800 --> 00:09:16,070 in the red stripes and you know are 140 00:09:16,070 --> 00:09:17,910 concerned with motivation and emotion. 141 00:09:21,241 --> 00:09:26,890 And so in-- this is the view we want. 142 00:09:26,890 --> 00:09:30,416 If you look at the striatum in the hemisphere, 143 00:09:30,416 --> 00:09:32,962 if the hemisphere's transparent, you 144 00:09:32,962 --> 00:09:34,670 will see the striatum in these locations. 145 00:09:34,670 --> 00:09:37,350 And the entire ventral striatum, I 146 00:09:37,350 --> 00:09:40,999 would include amygdala as part of it. 147 00:09:40,999 --> 00:09:42,540 We know that the amygdala is actually 148 00:09:42,540 --> 00:09:46,490 a combination of pallial and striatal structures, 149 00:09:46,490 --> 00:09:48,990 but a good part of it is striatal 150 00:09:48,990 --> 00:09:53,380 and it functions in many ways like a striatal. 151 00:09:53,380 --> 00:09:56,450 Like the dorsal striatum does with its connections 152 00:09:56,450 --> 00:10:00,050 from neocortex, the ventral striatum and amygdala 153 00:10:00,050 --> 00:10:04,660 do for the limbic system, including 154 00:10:04,660 --> 00:10:07,782 the formation of learned habits. 155 00:10:07,782 --> 00:10:09,240 But the habits, of course, are very 156 00:10:09,240 --> 00:10:10,531 different for ventral striatum. 157 00:10:10,531 --> 00:10:12,120 They're habits of feeling and emotion. 158 00:10:17,810 --> 00:10:21,200 I don't think I'm going to go through this in detail because, 159 00:10:21,200 --> 00:10:26,940 but it's Larry Swansons' more inclusive view of the striatum. 160 00:10:30,060 --> 00:10:32,400 I will simply summarize it this way-- 161 00:10:32,400 --> 00:10:37,840 he, of course, has first the dorsal striatum and pallidum, 162 00:10:37,840 --> 00:10:42,050 somatic system, caudate putamen with its outputs 163 00:10:42,050 --> 00:10:47,500 to the pallidum, which are the globus palladis-- two segments. 164 00:10:47,500 --> 00:10:50,000 I just want to point out if any of you deal with rodents 165 00:10:50,000 --> 00:10:53,030 and you try to find that internal segment, 166 00:10:53,030 --> 00:10:56,030 it's very difficult because they're basically 167 00:10:56,030 --> 00:10:58,920 cells embedded in the peduncle. 168 00:10:58,920 --> 00:11:00,530 It's called entopeduncular nucleus, 169 00:11:00,530 --> 00:11:03,817 the nucleus enclosed by the peduncle. 170 00:11:03,817 --> 00:11:05,400 But it is there, nevertheless, because 171 00:11:05,400 --> 00:11:07,220 of these cells with the connections. 172 00:11:07,220 --> 00:11:12,316 But in the larger animals the pallidum is quite separable. 173 00:11:12,316 --> 00:11:14,210 But all these other structures you 174 00:11:14,210 --> 00:11:16,690 could call part of the ventral striatum. 175 00:11:16,690 --> 00:11:18,490 But he includes the septal nuclei 176 00:11:18,490 --> 00:11:22,810 and he calls the medial striatum and pallidum. 177 00:11:22,810 --> 00:11:26,310 And amygdala structures. 178 00:11:26,310 --> 00:11:31,440 And he has the pallidal part as a bed nucleus of the stria 179 00:11:31,440 --> 00:11:31,940 termanalis. 180 00:11:34,670 --> 00:11:41,740 It's the way he-- some people really like to systematize this 181 00:11:41,740 --> 00:11:43,880 and Swanson liked to do that. 182 00:11:43,880 --> 00:11:46,895 In my-- I just take all of these structures 183 00:11:46,895 --> 00:11:50,515 and call it the ventral striatum because there 184 00:11:50,515 --> 00:11:56,940 are a lot of similarities in the way these structures function. 185 00:11:56,940 --> 00:11:59,550 They're all getting outputs. 186 00:11:59,550 --> 00:12:01,170 They're all getting out outputs from 187 00:12:01,170 --> 00:12:03,295 the limbic cortical regions. 188 00:12:07,229 --> 00:12:08,895 They're all involved in habit formation. 189 00:12:12,320 --> 00:12:14,580 Pretty much parallel to the way the dorsal striatum 190 00:12:14,580 --> 00:12:21,751 works for the non-olfactories and non-limbic systems. 191 00:12:21,751 --> 00:12:22,250 All right. 192 00:12:29,730 --> 00:12:32,940 Can anyone answer question eight for me? 193 00:12:32,940 --> 00:12:35,340 Just contrast the neocortical projections 194 00:12:35,340 --> 00:12:41,810 to the putamen versus the projections to the caudate. 195 00:12:41,810 --> 00:12:44,990 How are they different? 196 00:12:44,990 --> 00:12:47,330 Why is it when we treat Parkinson's 197 00:12:47,330 --> 00:12:51,420 we're always dealing with putamen when actually 198 00:12:51,420 --> 00:12:53,765 the caudate is also involved? 199 00:12:53,765 --> 00:12:54,681 AUDIENCE: [INAUDIBLE]. 200 00:12:54,681 --> 00:12:55,520 PROFESSOR: Sorry? 201 00:12:55,520 --> 00:12:57,875 AUDIENCE: [INAUDIBLE]. 202 00:12:57,875 --> 00:13:00,120 PROFESSOR: It's because-- exactly. 203 00:13:00,120 --> 00:13:05,420 The inputs to the putamen are from the sensory motor 204 00:13:05,420 --> 00:13:08,242 areas of the neocortex. 205 00:13:08,242 --> 00:13:11,750 Somatosensory and motor areas. 206 00:13:11,750 --> 00:13:13,780 Areas 3, 1, and 2. 207 00:13:13,780 --> 00:13:17,995 Area 4, area 6 in Brodmann's terms. 208 00:13:22,610 --> 00:13:30,010 Why, in question nine-- I'm trying to say here 209 00:13:30,010 --> 00:13:35,230 why would you expect the corpus striatum to be involved 210 00:13:35,230 --> 00:13:39,840 in almost all of the functions of neocortex? 211 00:13:39,840 --> 00:13:42,810 The answer is very simple. 212 00:13:42,810 --> 00:13:46,390 Almost all of the neocortex projects to the striatum. 213 00:13:46,390 --> 00:13:50,320 You can say a similar thing for the cerebellum. 214 00:13:50,320 --> 00:13:53,123 All of those structures, they get cerebellar input. 215 00:13:58,410 --> 00:14:01,380 Input from neocortical-- so many neocortical areas 216 00:14:01,380 --> 00:14:05,420 project to the pons, which then projects to the cerebellum. 217 00:14:05,420 --> 00:14:07,260 So we know that the cerebellum then 218 00:14:07,260 --> 00:14:12,660 has got to be involved in more than just simple coordination 219 00:14:12,660 --> 00:14:15,200 of movement. 220 00:14:15,200 --> 00:14:17,620 Because there's a coordination of a lot of things 221 00:14:17,620 --> 00:14:20,360 involved with timing adjustments that the cerebellum 222 00:14:20,360 --> 00:14:21,930 is so good at. 223 00:14:21,930 --> 00:14:25,020 In this case, it's the striatum. 224 00:14:25,020 --> 00:14:28,590 That means when you have corpus striatum pathologies 225 00:14:28,590 --> 00:14:31,940 you can get many different problems 226 00:14:31,940 --> 00:14:34,860 besides-- but the thing that people notice 227 00:14:34,860 --> 00:14:39,240 the most, the most common complaint of the people 228 00:14:39,240 --> 00:14:41,350 with damage to the corpus striatum, 229 00:14:41,350 --> 00:14:43,375 or of course any of these diseases, 230 00:14:43,375 --> 00:14:45,390 is the effects on movement. 231 00:14:45,390 --> 00:14:50,025 This is just a picture shows the central cortex here. 232 00:14:50,025 --> 00:14:54,420 And by central cortex, we always mean somatosensory, motor, 233 00:14:54,420 --> 00:14:56,940 and premotor or supplementary motor areas. 234 00:15:00,450 --> 00:15:03,250 There's a number of premotor areas or supplementary motor 235 00:15:03,250 --> 00:15:03,750 areas. 236 00:15:03,750 --> 00:15:07,200 One of [INAUDIBLE]. 237 00:15:07,200 --> 00:15:11,860 And it shows the projections from there in the reddish brown 238 00:15:11,860 --> 00:15:19,120 going to the putamen lateral to the cerebral peduncle. 239 00:15:19,120 --> 00:15:23,995 This is lateral to the internal capsule, I should say. 240 00:15:23,995 --> 00:15:25,890 And the internal capsule fits in here. 241 00:15:25,890 --> 00:15:30,090 The caudate nucleus is mostly medial to it. 242 00:15:34,200 --> 00:15:38,536 The anterior-most part is the largest [INAUDIBLE] caudate. 243 00:15:38,536 --> 00:15:43,150 It's getting inputs from all of the other cortical areas, 244 00:15:43,150 --> 00:15:45,590 including some of these areas [INAUDIBLE]. 245 00:15:45,590 --> 00:15:48,345 This is from a picture in [INAUDIBLE]. 246 00:15:48,345 --> 00:15:50,336 And we leave some of these white, 247 00:15:50,336 --> 00:15:51,960 including the visual areas here. 248 00:15:51,960 --> 00:15:55,260 But in fact, even in a hamster that I've studied 249 00:15:55,260 --> 00:15:58,834 I've traced projections here from the visual area 250 00:15:58,834 --> 00:16:02,050 as I see the projections of the caudate nucleus. 251 00:16:02,050 --> 00:16:05,090 And it also includes prefrontal areas here. 252 00:16:05,090 --> 00:16:05,590 All right. 253 00:16:05,590 --> 00:16:09,720 And this is an updated view of the projections 254 00:16:09,720 --> 00:16:10,926 from the cortex. 255 00:16:10,926 --> 00:16:15,334 And they just show one section of the cortex here. 256 00:16:15,334 --> 00:16:22,100 How it projects to the entire striatum, 257 00:16:22,100 --> 00:16:29,060 both dorsal and ventral, and also 258 00:16:29,060 --> 00:16:32,010 to the intalaminar and midline nuclei. 259 00:16:32,010 --> 00:16:35,270 Because these nuclei, remember, have direct projections 260 00:16:35,270 --> 00:16:37,090 to the striatum. 261 00:16:37,090 --> 00:16:38,809 So that means this little area here, 262 00:16:38,809 --> 00:16:40,850 the [? pair of them ?] [? trick ?] to the nucleus 263 00:16:40,850 --> 00:16:42,900 around the midline nuclei. 264 00:16:42,900 --> 00:16:46,550 It projects to this corner of the striatal structures, 265 00:16:46,550 --> 00:16:51,020 including where this basalis is. 266 00:16:51,020 --> 00:16:58,550 And this area of cortex projects to that same area. 267 00:16:58,550 --> 00:17:00,710 So you'll see it's a highly organized system. 268 00:17:00,710 --> 00:17:03,370 The parts most similar to dorsal-- 269 00:17:03,370 --> 00:17:05,730 what we've been calling dorsal striatum 270 00:17:05,730 --> 00:17:09,720 involved getting the input from somatosensory and motor cortex. 271 00:17:09,720 --> 00:17:11,165 They show in green here. 272 00:17:11,165 --> 00:17:13,079 You can see here that that's going 273 00:17:13,079 --> 00:17:22,609 to the dorsal lateral region of the striatum. 274 00:17:22,609 --> 00:17:28,300 So the ventral striatum is really ventromedial here. 275 00:17:28,300 --> 00:17:31,530 Dorsolateral then ventromedial according 276 00:17:31,530 --> 00:17:35,930 to more recent studies of these projections. 277 00:17:35,930 --> 00:17:39,590 And the input to the caudate is much more complex. 278 00:17:39,590 --> 00:17:41,290 I went through some of the studies 279 00:17:41,290 --> 00:17:46,420 and found this kind of system where you got projections 280 00:17:46,420 --> 00:17:48,410 from orbital frontal cortex that form 281 00:17:48,410 --> 00:17:52,500 these huge columns medially. 282 00:17:52,500 --> 00:17:57,760 And they can be traced in that same position all around 283 00:17:57,760 --> 00:18:00,050 to the very tail of the caudate. 284 00:18:00,050 --> 00:18:01,822 This is internal capsule in here. 285 00:18:07,070 --> 00:18:13,420 And here are other parts of the dorsolateral prefrontal cortex. 286 00:18:13,420 --> 00:18:18,278 Posterior parietal, which is very far from the prefrontal. 287 00:18:18,278 --> 00:18:22,650 See, it's all these different areas here 288 00:18:22,650 --> 00:18:28,430 and here are projecting this complex pattern to the caudate. 289 00:18:28,430 --> 00:18:30,750 But it's actually more complex than that 290 00:18:30,750 --> 00:18:34,640 because if you look at the actual studies like here, 291 00:18:34,640 --> 00:18:39,480 they trace projections here from prefrontal areas and here 292 00:18:39,480 --> 00:18:42,330 from parietal cortex. 293 00:18:42,330 --> 00:18:49,770 And then you look at a part of the striatum. 294 00:18:49,770 --> 00:18:57,900 You see these-- it's not entirely blue here 295 00:18:57,900 --> 00:19:00,130 and pink here, but in the middle here 296 00:19:00,130 --> 00:19:03,670 there's a lot of interdigitization indicating 297 00:19:03,670 --> 00:19:05,450 that there's a lot we don't understand 298 00:19:05,450 --> 00:19:07,490 about how this is working. 299 00:19:07,490 --> 00:19:10,510 That is, the striatum itself must 300 00:19:10,510 --> 00:19:12,946 be doing some integration of these inputs 301 00:19:12,946 --> 00:19:18,350 because the interdigitization of the projections of the anterior 302 00:19:18,350 --> 00:19:24,220 and posterior association areas-- 303 00:19:24,220 --> 00:19:28,450 this area and this area. 304 00:19:28,450 --> 00:19:31,380 Those two projections tend to be very 305 00:19:31,380 --> 00:19:35,020 close to each other in the striatum. 306 00:19:35,020 --> 00:19:37,560 Why is that? 307 00:19:37,560 --> 00:19:41,120 To do that we have to understand a lot more about that cortex, 308 00:19:41,120 --> 00:19:43,765 which we haven't talked so much about yet. 309 00:19:43,765 --> 00:19:47,695 But in fact, this pattern is not well understood. 310 00:19:47,695 --> 00:19:49,430 It's functions are not well understood. 311 00:19:57,000 --> 00:20:02,710 This slide is just talking about-- in clinical neurology 312 00:20:02,710 --> 00:20:06,040 they talk about these different functional circuits 313 00:20:06,040 --> 00:20:08,740 involving the striatum. 314 00:20:08,740 --> 00:20:10,620 All of that's to be expected when 315 00:20:10,620 --> 00:20:13,210 you know that all of these different cortical areas 316 00:20:13,210 --> 00:20:13,890 project there. 317 00:20:13,890 --> 00:20:18,620 For example, frontal eye fields of the frontal lobe we know 318 00:20:18,620 --> 00:20:24,720 are critical for intentional eye movements can 319 00:20:24,720 --> 00:20:27,493 be affected by striatal lesions. 320 00:20:27,493 --> 00:20:32,420 Well, that area projects to the striatum, 321 00:20:32,420 --> 00:20:39,050 just like the motor cortex and the somatosensory cortex do. 322 00:20:39,050 --> 00:20:41,030 Other parts of the prefrontal cortex 323 00:20:41,030 --> 00:20:43,705 project there and, because of that, 324 00:20:43,705 --> 00:20:45,815 other cognitive functions that are 325 00:20:45,815 --> 00:20:52,530 so important in human functioning that 326 00:20:52,530 --> 00:20:56,530 depend on prefrontal cortex, you'd 327 00:20:56,530 --> 00:20:58,040 expect them to be damaged. 328 00:20:58,040 --> 00:21:02,230 It's just not as common in these basal ganglia diseases. 329 00:21:02,230 --> 00:21:03,730 Maybe it's because we don't know. 330 00:21:06,880 --> 00:21:10,245 A lot of people go through life without actually exercising 331 00:21:10,245 --> 00:21:12,926 higher cognitive functions that well. 332 00:21:12,926 --> 00:21:15,154 I saw that with tongue in cheek, but I 333 00:21:15,154 --> 00:21:16,790 think it's probably right. 334 00:21:16,790 --> 00:21:19,750 So we don't notice when they suffer a pathology. 335 00:21:19,750 --> 00:21:27,260 We just think he had too much to drink a little bit too often 336 00:21:27,260 --> 00:21:30,030 or he's getting old or this or that. 337 00:21:30,030 --> 00:21:35,130 Whereas in fact, it can be due to these striatal functions. 338 00:21:35,130 --> 00:21:38,150 Similarly, the limbic areas affect movement and motion 339 00:21:38,150 --> 00:21:43,250 because they project to striatal as well. 340 00:21:43,250 --> 00:21:47,030 Striatal damage or any pathologies 341 00:21:47,030 --> 00:21:51,275 to the striatum, that's a common area for interruption 342 00:21:51,275 --> 00:21:54,812 in vascular supply to the fore brain. 343 00:21:54,812 --> 00:21:59,200 Vessels that come in from the base of the brain 344 00:21:59,200 --> 00:22:01,218 go up through the ventral striatum 345 00:22:01,218 --> 00:22:05,160 and sometimes they reach the internal capsule as well. 346 00:22:05,160 --> 00:22:08,610 So you'll get not just the movement disorders 347 00:22:08,610 --> 00:22:11,411 from the interruption of those axons of the internal capsule. 348 00:22:11,411 --> 00:22:13,369 You'll get changes in mood and emotion as well. 349 00:22:18,260 --> 00:22:21,170 Another complication that I mentioned in the chapter 350 00:22:21,170 --> 00:22:23,230 is the stria zones. 351 00:22:23,230 --> 00:22:27,630 This is an interesting compartmentalization. 352 00:22:27,630 --> 00:22:30,503 It's a little different from that interdigitization 353 00:22:30,503 --> 00:22:34,340 of the projections from the anterior and posterior 354 00:22:34,340 --> 00:22:36,950 association areas of cortex. 355 00:22:36,950 --> 00:22:44,750 This refers to the projections of acetylcholine axons 356 00:22:44,750 --> 00:22:48,975 and the staining [? for ?] cholinesterase, 357 00:22:48,975 --> 00:22:51,150 that you get in the striatum. 358 00:22:51,150 --> 00:22:56,280 There are areas in the striatum where there's 359 00:22:56,280 --> 00:23:02,170 almost no staining with cholinesterase and other areas 360 00:23:02,170 --> 00:23:04,230 where there's heavy staining. 361 00:23:04,230 --> 00:23:08,260 We call these p-zones where there's no staining. 362 00:23:08,260 --> 00:23:11,300 We know they have to be functionally different. 363 00:23:11,300 --> 00:23:14,905 It's been very difficult to work out the functional differences. 364 00:23:14,905 --> 00:23:20,450 I mentioned some of the recent work in that area [INAUDIBLE]. 365 00:23:20,450 --> 00:23:22,780 I think we talked about the-- oh, 366 00:23:22,780 --> 00:23:24,832 these are about the cell types. 367 00:23:24,832 --> 00:23:28,800 There's huge numbers, but most of them are characterized. 368 00:23:28,800 --> 00:23:31,690 These are just structural divisions 369 00:23:31,690 --> 00:23:36,328 where you have these large interneurons of the striatum. 370 00:23:36,328 --> 00:23:39,770 This is throughout the striatum you get these cell types. 371 00:23:39,770 --> 00:23:46,370 Acetycholine-containing cells that-- they're short axon 372 00:23:46,370 --> 00:23:49,710 interneurons using acetyocholine. 373 00:23:49,710 --> 00:23:52,190 So we know that that's why there's cholinesterase 374 00:23:52,190 --> 00:23:52,805 staining. 375 00:23:52,805 --> 00:23:58,860 And yet, now we know there's these areas that don't get it. 376 00:23:58,860 --> 00:24:02,220 We just don't know completely why that's true. 377 00:24:02,220 --> 00:24:05,330 And there's many cells that use GABA. 378 00:24:05,330 --> 00:24:08,872 There has to be because of all these inhibitory projections. 379 00:24:08,872 --> 00:24:12,340 We know that the dorsal striatum projects directly 380 00:24:12,340 --> 00:24:14,440 to the nigra with a GABA pathway. 381 00:24:14,440 --> 00:24:16,945 It projects to globus pallidus, both segments, 382 00:24:16,945 --> 00:24:19,590 with GABAergic pathways. 383 00:24:19,590 --> 00:24:23,860 But those GABA cells, the GABAergic cells, 384 00:24:23,860 --> 00:24:25,820 can be further characterized in terms 385 00:24:25,820 --> 00:24:30,540 of peptides they contain like one type contains 386 00:24:30,540 --> 00:24:33,680 not only GABA but substance P, and it 387 00:24:33,680 --> 00:24:38,200 tends to project to the nigra and to the internal segment 388 00:24:38,200 --> 00:24:40,430 of the globus pallidus. 389 00:24:40,430 --> 00:24:43,565 GABA with [? encephalon, ?] those cells project 390 00:24:43,565 --> 00:24:46,710 to the outer segment of the globus pallidus. 391 00:24:46,710 --> 00:24:52,010 So they're using the same main neurotransmitter 392 00:24:52,010 --> 00:24:54,950 but they're modulated by different peptides. 393 00:24:54,950 --> 00:24:57,950 Again, not fully understood. 394 00:24:57,950 --> 00:25:02,780 But clearly they have some functional difference. 395 00:25:13,120 --> 00:25:14,730 This is where I mentioned the stria 396 00:25:14,730 --> 00:25:18,570 zones and those acetylcholine internuerons. 397 00:25:18,570 --> 00:25:21,340 I just want to say a little bit about these terms used 398 00:25:21,340 --> 00:25:22,120 for humans. 399 00:25:22,120 --> 00:25:23,430 The lentiform nucleus. 400 00:25:23,430 --> 00:25:27,610 Did I talk about that before? 401 00:25:27,610 --> 00:25:32,940 This shape right here is the lentiform nucleus, 402 00:25:32,940 --> 00:25:36,200 the lens-shaped nucleus. 403 00:25:36,200 --> 00:25:40,470 The outer part is putamen and the inner parts 404 00:25:40,470 --> 00:25:43,510 are the two segments of the globus pallidus, the output 405 00:25:43,510 --> 00:25:44,470 structures. 406 00:25:44,470 --> 00:25:47,500 That's the lentiform nucleus. 407 00:25:47,500 --> 00:25:49,730 There's the internal capsule, and medial to it 408 00:25:49,730 --> 00:25:52,302 there's the caudate nucleus. 409 00:25:52,302 --> 00:25:56,030 It looks small here, but this a big human 410 00:25:56,030 --> 00:26:00,100 brain so it's actually not so small. 411 00:26:00,100 --> 00:26:03,190 So you see the same thing on the two sides. 412 00:26:03,190 --> 00:26:06,000 I think we saw this before when we talked about the output, 413 00:26:06,000 --> 00:26:07,980 the [INAUDIBLE] [? to the ?] [? meticularus ?], 414 00:26:07,980 --> 00:26:12,420 the pathway that goes from the globus pallidus here that loops 415 00:26:12,420 --> 00:26:16,521 around the internal capsule and goes to the ventral anterior 416 00:26:16,521 --> 00:26:17,020 thalamus. 417 00:26:20,790 --> 00:26:25,635 OK, so you can see if you were doing a dissection how 418 00:26:25,635 --> 00:26:33,080 you would get to it and go into the sylvian fissure here. 419 00:26:33,080 --> 00:26:36,588 Here it is in the photograph. 420 00:26:36,588 --> 00:26:37,920 You can just push it apart. 421 00:26:37,920 --> 00:26:40,300 You'll expose this buried cortex. 422 00:26:40,300 --> 00:26:44,820 What is the buried cortex called? 423 00:26:44,820 --> 00:26:46,130 It's called the island. 424 00:26:46,130 --> 00:26:49,679 The insula, the island cortex. 425 00:26:49,679 --> 00:26:52,637 Sort of a-- I guess it looked like that 426 00:26:52,637 --> 00:26:54,790 to anatomists going in through the fissure 427 00:26:54,790 --> 00:26:58,780 and finding a cortex down there that's 428 00:26:58,780 --> 00:27:04,310 covering the outer part of the striatum here, the putamen. 429 00:27:07,770 --> 00:27:09,480 There's another little layer of cells 430 00:27:09,480 --> 00:27:12,490 there between the putamen and the neocortex 431 00:27:12,490 --> 00:27:14,500 called the colostrum. 432 00:27:14,500 --> 00:27:17,380 It's very widespread inputs and I'm not 433 00:27:17,380 --> 00:27:19,630 spending time on that in the class now. 434 00:27:22,862 --> 00:27:24,320 But we talked about temporalization 435 00:27:24,320 --> 00:27:29,020 and how that forms. 436 00:27:29,020 --> 00:27:33,500 I just wanted to point out that in this picture 437 00:27:33,500 --> 00:27:36,920 these are the axons that form the internal capsule coming 438 00:27:36,920 --> 00:27:38,825 down through the striatum. 439 00:27:38,825 --> 00:27:40,630 So this is left hemisphere. 440 00:27:40,630 --> 00:27:43,350 The caudate nucleus is on the other side of it. 441 00:27:43,350 --> 00:27:45,290 It would go all the way around. 442 00:27:45,290 --> 00:27:47,600 But back here what does it do? 443 00:27:47,600 --> 00:27:51,130 Well, the caudate goes all the way around. 444 00:27:51,130 --> 00:27:54,960 So down here you see it below those axons. 445 00:27:54,960 --> 00:27:56,840 So if you make a cross-section, you 446 00:27:56,840 --> 00:28:01,640 can see the caudate there and there. 447 00:28:01,640 --> 00:28:07,850 There's white matter in between the caudate 448 00:28:07,850 --> 00:28:11,290 and the other parts of the putamen. 449 00:28:11,290 --> 00:28:14,490 And here we see white matter here 450 00:28:14,490 --> 00:28:16,700 between cuadate and putamen. 451 00:28:16,700 --> 00:28:21,530 [? And ?] the whole length of [? that nucleus ?] in fact. 452 00:28:21,530 --> 00:28:27,920 And remember that if we follow the caudate all the way around 453 00:28:27,920 --> 00:28:30,253 right here it abuts the amygdala. 454 00:28:30,253 --> 00:28:33,550 So this would be the position of the amygdala here. 455 00:28:38,420 --> 00:28:41,048 So let's talk about Parkinson's disease now. 456 00:28:41,048 --> 00:28:44,280 I'm sorry I didn't deal with-- I left a lot of things hanging 457 00:28:44,280 --> 00:28:46,950 there, but it represents the way the field is 458 00:28:46,950 --> 00:28:48,090 to tell you the truth. 459 00:28:48,090 --> 00:28:49,390 There's a lot we don't know. 460 00:28:58,600 --> 00:29:02,480 So I want to talk about one of the major treatments that 461 00:29:02,480 --> 00:29:04,665 was developed in recent years. 462 00:29:04,665 --> 00:29:08,320 It's interesting because it was based on neuroscientific study 463 00:29:08,320 --> 00:29:13,327 that began with studies of rats and then moved 464 00:29:13,327 --> 00:29:18,670 to a new treatment for Parkinson's disease 465 00:29:18,670 --> 00:29:26,500 using tissue transplantation from fetal humans, 466 00:29:26,500 --> 00:29:28,710 the product of abortions. 467 00:29:28,710 --> 00:29:31,890 They're obtained in abortions. 468 00:29:31,890 --> 00:29:34,560 Tissue that would normally be thrown out, 469 00:29:34,560 --> 00:29:42,490 but they were legally able to get that tissue and use some. 470 00:29:42,490 --> 00:29:47,905 You will see about how old they had to be, 471 00:29:47,905 --> 00:29:52,810 but they were always from tissue that 472 00:29:52,810 --> 00:29:55,940 would have simply died if it wasn't used. 473 00:29:55,940 --> 00:30:00,060 But then we'll talk about new neurons for the adult brain. 474 00:30:00,060 --> 00:30:04,970 Not just implanted, but neurons that are either from stem cells 475 00:30:04,970 --> 00:30:10,248 or normally generated in the brain of adult animals 476 00:30:10,248 --> 00:30:12,832 and mammals, including humans. 477 00:30:12,832 --> 00:30:15,740 We walked about that once before when 478 00:30:15,740 --> 00:30:17,780 we talked about the olfactory bulb. 479 00:30:17,780 --> 00:30:21,080 I talked about new neurons being generated 480 00:30:21,080 --> 00:30:23,830 in the lateral ventricles even in adulthood 481 00:30:23,830 --> 00:30:28,630 and how they migrate forward into the granular layer 482 00:30:28,630 --> 00:30:31,530 of the olfactory bulb where there's cell turnover. 483 00:30:31,530 --> 00:30:33,860 Constantly those cells in the olfactory bulb 484 00:30:33,860 --> 00:30:37,240 are being replaced. 485 00:30:37,240 --> 00:30:41,140 The same thing happens in the hippocampus 486 00:30:41,140 --> 00:30:44,140 so we'll talk about that. 487 00:30:44,140 --> 00:30:47,430 So let's talk first about the fetal nigral 488 00:30:47,430 --> 00:30:52,558 transplantations, a therapy for Parkinson's disease. 489 00:30:52,558 --> 00:30:55,630 [? High ?] brain imaging is used to assess 490 00:30:55,630 --> 00:30:58,450 the success of those transplants. 491 00:30:58,450 --> 00:31:01,613 Before any functional effects are seen, 492 00:31:01,613 --> 00:31:07,650 they can find out if the cells are surviving. 493 00:31:07,650 --> 00:31:10,040 And then we'll talk about the new cells. 494 00:31:13,762 --> 00:31:16,012 Does everybody understand what Parkinson's disease is? 495 00:31:18,850 --> 00:31:24,600 Why is it that-- we know the cells of the nigra that produce 496 00:31:24,600 --> 00:31:28,080 dopamine are gradually lost in Parkinson's disease. 497 00:31:28,080 --> 00:31:33,430 Why is it they don't see any symptoms of Parkinson's disease 498 00:31:33,430 --> 00:31:36,250 until 80% of those cells are gone? 499 00:31:38,870 --> 00:31:40,130 Any suggestions? 500 00:31:40,130 --> 00:31:44,080 You remember what I said in the book? 501 00:31:44,080 --> 00:31:48,870 Why don't you see symptoms until 80% of them are gone? 502 00:31:48,870 --> 00:31:53,770 In fact, as we will see, the treatments for it 503 00:31:53,770 --> 00:31:56,540 would be more successful if they could catch it earlier. 504 00:31:56,540 --> 00:31:58,270 But they don't. 505 00:31:58,270 --> 00:32:04,050 The reason seems to be collateral sprouting. 506 00:32:04,050 --> 00:32:08,910 When you remove a small proportion 507 00:32:08,910 --> 00:32:10,935 of the dopamine-containing cells, 508 00:32:10,935 --> 00:32:17,040 the axons die going to striatum, the dopamine axons. 509 00:32:17,040 --> 00:32:20,180 But the remaining ones simply sprout collaterals, 510 00:32:20,180 --> 00:32:21,360 take over the space. 511 00:32:21,360 --> 00:32:23,930 There's a lot of evidence for that 512 00:32:23,930 --> 00:32:25,680 because it happens in many systems, 513 00:32:25,680 --> 00:32:28,695 not just in baby animals but in adult animals. 514 00:32:28,695 --> 00:32:33,250 You get collateral sprouting into denevated areas. 515 00:32:33,250 --> 00:32:35,690 So for example, if I cut-- remember 516 00:32:35,690 --> 00:32:39,410 I gave this example a long time ago, Chapter 13. 517 00:32:39,410 --> 00:32:45,896 You lose axons in your hand due to an arm injury 518 00:32:45,896 --> 00:32:52,570 or maybe pressure too long on your arm transects some axons. 519 00:32:52,570 --> 00:32:58,170 They will regrow, before they regrow, you can lose function. 520 00:32:58,170 --> 00:33:01,745 You can lose your ability to extend your hand, for example. 521 00:33:01,745 --> 00:33:05,030 I mentioned that that happened to me once. 522 00:33:05,030 --> 00:33:07,290 And then what happens? 523 00:33:07,290 --> 00:33:09,660 You don't have to wait for the regeneration 524 00:33:09,660 --> 00:33:12,760 to occur before you get return of function. 525 00:33:12,760 --> 00:33:14,256 Why is that? 526 00:33:14,256 --> 00:33:15,630 Collateral sprouting, because you 527 00:33:15,630 --> 00:33:18,560 haven't killed all the axons, the remaining ones 528 00:33:18,560 --> 00:33:21,940 will sprout over a period of about two weeks. 529 00:33:21,940 --> 00:33:25,100 That will happen and you start getting most of your function 530 00:33:25,100 --> 00:33:26,940 back. 531 00:33:26,940 --> 00:33:29,380 You have to have adequate innervation 532 00:33:29,380 --> 00:33:32,610 or you feel extremely weak. 533 00:33:32,610 --> 00:33:34,970 You have to have a lot of innervation 534 00:33:34,970 --> 00:33:37,660 to get those muscles to discharge properly. 535 00:33:40,320 --> 00:33:44,530 But the same things happening in the corpus striatum. 536 00:33:44,530 --> 00:33:45,776 Collateral sprouting. 537 00:33:45,776 --> 00:33:49,310 And because it's ongoing, it's probably the reason 538 00:33:49,310 --> 00:33:57,520 why making lesions gradually, as the skin a slow-growing tumor. 539 00:33:57,520 --> 00:34:01,490 It's also a lot harder to detect because you're 540 00:34:01,490 --> 00:34:04,025 getting connections being replaced. 541 00:34:04,025 --> 00:34:06,150 It's when you make the lesion all at once 542 00:34:06,150 --> 00:34:09,288 that you see the maximum effects of the lesion. 543 00:34:15,710 --> 00:34:20,090 Anyway, the most dramatic discovery of a treatment 544 00:34:20,090 --> 00:34:24,929 concerns this use of tissue from fetal nigra. 545 00:34:28,199 --> 00:34:29,850 And this is what I mainly what I want 546 00:34:29,850 --> 00:34:31,850 to talk about here, fetal nigra transplantation. 547 00:34:37,380 --> 00:34:41,930 They're basically taking nigral tissue just removed 548 00:34:41,930 --> 00:34:45,389 from a fetus. 549 00:34:45,389 --> 00:34:48,894 It's little chunks of tissue but in a solution. 550 00:34:48,894 --> 00:34:52,620 They suck them into a pipette and inject them. 551 00:34:52,620 --> 00:34:54,290 That's basically what they're doing. 552 00:34:58,700 --> 00:35:02,590 Why do you think it might be true 553 00:35:02,590 --> 00:35:05,220 that the topographic organization of connections 554 00:35:05,220 --> 00:35:08,690 isn't a critical factor in the functioning 555 00:35:08,690 --> 00:35:12,860 of the nigral striatal connections? 556 00:35:12,860 --> 00:35:17,570 You're not causing a regeneration of nigra 557 00:35:17,570 --> 00:35:19,515 to striatum. 558 00:35:19,515 --> 00:35:23,840 You're just putting the nigral tissue directly 559 00:35:23,840 --> 00:35:25,400 into the striatum. 560 00:35:25,400 --> 00:35:30,990 So normally the striatum doesn't contain dopamine cells. 561 00:35:30,990 --> 00:35:36,865 But if they put the dopamine cells into the midbrain, 562 00:35:36,865 --> 00:35:39,802 do you think the axons are ever going to reach the striatum? 563 00:35:39,802 --> 00:35:42,946 It's a big distance in an adult human. 564 00:35:42,946 --> 00:35:43,655 It wouldn't work. 565 00:35:43,655 --> 00:35:44,154 Yes? 566 00:35:44,154 --> 00:35:45,150 AUDIENCE: [INAUDIBLE]. 567 00:35:53,650 --> 00:35:54,550 PROFESSOR: Right. 568 00:35:54,550 --> 00:35:56,660 That's part of the research that was done. 569 00:35:56,660 --> 00:35:57,616 AUDIENCE: [INAUDIBLE]. 570 00:36:01,918 --> 00:36:03,430 PROFESSOR: No. 571 00:36:03,430 --> 00:36:06,390 No, but they were interested in working out 572 00:36:06,390 --> 00:36:10,100 the best ages of the human tissue 573 00:36:10,100 --> 00:36:15,270 because you don't want to go doing that procedure on humans 574 00:36:15,270 --> 00:36:20,060 when the fetal tissue is not in plentiful supply, 575 00:36:20,060 --> 00:36:23,174 especially because then putamen-- they're putting it 576 00:36:23,174 --> 00:36:24,590 all in the putamen because they're 577 00:36:24,590 --> 00:36:28,420 trying to treat these bad motor symptoms, you see. 578 00:36:28,420 --> 00:36:31,050 So they're not focused on caudate nucleus. 579 00:36:31,050 --> 00:36:34,850 They're focused on the putamen. 580 00:36:34,850 --> 00:36:40,940 And the putamen is very large in adult humans. 581 00:36:40,940 --> 00:36:43,370 And those fetuses are very tiny. 582 00:36:43,370 --> 00:36:46,590 So to get-- the problem is you put it 583 00:36:46,590 --> 00:36:52,050 in the putamen, the axons from those new cells 584 00:36:52,050 --> 00:36:56,200 that they're putting in there don't grow very far. 585 00:36:56,200 --> 00:36:59,870 They grow very slowly and they don't grow very far. 586 00:36:59,870 --> 00:37:03,250 We'll review that quickly here. 587 00:37:03,250 --> 00:37:06,710 So you need a number of fetuses to get 588 00:37:06,710 --> 00:37:12,640 a really adequate implant for one patient. 589 00:37:12,640 --> 00:37:15,186 And that means it's hard to get enough fetuses. 590 00:37:15,186 --> 00:37:16,162 AUDIENCE: [INAUDIBLE]. 591 00:37:16,162 --> 00:37:18,420 PROFESSOR: Because there's a lot of people with Parkinson's. 592 00:37:18,420 --> 00:37:19,418 AUDIENCE: [INAUDIBLE]. 593 00:37:25,905 --> 00:37:27,410 PROFESSOR: Yeah. 594 00:37:27,410 --> 00:37:31,300 Even if they could do that-- and I don't know of any research 595 00:37:31,300 --> 00:37:32,730 that really tried that. 596 00:37:32,730 --> 00:37:35,550 But in other systems they have tried, 597 00:37:35,550 --> 00:37:40,090 and generally it fails because once systems contain 598 00:37:40,090 --> 00:37:45,810 a lot of myelin, the myelin inhibits the growth of axons 599 00:37:45,810 --> 00:37:48,185 because of [? the nodal ?] protein. 600 00:37:48,185 --> 00:37:51,370 It's very difficult to get it to grow. 601 00:37:51,370 --> 00:37:55,280 [? If ?] maybe a prior knowledge of how to get it to happen 602 00:37:55,280 --> 00:37:59,050 were a little more advanced, we could create pathways 603 00:37:59,050 --> 00:38:00,420 where it would go. 604 00:38:00,420 --> 00:38:05,070 You see, the problem is you're putting the dopamine cells 605 00:38:05,070 --> 00:38:07,310 directly into the putamen. 606 00:38:07,310 --> 00:38:11,180 That means the normal circuitry, the normal stimulus 607 00:38:11,180 --> 00:38:13,540 for nigral cells is missing. 608 00:38:16,210 --> 00:38:19,510 But what they were counting on is-- 609 00:38:19,510 --> 00:38:23,320 and this worked in rat research. 610 00:38:23,320 --> 00:38:27,910 They got a lot of function back in spite of all that. 611 00:38:27,910 --> 00:38:28,410 OK. 612 00:38:28,410 --> 00:38:30,930 So if you don't think the topography is very important 613 00:38:30,930 --> 00:38:34,100 because we're just dealing with a-- as I point out here, 614 00:38:34,100 --> 00:38:35,930 the actual dopamine release doesn't 615 00:38:35,930 --> 00:38:37,390 require high information content. 616 00:38:37,390 --> 00:38:39,485 It's a neuromodulator. 617 00:38:39,485 --> 00:38:41,630 It's simply changing the way those cells are 618 00:38:41,630 --> 00:38:44,920 working in the putamen. 619 00:38:44,920 --> 00:38:47,630 So that's why we think. 620 00:38:47,630 --> 00:38:50,410 It really doesn't matter the topography [? for it. ?] 621 00:38:50,410 --> 00:38:51,326 AUDIENCE: [INAUDIBLE]. 622 00:38:54,588 --> 00:38:58,040 PROFESSOR: Yeah, well, that's another issue, isn't it? 623 00:38:58,040 --> 00:39:00,375 Stria zones versus non-stria zones 624 00:39:00,375 --> 00:39:02,560 could drastically affect how it's 625 00:39:02,560 --> 00:39:05,660 working, at least subtle aspects of movement 626 00:39:05,660 --> 00:39:08,650 and the way people learn habits and so forth. 627 00:39:08,650 --> 00:39:11,450 Maybe they can't learn much. 628 00:39:11,450 --> 00:39:13,900 You'd like to look to see how much do they really study 629 00:39:13,900 --> 00:39:17,600 these patients that do get some recovery. 630 00:39:17,600 --> 00:39:20,600 But the question you're asking is a major one. 631 00:39:20,600 --> 00:39:24,930 You need to find those things out. 632 00:39:24,930 --> 00:39:27,280 We know that the donor age is critical. 633 00:39:27,280 --> 00:39:29,520 And why would we expect that? 634 00:39:29,520 --> 00:39:35,650 Well, studies of the development in, 635 00:39:35,650 --> 00:39:38,900 ontogeny of human dopamine producing cells, 636 00:39:38,900 --> 00:39:42,555 indicate that they first appear five and a half 637 00:39:42,555 --> 00:39:45,880 to six and a half weeks post-conception. 638 00:39:45,880 --> 00:39:49,780 And little processes grow out from those cells beginning 639 00:39:49,780 --> 00:39:52,320 at eight weeks post-conception. 640 00:39:52,320 --> 00:39:56,705 And the axons first reach the striatum at nine weeks. 641 00:39:59,525 --> 00:40:03,830 Well, once they've already grown all the way to the striatum, 642 00:40:03,830 --> 00:40:07,250 we already know from various studies of animals 643 00:40:07,250 --> 00:40:09,860 that when you damage cells that have already grown 644 00:40:09,860 --> 00:40:15,060 a lot of processes, that they become much more vulnerable. 645 00:40:15,060 --> 00:40:18,386 They're going to die if you damage them very much. 646 00:40:18,386 --> 00:40:20,385 Because then you're damaging a lot of processes. 647 00:40:22,920 --> 00:40:25,920 So it was predicted that you would 648 00:40:25,920 --> 00:40:28,840 have to go in this early period before most 649 00:40:28,840 --> 00:40:34,540 of those process, the dendrites and axons, have even grown. 650 00:40:34,540 --> 00:40:36,470 And that's what they found. 651 00:40:36,470 --> 00:40:40,590 And to do that research, as you mentioned they're actually 652 00:40:40,590 --> 00:40:43,407 taking the human tissue and putting it in rats 653 00:40:43,407 --> 00:40:44,990 striatum when they found out that they 654 00:40:44,990 --> 00:40:46,850 could do that successfully. 655 00:40:46,850 --> 00:40:50,060 They wanted to find out which ages to use. 656 00:40:50,060 --> 00:40:53,420 So here they took-- you see a lot of surviving cells. 657 00:40:53,420 --> 00:40:56,090 The black indicates the dopamine. 658 00:40:56,090 --> 00:41:00,055 Actually it's tyrosine hydroxylase, the enzyme 659 00:41:00,055 --> 00:41:03,940 that you always find in dopamine processes themselves. 660 00:41:03,940 --> 00:41:06,470 They took it from a fetus 41 days post-conception 661 00:41:06,470 --> 00:41:09,985 and it survived very well in the rat striatum. 662 00:41:09,985 --> 00:41:15,090 If they took from 72 day post-conception, that's 663 00:41:15,090 --> 00:41:19,460 after the axons have normally already started 664 00:41:19,460 --> 00:41:23,490 reaching the striatum, then they didn't get good survival. 665 00:41:23,490 --> 00:41:25,090 So they knew they had what-- that's 666 00:41:25,090 --> 00:41:28,920 how they found out the age range they had to use. 667 00:41:32,690 --> 00:41:35,630 Now how can they use imaging of the living brain 668 00:41:35,630 --> 00:41:37,805 to assess transplant success? 669 00:41:40,670 --> 00:41:45,110 By using fluorodopa, which allows 670 00:41:45,110 --> 00:41:50,340 you to use positron emission tomography and find evidence 671 00:41:50,340 --> 00:41:52,610 for living dopamine cells. 672 00:41:52,610 --> 00:41:54,380 And of course if the patient dies, 673 00:41:54,380 --> 00:41:56,850 they can use nueroanatomical methods. 674 00:41:56,850 --> 00:41:58,770 Basically [? indianal ?] staining 675 00:41:58,770 --> 00:42:01,795 for tyrosine hydroxylase. 676 00:42:01,795 --> 00:42:03,940 And they can assess then post-mortum. 677 00:42:09,260 --> 00:42:10,110 OK. 678 00:42:10,110 --> 00:42:14,880 You can read about fluorodopa online and how it's [? the-- ?] 679 00:42:14,880 --> 00:42:20,260 and this just mentions histological procedure 680 00:42:20,260 --> 00:42:23,530 on the autopsy material to find out 681 00:42:23,530 --> 00:42:25,320 where those dopamine cells are. 682 00:42:25,320 --> 00:42:27,070 And this is just some of the results. 683 00:42:27,070 --> 00:42:29,040 The dark staining here is dopamine. 684 00:42:29,040 --> 00:42:31,050 And you don't get tyrosine hydroxylase 685 00:42:31,050 --> 00:42:33,923 unless it's in live cells. 686 00:42:33,923 --> 00:42:36,006 And you see, if you look in higher magnifications, 687 00:42:36,006 --> 00:42:38,430 the whole feltwork of processes dopamine 688 00:42:38,430 --> 00:42:46,400 has-- this is all from a graft because when they do these-- 689 00:42:46,400 --> 00:42:50,260 this is from a human brain with surviving 690 00:42:50,260 --> 00:42:52,890 graft of fetal tissue. 691 00:42:52,890 --> 00:42:59,372 There's a lot of dopamine axons in parts of the putamen. 692 00:42:59,372 --> 00:43:02,700 If they get a long ways from where they put the implants in, 693 00:43:02,700 --> 00:43:04,990 this is what it looks like. 694 00:43:04,990 --> 00:43:05,820 Almost nothing. 695 00:43:05,820 --> 00:43:06,460 On the right. 696 00:43:06,460 --> 00:43:10,867 Because they don't [? grow ?] very far. 697 00:43:10,867 --> 00:43:12,325 Here's where they're putting in rat 698 00:43:12,325 --> 00:43:14,125 and you see very good survival here. 699 00:43:18,680 --> 00:43:21,430 And here you see them surviving, how 700 00:43:21,430 --> 00:43:24,590 they use to predict when they would 701 00:43:24,590 --> 00:43:27,660 to be successful in humans. 702 00:43:30,590 --> 00:43:32,270 So-- and I mentioned this. 703 00:43:32,270 --> 00:43:34,000 It makes a big difference on where 704 00:43:34,000 --> 00:43:36,970 you put it because of the size. 705 00:43:36,970 --> 00:43:38,320 The striatum is so big. 706 00:43:38,320 --> 00:43:42,280 This is about the rate of growth. 707 00:43:42,280 --> 00:43:44,340 I used six here to calculate that they 708 00:43:44,340 --> 00:43:48,890 would grow about a millimeter in seven days 709 00:43:48,890 --> 00:43:52,280 at six microns an hour. 710 00:43:52,280 --> 00:43:55,135 And we know that they never seem to grow more than 711 00:43:55,135 --> 00:43:56,510 about two and a half millimeters. 712 00:43:56,510 --> 00:43:58,185 Because remember, this is adult tissue 713 00:43:58,185 --> 00:44:00,845 and there's a lot of inhibitory factors. 714 00:44:00,845 --> 00:44:04,990 It's surprising to some people that they grow even that far. 715 00:44:04,990 --> 00:44:09,335 OK, so we know the locus is important 716 00:44:09,335 --> 00:44:11,202 because of the functions of the striatum. 717 00:44:11,202 --> 00:44:12,910 They occur in different parts and they're 718 00:44:12,910 --> 00:44:16,090 interested in the motor symptoms so they put it in the putamen. 719 00:44:24,840 --> 00:44:27,370 So why do you think it's so slow? 720 00:44:27,370 --> 00:44:30,570 It takes many months, even longer 721 00:44:30,570 --> 00:44:34,910 than the axons are grown out, according 722 00:44:34,910 --> 00:44:37,260 to [INAUDIBLE] results. 723 00:44:37,260 --> 00:44:40,723 So we know that there's probably other aspects of maturation 724 00:44:40,723 --> 00:44:45,590 of the neurons require a lot of time. 725 00:44:45,590 --> 00:44:50,220 So it took a lot of patience in doing this. 726 00:44:50,220 --> 00:44:54,820 And I mentioned other issues that are involved. 727 00:44:54,820 --> 00:45:00,700 Lack of normal inputs, the fact that Parkinson's disease 728 00:45:00,700 --> 00:45:04,702 involves other cell groups than just the dopamine cells. 729 00:45:04,702 --> 00:45:07,470 It involved norepinephrine cells, for example. 730 00:45:10,910 --> 00:45:12,660 We know less of about the function 731 00:45:12,660 --> 00:45:16,110 of those groups in the striatum. 732 00:45:16,110 --> 00:45:19,720 Then I mentioned collateral sprouting in addition. 733 00:45:19,720 --> 00:45:24,140 The point is if the dopamine axons are showing collateral 734 00:45:24,140 --> 00:45:26,635 sprouting, well, what about other axons? 735 00:45:26,635 --> 00:45:29,090 When there's denervation, other axons 736 00:45:29,090 --> 00:45:30,840 can show collateral sprouting, too. 737 00:45:30,840 --> 00:45:35,190 So then the dopamine axons have to compete with those. 738 00:45:35,190 --> 00:45:38,950 And the competition can take a very long time. 739 00:45:38,950 --> 00:45:41,070 And it might not always be successful. 740 00:45:41,070 --> 00:45:44,450 It's not easy to predict which axon [? is moving ?] out. 741 00:45:44,450 --> 00:45:47,620 Usually the normal axon is [? moving ?] out. 742 00:45:47,620 --> 00:45:51,910 But now they're not from the same person. 743 00:45:51,910 --> 00:45:53,590 They came from elsewhere. 744 00:45:53,590 --> 00:45:55,620 Does that mean they can compete just 745 00:45:55,620 --> 00:45:58,065 as well as the person's own dopamine cells would? 746 00:45:58,065 --> 00:45:59,300 We don't know. 747 00:46:02,490 --> 00:46:07,145 So I'm asking about alternatives for that treatment. 748 00:46:11,340 --> 00:46:13,522 I think I won't take time to go through this. 749 00:46:13,522 --> 00:46:14,730 We're going to read about it. 750 00:46:14,730 --> 00:46:18,890 The stem cells are the most interesting. 751 00:46:18,890 --> 00:46:22,780 Scientific studies indicate that for advanced Parkinson's 752 00:46:22,780 --> 00:46:24,930 patients there doesn't appear to be 753 00:46:24,930 --> 00:46:26,860 much use of using this procedure. 754 00:46:26,860 --> 00:46:28,950 It just doesn't work. 755 00:46:28,950 --> 00:46:31,720 It worked well, though, for people that are less severe. 756 00:46:31,720 --> 00:46:35,880 That is, the Parkinson's hasn't progressed as far. 757 00:46:35,880 --> 00:46:37,615 So for them, it did work. 758 00:46:37,615 --> 00:46:39,680 But of course, they're really concerned 759 00:46:39,680 --> 00:46:43,766 with those people with the more advanced symptoms. 760 00:46:43,766 --> 00:46:46,710 And they decided that the transplant procedure just 761 00:46:46,710 --> 00:46:55,037 wasn't good enough, so that led to other types of treatments. 762 00:46:55,037 --> 00:46:56,620 The thing used in the clinic-- there's 763 00:46:56,620 --> 00:46:58,610 two methods used in the clinic. 764 00:46:58,610 --> 00:47:00,680 One is called deep brain stimulation. 765 00:47:00,680 --> 00:47:03,360 If you go online and just type in deep brain stimulation, 766 00:47:03,360 --> 00:47:05,740 you'll find all kinds of articles 767 00:47:05,740 --> 00:47:10,595 because residents-- medical residents in hospitals 768 00:47:10,595 --> 00:47:13,660 love to do research and get their names on papers, 769 00:47:13,660 --> 00:47:15,660 so you'll find paper after paper after paper 770 00:47:15,660 --> 00:47:18,450 on their use of deep brain stimulation. 771 00:47:18,450 --> 00:47:19,950 And yes, it works very well. 772 00:47:19,950 --> 00:47:21,430 You stimulate the globus pallidus. 773 00:47:21,430 --> 00:47:24,570 You stimulate the subthalamic nucleus. 774 00:47:24,570 --> 00:47:26,570 You can get effects. 775 00:47:26,570 --> 00:47:31,736 Often you can benefit the patients. 776 00:47:31,736 --> 00:47:34,890 Which remember, they're missing a lot of the normal input 777 00:47:34,890 --> 00:47:37,010 from those pathways that affect the system. 778 00:47:37,010 --> 00:47:39,260 So if you stimulate it artificially, 779 00:47:39,260 --> 00:47:44,031 you can improve their symptoms and that's what they 780 00:47:44,031 --> 00:47:44,530 [? found. ?] 781 00:47:44,530 --> 00:47:47,120 They also have gone in and just ablated structures. 782 00:47:49,720 --> 00:47:54,200 And if they do that right-- the problem here is predicting. 783 00:47:54,200 --> 00:47:55,360 Well, how do you know? 784 00:47:55,360 --> 00:47:57,055 You only get one chance. 785 00:47:57,055 --> 00:48:00,680 Ablated, you're not going to get a second change. 786 00:48:00,680 --> 00:48:02,820 But they have found specific lesions 787 00:48:02,820 --> 00:48:07,140 that-- they base it on animal work first. 788 00:48:07,140 --> 00:48:13,410 And they do get some benefits, reducing movement problems. 789 00:48:13,410 --> 00:48:16,105 And I just mentioned examples of lesion. 790 00:48:19,730 --> 00:48:23,490 I'll talk a little more about the neurogenesis things, 791 00:48:23,490 --> 00:48:27,900 but make sure you read that here and I'll answer any questions 792 00:48:27,900 --> 00:48:28,719 you have about it. 793 00:48:28,719 --> 00:48:30,260 There's a few very interesting issues 794 00:48:30,260 --> 00:48:38,970 here about using-- both in using stem cells, which-- if you just 795 00:48:38,970 --> 00:48:44,090 look now, do a search on stem cell treatment for Parkinson's, 796 00:48:44,090 --> 00:48:47,240 you'll see there's a lot of recent things. 797 00:48:47,240 --> 00:48:50,194 Some of it's by patented cell lines, 798 00:48:50,194 --> 00:48:52,860 which I think is a horrible idea that the government has allowed 799 00:48:52,860 --> 00:48:53,359 it. 800 00:48:53,359 --> 00:48:59,740 And so now that creates all the problems that patents caused 801 00:48:59,740 --> 00:49:02,700 and a lot of competition between groups and so forth. 802 00:49:02,700 --> 00:49:06,510 But they are getting stem cells to work, 803 00:49:06,510 --> 00:49:08,320 but it's not an easy thing. 804 00:49:08,320 --> 00:49:11,180 There's many issues in getting those cells 805 00:49:11,180 --> 00:49:14,240 to do what you want. 806 00:49:14,240 --> 00:49:23,506 And the-- but I want to say a little bit 807 00:49:23,506 --> 00:49:29,140 about the normal stem cells we have, creating new neurons. 808 00:49:29,140 --> 00:49:31,840 In the hippocampal formation, not just in the olfactory 809 00:49:31,840 --> 00:49:33,320 bulbs. 810 00:49:33,320 --> 00:49:34,820 So we'll say a little bit about that 811 00:49:34,820 --> 00:49:37,370 because we've talked about hippocampus before. 812 00:49:37,370 --> 00:49:43,610 And then the main topic for next time will be neocortex. 813 00:49:43,610 --> 00:49:49,240 First chapter on neocortex, Chapter 32. 814 00:49:49,240 --> 00:49:52,225 And I posted questions on that chapter. 815 00:49:52,225 --> 00:49:54,320 I've written questions for the next one too. 816 00:49:54,320 --> 00:49:58,588 I'll get those posted probably later today.