1. Brain Transplant: 1992 NOVA Documentary Follow up

2. List of Methods Behavioral Various tests of motor function - pupillary reflex, walking, sitting, standing, talking, finger touching, balance (from a push), blinking (tap of forehead), rigidity (movement of wrist or limb) Nervous system L-DOPA and other drug treatments (e.g., neuroprotection) Chemical identification of MPTP Adrenal tissue to brain transplant Animal model of PD using MPTP Nerve graft tissue transplant in monkeys and humans Dissecting fresh fetal nerve cells from substantia nigra Stereotaxic surgery – intracerebral injection of fresh tissue suspension into caudate and putamen (striatum) postoperative care (baseball game) immunosuppression therapy PET scan of flora-dopa uptake in striatum and Estimation of percentage of graft secreting dopamine

3. Follow-up questions Given that it took George and Juanita two years to show miraculous recovery, what was the status of Connie at this time point following surgery? Are there any more recent reports of her progress, or lack thereof? What is her present condition? Why didn’t NOVA report on her progress as promised in the documentary?

5. JOURNEY OUT OF HOPELESSNESS GREENFIELD WOMAN THANKS READERS WHOSE DONATIONS RESTORED HER HUMANITY from PARKINSN Archives: Sun, 28 May 1995 JOURNEY OUT OF HOPELESSNESS GREENFIELD WOMAN THANKS READERS WHOSE DONATIONS RESTORED HER HUMANITY from PARKINSN Archives: Sun, 28 May 1995 Langston, the renowned Parkinson's disease scientist, described the essence of Connie's improvement this way: Langston, the renowned Parkinson's disease scientist, described the essence of Connie's improvement this way: ''What makes you human is the ability to interact with other humans. If you lose that, and Connie had, you lose the essence of life. It takes away what makes you a person. Connie is still very disabled, but she has regained her humanity. She is no longer a statue in the corner.'' ''What makes you human is the ability to interact with other humans. If you lose that, and Connie had, you lose the essence of life. It takes away what makes you a person. Connie is still very disabled, but she has regained her humanity. She is no longer a statue in the corner.''

6. Local news report from 1995, a year after Connie’s transplant Writer Jim Trotter at the Mercury News Two years ago, when I drove down with Langston from the Parkinson's Institute to visit Connie in Greenfield, the scene was far different. Sophisticated computer testing indicated that she was still cognitive, that her brain comprehended, beyond the frozen mask. But even with the aid of elaborate computer switches, she couldn't communicate. Two years ago, when I drove down with Langston from the Parkinson's Institute to visit Connie in Greenfield, the scene was far different. Sophisticated computer testing indicated that she was still cognitive, that her brain comprehended, beyond the frozen mask. But even with the aid of elaborate computer switches, she couldn't communicate. Now she is a smiling human being who can walk a bit and respond to questions. Surgery to reattach her ankle ligaments will greatly enhance her mobility. But Langston said overcoming language ''ignition failure'' -- the inability to talk spontaneously in expressing one's thoughts -- will take more time. ''But when that happens, she will really be back,'' he said. Now she is a smiling human being who can walk a bit and respond to questions. Surgery to reattach her ankle ligaments will greatly enhance her mobility. But Langston said overcoming language ''ignition failure'' -- the inability to talk spontaneously in expressing one's thoughts -- will take more time. ''But when that happens, she will really be back,'' he said. I could not resist sitting down next to Connie and telling her how much I admired her courage. She turned her eyes and said, ''Thank you.'' Don't give up, I said. Painstakingly, but clearly, she responded. ''I won't.''

7. Symptoms of PD 1) resting tremor (rhythmic shaking of an extremity), 2) slowness of movement (hypokinesia or bradykinesia) - movements take much longer to execute and there is also a general lack of movement (akinesia), 3) cogwheel rigidity (arms and legs become stiff with a ratchet or jerky quality of movement - almost no other disease produces this symptom), 4) slow shuffling gait, short steps with the patient bent or flexed over (very characteristic of PD) and 5) loss of facial expression and lack of spontaneous blinking which gives the appearance staring.

8. L-DOPA treatment Reversed symptoms but the therapeutic window closed as severe side effects set in – hallucinations, dyskinesia, and uncontrollable movement

9. “Parkinson’s disease is not caused by transient exposure to MPTP” That is, only f you use a strict neurobiological marker as the criterion. The similarities in behavioral changes suggests strongly that MPTP exposure replicates virtually all the behavioral symptoms of PD.

10. NormalPD Moderate MPTP Severe MPTP Radiolabeled FD uptake in the striatum PD – reduced uptake in the putamen MPTP – uniform reductions in both the caudate nucleus and putamen

11. NIH-sponsored placebo controlled trials

12. Winkler et al, 2005 Figure 1. Functional recovery after neural transplantation in Parkinson’s disease (PD). Recovery is suggested to occur in two phases: phase one is characterized by functional changes limited to the striatum, whereas in phase two changes of cortical activation can also be detected.

13. Figure 2. Allografts of fetal dopaminergic neurons are accompanied by a delayed immune/ inflammatory response, which could affect long- term survival and functional efficacy of the transplanted dopaminergic neurons. Winkler et al, 2005

14. variability in individual outcomes in the open label studies suggest that other factors might contribute to the success of the treatment. 1)preparation and composition of the graft tissue - prolonged cold storage and use of solid grafts are not as good 2)selection of patients - older patients do not tend to benefit as much as young patients due to less confined damage and reduced ability to accept to graft 3)pre-graft medication – low-dose patients tend to benefit more from graft. In fact, one of the controlled studies with older patients with no significant group improvement there was a correlation between the magnitude of the response to dose of L- dopa and the magnitude of the postsurgical improvement. 4)graft placement – grafts only innervate tissue 2-3 mm from the graft site so benefits will depend on the location of the placement and whether there is limited damage outside of the striatum. The authors conclude that standardized procedures for selection of patients, graft preparation and immunosuppresion, combined with tailoring the placement of grafts may improve the outcome of this promising therapy for PD.

15. MPTP exposure initiates long-term neurodegeneration

16. Practice questions Where was the fetal tissue taken from and where was it transplanted to? Immunosuppresion is important for post- surgical improvement to occur in the first 6 months or after that time. What was shown to be a misconception regarding MPTP exposure and why? What data suggests that MPTP does not induce PD?

17. Hubel and Wiesel

18. Receptive fields of visual neurons Neurons from all levels of the retina- geniculate-striate pathway: –Receptive fields of foveal area were smaller than those from the periphery (high-acuity) –Receptive fields were circular –Receptive fields were monocular –Receptive fields had excitatory and inhibitory areas separated by a circular boundary “on” firing when light was turned on “off” firing inhibition when light was on followed by a burst of activity when it was turned off

19. Receptive fields On-center cell Off-center cell Both respond best to contrast

20. Lower Layer IV neurons ‘on’ or ‘off’ center-surround receptive fields. M-layer projections terminate just above P-layer projections Monocular

21. Simple cortical cells Neurons from lower layer IV of striate cortex are exceptions compared to all other striate neurons, which are categorized as simple or complex: Simple cells –Have “on” and “off” regions –Are monocular –Borders of “on” and “off” regions are straight lines rather than circles (rectangular receptive fields) –Respond best when it’s preferred straight edge is in a particular orientation and position

22. Complex cortical cells Are more numerous Have rectangular receptive fields Respond best to straight line stimuli in a specific orientation Unresponsive to diffuse light Differ from simple cells in 3 important ways: 1.Larger receptive fields 2.No “on-off” regions – responds best to a straight edge stimulus of a particular orientation swept across the receptive field (fires continuously) 3.Many complex cells are binocular (respond to stimulation of either eye and will respond more robustly to stimulation of both eyes simultaneously).

23. Receptive Fields in Striate Cortex SIMPLERectangular “on” and “off” regions, like cells in layer IV Orientation and location sensitive All are monocular COMPLEXRectangular Larger receptive fields Do not have static “on” and “off” regions Not location sensitive Motion sensitive Many are binocular

24. Characteristics of complex cells Respond best to straight-line stimuli Of a particular orientation swept across the receptive field in a particular direction Receptive fields of binocular complex cells Occupy corresponding positions within the visual fields of both eyes Have the same straight-line orientation preference

25. Binocular complex cells fire more robustly when both eyes are stimulated simultaneously respond best when the preferred straight-line stimulus falls on slightly different positions of the two retinas – Retinal disparity respond more robustly to stimulation of one eye than to the same stimulation of the other eye - Ocular dominance

26. Binocular cell Mapping the receptive field of a complex binocular cell in primary visual (striate) cortex. http://www.physiology.wisc.edu/yin/public/hubel_wiesel_binocular_cell.asf

27. Columnar organization of V1 Vertical electrode tract Horizontal electrode tract 1 right eye 2 right eye 3 right eye 4 right eye 1 right eye 2 right eye 3 left eye 4 left eye

28. Hubel & Wiesel’s model of the columnar organization of the primary visual cortex  Big block of tissue analyzes signals from one area of the visual field  Sub-blocks analyze signals from the left and right eyes  Slices of block prefer lines in a particular orientation

29. Component theory of color vision  Three kinds of color receptors (cones) each with a different spectral sensitivity  Color of a particular stimulus is determined by the ratio of activity in the three kinds of receptors

30. Component theory of color vision The evidence:  Any color in the visible spectrum can be matched by mixing together 3 different wavelengths of light in different proportions.  3 types of receptors must exist to match all the colors in the visible spectrum

31. Opponent-process theory of color vision  Two different classes of cells in the visual system for encoding color  One class of cells signaled red by changing its activity in one direction and green by changing its activity in the opposite direction  Another class signaled blue and its complement, yellow.

32. Opponent-process theory of color vision The evidence:  Complementary colors cannot exist together (no reddish green or bluish yellow)  afterimage of red is green and the afterimage of blue is yellow

33. Afterimage demo Stare at fixation point for 1 minute XX quickly shift gaze to the point below

34. Which theory is correct? The Answer: both (and a third one)  Cones code color on a purely component basis (different photopigments maximally sensitive to low, medium and high wavelengths of light)  Opponent processing of color occurs at all other levels of the retina- geniculate-striate system

35. Component theory of color vision Microspectrophotometry - a technique for measuring the absorption spectrum of the photopigments contained in a single cone Confirmed the existence of 3 different kinds of cones, each containing a different photo-pigment with different characteristic absorption spectrums

36. Retinex theory of color vision Color is determined by reflectance – the proportion of light of different wavelengths a surface reflects –Reflected light changes based on different illumination –The efficiency of light absorbed and reflected by a surface is constant. –The visual system compares the light reflected by adjacent surfaces in at least 3 different wavelength bands.

37. Reflectance and Color Constancy Wavelengths absorbed: A, B & C Wavelengths reflected: D, E & F A B C A B C D E F Incandescent Light Wavelengths absorbed: A, B & C Wavelengths reflected: G, H & I A B C A B C G H I Fluorescent Light

38. Land (1977) experiment 1. Subjects adjusted the intensity of each projector to produce a pure white light in a dark room 2. Subjects were then shown Mondrians (Blue was adjusted to reflect the same combinations of wavelengths just judged to be white) 3. Despite the adjustment, blue still appeared as blue in the Mondrian 4. However, when viewed in isolation in a dark field it appeared as white

39. Principles of sensory system organization Three different types of sensory cortex: 1. Primary sensory cortex – receives most of its input from thalamic relays 2. Secondary sensory cortex – receives most of its input from the primary sensory cortex of a system 3. Association cortex – receives input from more than one sensory system

40. Visual areas of the cortex

41. Scotoma Karl Lashley’s scotoma experienced during a migraine Perimetry test determines the area of blindness in the visual field of each eye. Hemianopsia – scotoma covering half the visual field of both eyes

42. Two Visual Streams

43. Two Visual streams: Two theories ‘What’ versus ‘Where’ (Ungerleider & Mishkin, 1982) – kinds of information processed Ventral pathway – perception of what an object is Dorsal pathway – perception of where the object is located

44. Two Visual streams: Two theories ‘What’ versus ‘How’ (Milner & Goodale, 1993) – the use to which information is put. Ventral pathway – conscious perception of objects Dorsal pathway – direct behavioral interactions with objects

45. Visual agnosia Gnosis means “to know” Visual agnosics can see stimuli but do not know what they are –Movement agnosia –Object agnosia –Color agnosia –Prosopagnosia (faces)

46. Prosopagnosia Can recognize faces as faces but cannot idenify particular faces, including their own The farmer and bird watcher General problem recognizing specific objects that belong to complex classes of objects Due to damage to the fusiform face area (border between visual occipital and temporal areas)

47. FFA