Brain Transplant: 1992 NOVA Documentary

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Brain Transplant1992 NOVA Documentary

• Follow up

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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

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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 didnt NOVA report on her progress as
  promised in the documentary?

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(No Transcript)
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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
• ''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.''

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Local news report from 1995, a year after
Connies transplantWriter 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.  
• 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.''

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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.

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L-DOPA treatment
Reversed symptoms but the therapeutic window
closed as severe side effects set in
hallucinations, dyskinesia, and uncontrollable
movement
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Parkinsons 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.
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Radiolabeled FD uptake in the striatum
Normal
PD
PD reduced uptake in the putamen MPTP
uniform reductions in both the caudate nucleus
and putamen
Moderate MPTP
Severe MPTP
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NIH-sponsored placebo controlled trials
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Winkler et al, 2005

• Figure 1. Functional recovery after neural
  transplantation in Parkinsons 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.

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Winkler et al, 2005

• 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.

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variability in individual outcomes in the open
label studies suggest that other factors might
contribute to the success of the treatment.

• preparation and composition of the graft tissue -
  prolonged cold storage and use of solid grafts
  are not as good
• 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
• 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.
• 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.

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MPTP exposure initiates long-term
neurodegeneration
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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?

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Hubel and Wiesel
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Receptive fields of visual neurons

• Neurons from all levels of the retina-geniculate-s
  triate 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

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Receptive fields

• On-center cell
• Off-center cell
• Both respond best to contrast

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Lower Layer IV neurons

• on or off center-surround receptive fields.
• M-layer projections terminate just above P-layer
  projections
• Monocular

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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 its preferred straight edge is
  in a particular orientation and position

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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
• Larger receptive fields
• No on-off regions responds best to a straight
  edge stimulus of a particular orientation swept
  across the receptive field (fires continuously)
• Many complex cells are binocular (respond to
  stimulation of either eye and will respond more
  robustly to stimulation of both eyes
  simultaneously).

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Receptive Fields in Striate Cortex

• SIMPLE
• Rectangular
• on and off regions, like cells in layer IV
• Orientation and location sensitive
• All are monocular

• COMPLEX
• Rectangular
• Larger receptive fields
• Do not have static on and off regions
• Not location sensitive
• Motion sensitive
• Many are binocular

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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

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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

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Binocular cell
http//www.physiology.wisc.edu/yin/public/hubel_wi
esel_binocular_cell.asf

• Mapping the receptive field of a complex
  binocular cell in primary visual (striate) cortex.

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Columnar organization of V1
Vertical electrode tract
Horizontal electrode tract
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Hubel Wieselsmodel 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

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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

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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

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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.

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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

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Afterimage demo

• Stare at fixation point for 1 minute

quickly shift gaze to the point below
X
X
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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

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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
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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.

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

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Principles of sensory system organization

• Three different types of sensory cortex
• Primary sensory cortex receives most of its
  input from thalamic relays
• Secondary sensory cortex receives most of its
  input from the primary sensory cortex of a system
• Association cortex receives input from more
  than one sensory system

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Visual areas of the cortex
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Scotoma
Perimetry test determines the area of blindness
in the visual field of each eye. Hemianopsia
scotoma covering half the visual field of both
eyes
Karl Lashleys scotoma experienced during a
migraine
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Two Visual Streams
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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

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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

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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)

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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)

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FFA