Brain Transplant:Brain Transplant:1992 NOVA Documentary1992 NOVA Documentary

Follow upFollow up

List of MethodsList of MethodsBehavioralBehavioralVarious tests of motor function - pupillary reflex, walking, sitting, standing, Various tests of motor function - pupillary reflex, walking, sitting, standing, talking, finger touching, balance (from a push), blinking (tap of forehead), talking, finger touching, balance (from a push), blinking (tap of forehead), rigidity (movement of wrist or limb)rigidity (movement of wrist or limb)

Nervous systemNervous systemL-DOPA and other drug treatments (e.g., neuroprotection)L-DOPA and other drug treatments (e.g., neuroprotection)Chemical identification of MPTPChemical identification of MPTPAdrenal tissue to brain transplantAdrenal tissue to brain transplantAnimal model of PD using MPTPAnimal model of PD using MPTPNerve graft tissue transplantNerve graft tissue transplant in monkeys and humans in monkeys and humans

DissectingDissecting fresh fetal nerve cells from substantia nigra fresh fetal nerve cells from substantia nigraStereotaxic surgeryStereotaxic surgery – –

intracerebral injectionintracerebral injection of fresh tissue suspension of fresh tissue suspension into caudate and putamen (striatum)into caudate and putamen (striatum)

postoperative care (baseball game)postoperative care (baseball game)immunosuppression therapy immunosuppression therapy PET PET scan of flora-dopa uptake in striatum and scan of flora-dopa uptake in striatum and Estimation of percentage of graft secreting dopamine Estimation of percentage of graft secreting dopamine

Follow-up questionsFollow-up questions

Given that it took George and Juanita two Given that it took George and Juanita two years to show miraculous recovery, what years to show miraculous recovery, what was the status of Connie at this time point was the status of Connie at this time point following surgery?following surgery?

Are there any more recent reports of her Are there any more recent reports of her progress, or lack thereof?progress, or lack thereof?

What is her present condition?What is her present condition?

Why didn’t NOVA report on her progress as Why didn’t NOVA report on her progress as promised in the documentary?promised in the documentary?

JOURNEY OUT OF HOPELESSNESS   GREENFIELD JOURNEY OUT OF HOPELESSNESS   GREENFIELD WOMAN THANKS READERS WHOSE DONATIONS WOMAN THANKS READERS WHOSE DONATIONS

RESTORED HER HUMANITY RESTORED HER HUMANITY from PARKINSN Archives: Sun, 28 May 1995   from PARKINSN Archives: Sun, 28 May 1995  

Langston, the renowned Parkinson's disease Langston, the renowned Parkinson's disease scientist, described the essence of Connie's scientist, described the essence of Connie's improvement this way: improvement this way:

''What makes you human is the ability to interact ''What makes you human is the ability to interact with other humans. If you lose that, and Connie with other humans. If you lose that, and Connie had, you lose the essence of life. It takes away had, you lose the essence of life. It takes away what makes you a person. Connie is still very what makes you a person. Connie is still very disabled, but she has regained her humanity. disabled, but she has regained her humanity. She is no longer a statue in the corner.'' She is no longer a statue in the corner.''

Local news report from 1995, a year after Local news report from 1995, a year after Connie’s transplantConnie’s transplant

Writer Writer Jim Trotter Jim Trotter at the Mercury Newsat the Mercury News

Two years agoTwo years ago, when I drove down with Langston from the Parkinson's , when I drove down with Langston from the Parkinson's Institute to visit Connie in Greenfield, the scene was far different. Institute to visit Connie in Greenfield, the scene was far different. Sophisticated computer testing indicated that Sophisticated computer testing indicated that she was still cognitive, she was still cognitive, that her brain comprehended, beyond the frozen maskthat her brain comprehended, beyond the frozen mask. But even . But even with the aid of elaborate computer switches, with the aid of elaborate computer switches, she couldn't she couldn't communicatecommunicate.   .  

Now she is a smiling human being who can walk a bit and respond to Now she is a smiling human being who can walk a bit and respond to questions. questions. Surgery to reattach her ankle ligaments will greatly Surgery to reattach her ankle ligaments will greatly enhance her mobility. But enhance her mobility. But Langston said overcoming language Langston said overcoming language ''ignition failure'' -- the inability to talk spontaneously in expressing ''ignition failure'' -- the inability to talk spontaneously in expressing one's thoughts -- will take more time.one's thoughts -- will take more time.   ''But when that happens, she   ''But when that happens, she will really be back,'' he said.   will really be back,'' he said.  

I could not resist sitting down next to Connie and telling her how much I 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.''   admired her courage. She turned her eyes and said, ''Thank you.''   Don't give up, I said.   Painstakingly, but clearly, she responded.   ''I Don't give up, I said.   Painstakingly, but clearly, she responded.   ''I won't.'' won't.''

Symptoms of PDSymptoms of PD

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

L-DOPA treatmentL-DOPA treatment

Reversed symptoms but the therapeutic window closed as Reversed symptoms but the therapeutic window closed as severe side effects set in – hallucinations, dyskinesia, and severe side effects set in – hallucinations, dyskinesia, and uncontrollable movementuncontrollable movement

“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.

Normal PD

ModerateMPTP

SevereMPTP

Radiolabeled FD uptake in the striatum

PD – reduced uptake in the putamen

MPTP – uniform reductions in both the caudate nucleus and putamen

NIH-sponsored placebo controlled trials

Winkler et al, 2005Winkler et al, 2005

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

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

Winkler et al, 2005Winkler et al, 2005

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

1)1) preparation and composition of the graft tissuepreparation and composition of the graft tissue - prolonged - prolonged cold storage and use of solid grafts are not as goodcold storage and use of solid grafts are not as good

2)2) selection of patientsselection of patients - older patients do not tend to benefit as - older patients do not tend to benefit as much as young patients due to less confined damage and much as young patients due to less confined damage and reduced ability to accept to graftreduced ability to accept to graft

3)3) pre-graft medicationpre-graft medication – low-dose patients tend to benefit more – low-dose patients tend to benefit more from graft. In fact, one of the controlled studies with older from graft. In fact, one of the controlled studies with older patients with no significant group improvement there was a patients with no significant group improvement there was a correlation between the magnitude of the response to dose of correlation between the magnitude of the response to dose of L-dopa and the magnitude of the postsurgical improvement.L-dopa and the magnitude of the postsurgical improvement.

4)4) graft placementgraft placement – grafts only innervate tissue 2-3 mm from the – grafts only innervate tissue 2-3 mm from the graft site so benefits will depend on the location of the graft site so benefits will depend on the location of the placement and whether there is limited damage outside of the placement and whether there is limited damage outside of the striatum.striatum.

The authors conclude that standardized procedures for The authors conclude that standardized procedures for selection of patients, graft preparation and selection of patients, graft preparation and immunosuppresion, combined with tailoring the placement immunosuppresion, combined with tailoring the placement of grafts may improve the outcome of this promising of grafts may improve the outcome of this promising therapy for PD.therapy for PD.

MPTP exposure initiates long-term neurodegeneration

Practice questionsPractice questions

Where was the fetal tissue taken from and where Where was the fetal tissue taken from and where was it transplanted to?was it transplanted to?

Immunosuppresion is important for post-surgical Immunosuppresion is important for post-surgical improvement to occur in the first 6 months or after improvement to occur in the first 6 months or after that time.that time.

What was shown to be a misconception regarding What was shown to be a misconception regarding MPTP exposure and why?MPTP exposure and why?

What data suggests that MPTP does not induce What data suggests that MPTP does not induce PD?PD?

Hubel and WieselHubel and Wiesel

Receptive fields of visual neuronsReceptive fields of visual neurons

Neurons from all levels of the retina-Neurons from all levels of the retina-geniculate-striate pathway:geniculate-striate pathway:– Receptive fields of foveal area were smaller Receptive fields of foveal area were smaller

than those from the periphery (high-acuity)than those from the periphery (high-acuity)– Receptive fields were circularReceptive fields were circular– Receptive fields were monocularReceptive fields were monocular– Receptive fields had excitatory and inhibitory Receptive fields had excitatory and inhibitory

areas separated by a circular boundaryareas separated by a circular boundary““on” firing when light was turned on on” firing when light was turned on

““off” firing inhibition when light was on followed by off” firing inhibition when light was on followed by a burst of activity when it was turned offa burst of activity when it was turned off

Receptive Receptive fieldsfields

On-center cellOn-center cell

Off-center cellOff-center cell

Both respond Both respond best to contrastbest to contrast

Lower Layer IV neuronsLower Layer IV neurons

‘‘on’ or ‘off’ center-surround receptive on’ or ‘off’ center-surround receptive fields.fields.

M-layer projections terminate just above M-layer projections terminate just above P-layer projectionsP-layer projections

MonocularMonocular

Simple cortical cellsSimple cortical cells

Neurons from lower layer IV of striate Neurons from lower layer IV of striate cortex are exceptions compared to all cortex are exceptions compared to all other striate neurons, which are other striate neurons, which are categorized as simple or complex:categorized as simple or complex:Simple cellsSimple cells– Have “on” and “off” regions Have “on” and “off” regions – Are monocularAre monocular– Borders of “on” and “off” regions are straight Borders of “on” and “off” regions are straight

lines rather than circles (rectangular receptive lines rather than circles (rectangular receptive fields)fields)

– Respond best when it’s preferred straight Respond best when it’s preferred straight edge is in a particular orientation and positionedge is in a particular orientation and position

Complex cortical cellsComplex cortical cellsAre more numerousAre more numerous

Have rectangular receptive fieldsHave rectangular receptive fields

Respond best to straight line stimuli in a Respond best to straight line stimuli in a specific orientationspecific orientation

Unresponsive to diffuse lightUnresponsive to diffuse light

Differ from simple cells in 3 important ways:Differ from simple cells in 3 important ways:1.1. Larger receptive fieldsLarger receptive fields

2.2. No “on-off” regions – responds best to a straight No “on-off” regions – responds best to a straight edge stimulus of a particular orientation swept edge stimulus of a particular orientation swept across the receptive field (fires continuously)across the receptive field (fires continuously)

3.3. Many complex cells are binocular (respond to Many complex cells are binocular (respond to stimulation of either eye and will respond more stimulation of either eye and will respond more robustly to stimulation of both eyes simultaneously).robustly to stimulation of both eyes simultaneously).

Receptive Fields in Striate Receptive Fields in Striate CortexCortex

SIMPLESIMPLERectangularRectangular““on” and “off” regions, on” and “off” regions, like cells in layer IVlike cells in layer IVOrientation and Orientation and location sensitivelocation sensitiveAll are monocularAll are monocular

COMPLEXCOMPLEX

RectangularRectangular

Larger receptive fieldsLarger receptive fields

Do not have static Do not have static “on” and “off” regions“on” and “off” regions

Not location sensitiveNot location sensitive

Motion sensitiveMotion sensitive

Many are binocularMany are binocular

Characteristics of complex cellsCharacteristics of complex cellsRespond best to straight-line stimuliRespond best to straight-line stimuli

Of a particular orientationOf a particular orientation

swept across the receptive fieldswept across the receptive field

in a particular directionin a particular direction

Receptive fields of Receptive fields of binocularbinocular complex cells complex cells

Occupy corresponding positions within the Occupy corresponding positions within the visual fields of both eyesvisual fields of both eyes

Have the same straight-line orientation Have the same straight-line orientation preferencepreference

Binocular complex cellsBinocular complex cells

fire more robustly when both eyes are stimulated fire more robustly when both eyes are stimulated simultaneouslysimultaneously

respond best when the preferred straight-line respond best when the preferred straight-line stimulus falls on slightly different positions of the stimulus falls on slightly different positions of the two retinas – two retinas – Retinal disparityRetinal disparity

respond more robustly to stimulation of one eye respond more robustly to stimulation of one eye than to the same stimulation of the other eye - than to the same stimulation of the other eye - Ocular dominanceOcular dominance

Binocular cellBinocular cell

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

http://www.physiology.wisc.edu/yin/public/hubel_wiesel_binocular_cell.asf

Columnar organization of V1Columnar 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

Hubel & Wiesel’sHubel & Wiesel’smodel of the columnar model of the columnar

organization of the organization of the primary visual cortexprimary visual cortex

Big block of tissue Big block of tissue analyzes signals from one analyzes signals from one area of the visual fieldarea of the visual field

Sub-blocks analyze Sub-blocks analyze signals from the left and signals from the left and right eyesright eyes

Slices of block prefer Slices of block prefer lines in a particular lines in a particular orientationorientation

Component theory of color visionComponent theory of color vision

Three kinds of color Three kinds of color receptors (cones) receptors (cones) each with a different each with a different spectral sensitivityspectral sensitivity

Color of a particular Color of a particular stimulus is stimulus is determined by the determined by the ratio of activity in the ratio of activity in the three kinds of three kinds of receptorsreceptors

Component theory of color visionComponent theory of color vision

The evidence:The evidence: Any color in the visible spectrum can Any color in the visible spectrum can

be matched by mixing together 3 be matched by mixing together 3 different wavelengths of light in different wavelengths of light in different proportions. different proportions.

3 types of receptors must exist to 3 types of receptors must exist to match all the colors in the visible match all the colors in the visible spectrumspectrum

Opponent-process theory of color visionOpponent-process theory of color vision

Two different classes of cells in the visual Two different classes of cells in the visual system for encoding colorsystem for encoding color

One class of cells signaled red by One class of cells signaled red by changing its activity in one direction and changing its activity in one direction and green by changing its activity in the green by changing its activity in the opposite directionopposite direction

Another class signaled blue and its Another class signaled blue and its complement, yellow.complement, yellow.

Opponent-process theory of color visionOpponent-process theory of color vision

The evidence:The evidence: Complementary colors cannot exist Complementary colors cannot exist

together (no reddish green or bluish together (no reddish green or bluish yellow) yellow)

afterimage of red is green and the afterimage of red is green and the afterimage of blue is yellowafterimage of blue is yellow

Afterimage demoAfterimage demo

Stare at fixation point for Stare at fixation point for 1 minute1 minute

X X

quickly shift gaze to the quickly shift gaze to the point belowpoint below

Which theory is correct?Which theory is correct?

The Answer: both (and a third one)The Answer: both (and a third one) Cones code color on a purely Cones code color on a purely

component basis (different component basis (different photopigments maximally sensitive to photopigments maximally sensitive to low, medium and high wavelengths of low, medium and high wavelengths of light) light)

Opponent processing of color occurs Opponent processing of color occurs at all other levels of the retina-at all other levels of the retina-geniculate-striate systemgeniculate-striate system

Component theory of color visionComponent theory of color visionMicrospectrophotometryMicrospectrophotometry - - a technique for measuring the a technique for measuring the

absorption spectrum of the photopigments contained in absorption spectrum of the photopigments contained in a single conea single cone

Confirmed the Confirmed the existence of 3 existence of 3 different kinds of different kinds of cones, each cones, each containing a different containing a different photo-pigment with photo-pigment with different characteristic different characteristic absorption spectrumsabsorption spectrums

Retinex theory of color visionRetinex theory of color vision

Color is determined by Color is determined by reflectancereflectance – the – the proportion of light of different wavelengths proportion of light of different wavelengths a surface reflectsa surface reflects– Reflected light changes based on different Reflected light changes based on different

illuminationillumination– The efficiency of light absorbed and reflected The efficiency of light absorbed and reflected

by a surface is constant.by a surface is constant.– The visual system compares the light The visual system compares the light

reflected by adjacent surfaces in at least 3 reflected by adjacent surfaces in at least 3 different wavelength bands. different wavelength bands.

Reflectance and Color ConstancyReflectance and Color Constancy

Wavelengths absorbed: A, B & CWavelengths reflected: D, E & F

ABC

AB

C

DE

F

IncandescentLight

Wavelengths absorbed: A, B & CWavelengths reflected: G, H & I

ABC

AB

C

GH

I

FluorescentLight

Land (1977) experimentLand (1977) experiment

1.1. Subjects adjusted the Subjects adjusted the intensity of each projector to intensity of each projector to produce a pure white light in produce a pure white light in a dark rooma dark room

2.2. Subjects were then shown Subjects were then shown Mondrians Mondrians (Blue was adjusted to (Blue was adjusted to reflect the same combinations of reflect the same combinations of wavelengths just judged to be white)wavelengths just judged to be white)

3.3. Despite the adjustment, blue Despite the adjustment, blue still appeared as blue in the still appeared as blue in the Mondrian Mondrian

4.4. However, when viewed in However, when viewed in isolation in a dark field it isolation in a dark field it appeared as whiteappeared as white

Principles of sensory Principles of sensory system organizationsystem organization

Three different types of sensory cortex:Three different types of sensory cortex:

1.1. Primary sensory cortexPrimary sensory cortex – receives most – receives most of its input from thalamic relaysof its input from thalamic relays

2.2. Secondary sensory cortexSecondary sensory cortex – receives – receives most of its input from the primary most of its input from the primary sensory cortex of a systemsensory cortex of a system

3.3. Association cortexAssociation cortex – receives input from – receives input from more than one sensory systemmore than one sensory system

Visual areas of the cortexVisual areas of the cortex

ScotomaScotoma

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

Two Visual StreamsTwo Visual Streams

Two Visual streams: Two theoriesTwo Visual streams: Two theories

‘‘What’ versus ‘Where’ (Ungerleider & What’ versus ‘Where’ (Ungerleider & Mishkin, 1982) – kinds of information Mishkin, 1982) – kinds of information processedprocessed

Ventral pathway – perception of what an Ventral pathway – perception of what an object isobject is

Dorsal pathway – perception of where the Dorsal pathway – perception of where the object is locatedobject is located

Two Visual streams: Two theoriesTwo Visual streams: Two theories

‘‘What’ versus ‘How’ (Milner & Goodale, What’ versus ‘How’ (Milner & Goodale, 1993) – the use to which information is 1993) – the use to which information is put.put.

Ventral pathway – conscious perception of Ventral pathway – conscious perception of objectsobjects

Dorsal pathway – direct behavioral Dorsal pathway – direct behavioral interactions with objectsinteractions with objects

Visual agnosiaVisual agnosia

GnosisGnosis means “to know” means “to know”

Visual agnosics can see stimuli but do not Visual agnosics can see stimuli but do not know what they areknow what they are– Movement agnosiaMovement agnosia– Object agnosiaObject agnosia– Color agnosiaColor agnosia– Prosopagnosia (faces)Prosopagnosia (faces)

ProsopagnosiaProsopagnosia

Can recognize faces as faces but cannot Can recognize faces as faces but cannot idenify particular faces, including their ownidenify particular faces, including their ownThe farmer and bird watcherThe farmer and bird watcherGeneral problem recognizing specific General problem recognizing specific objects that belong to complex classes of objects that belong to complex classes of objectsobjectsDue to damage to the fusiform face area Due to damage to the fusiform face area (border between visual occipital and (border between visual occipital and temporal areas)temporal areas)

FFAFFA