Imaging Drugs in the BrainENAS 880 / NSCI 523

Fall 2010Morris/Cosgrove

evan.morris@yale.edukelly cosgrove@yale.edu

http://tauruspet.med.yale.edu/staff/edm42/courses/ENAS_880/index.html

Quiz 1

Course business

• info posted on Evan’s website• a few classes in N203 at end of semester• lectur-ettes, followed by…• paper discussions – participation expected• paper synopses to be written, emailed• collaborative presentation or other work• what are your interests?• what are your goals?

Terms in first papers

dopamine

neuroleptic

tomographic method

spatial resolution

cyclotron (‘in-hospital’… why)

specific activity

specific binding

attentuation correction

septa

reference region

recovery coefficient

ligand vs tracer vs isotope

contrast

noise

model

compartments

steady state

structural vs functional

caudate, cerebellum

Warmup: What is this?

http://www.cscs.umich.edu/~crshalizi/

OK, start with this…

http://www.cscs.umich.edu/~crshalizi/election/

functional image overlaid on a structural image:

the ‘pixels’ in a structural image convey some physical, anatomical, or geographical information about the object.

now this

http://www.cscs.umich.edu/~crshalizi/election/

functional image:

the color and size of the ‘pixels’ convey some functional information about how the object WORKS.

now this

Electoral Map (Cartogram)

Every county is displayed in color according to vote (in 2004) of the majority of the voters. The size of the county represents the number of voters. (Note that the western

plain states are smaller than the east coast.)In this case, the cartogram shows us that –contrary to popular belief- the country’s distribution of Dems and

Repubs was reasonably heterogeneous.http://www.cscs.umich.edu/~crshalizi/

but do “functional images” of the brain ever change the apparent

shape of the brain?

..actually, yes…

perhaps we’ll get to this advanced topic this semester

Our goal: Understand how functional maps of the human brain are used to study drugs and drug

action

what’s going on here?

Christian et al.

which ones are…functional vs structural

which ones do “detection” vs “characterization”

Fowler et al., Science & Practice Perspectives, April 2007, 4-16

what’s the modality?

what is the orientation of the brain?

what is the orientation of the person?

what’s the yellow stuff?

is this a single subject?

Fowler et al., Science & Practice Perspectives, April 2007, 4-16

what’s the prominent neurotransmitter in the nucleus accumbens?

Fowler et al., Science & Practice Perspectives, April 2007, 4-16

Carboni et al, J Neurosci 20:RC102(1-5), 2000

Many drugs cause release of dopamine

“… cocaine, morphine, nicotine, and ethanol share the property of increasing DA transmission in the BNST. This effect may be related to an action at the level of neuronal circuits activated by natural reinforcers … suggest[ing] that DA transmission of the BNST plays a role in the mechanism of drug abuse and addiction.”

is everyone familiar with

this diagram?

to what other site(s) could we direct a

tracer?

Fowler et al., Science & Practice Perspectives, April 2007, 4-16

which one is specific for neurotransmitter system?

which one is a non-specific marker of ‘activation’?

what are they ‘tracing’

are these molecules biologically the same as their

tracees?

is there a mistake on this slide?

Fowler et al., Science & Practice Perspectives, April 2007, 4-16

which end is up?

which end has high uptake in healthy controls?

how do you know?

what does that mean?

why are these images so blurry?

Fowler et al., Science & Practice Perspectives, April 2007, 4-16

what is the claim here?

what assumption(s) is(are) at work?

are they measuring the phenomenon or something

related to it?

Fowler et al., Science & Practice Perspectives, April 2007, 4-16

why is most of the brain blue?

are these “early” or “late” images?

is this structural or functional?

is this a ‘detection’ or a ‘characterization’ experiment?

Fowler et al., Science & Practice Perspectives, April 2007, 4-16

Schematic Diagram of Ligand Binding

“Rest” condition

endogenous NT unlabeled tracer radiolabeled tracer

BP = B/F at steady state

Schematic Diagram of Ligand Binding

“Rest” condition

endogenous NT unlabeled tracer radiolabeled tracer

loss of receptors

BP ↓

Schematic Diagram of Ligand Binding

DA-release condition

endogenous NT unlabeled tracer radiolabeled tracer

DA ↑

BP ↓

BP is the (fractional) difference in BP between conditions

BP= (BP1-BP2)/BP1

questions/thoughts on the review article by Fowler et al.

1. What is functional imaging and how is it different from structural imaging?

a. sort of related: detection (as in tumor…but could be simply distribution of receptors) vs characterization (as in kinetic characterization… requires modeling)

2. Are effects of chronic drug use permanent?

3. How can I get my basal ganglia to grow larger?

4. Is there really such a thing as a functional MRI machine? Is there a forward-moving car a different thing than a car going in reverse? Bottom line: is fMRI really a different modality than MRI?

5. what is wrong with this statement: “Biologically, the more oxygen that cells in a region utilize, the more oxygen-carrying hemoglobin molecules will be found in the blood vessels responsible for supplying them”?

6. a big potential use of imaging is to predict vulnerability to addiction… but I am not sure it is being done successfully yet.

7. in Wexler 2001 (see Figure 4) why is there so much activity in visual cortex in healthy volunteers but not in cocaine addicts.

8. why is fMRI not “specific” like PET or SPECT or even MRS? cannot differentiate neurotransmitters or circuits or even inhibitory vs excitatory activity.

questions (2)

1. fMRI and MRS image endogenous materials. PET and SPECT (in most basic mode) image exogenous tracers. PET and SPECT can be used to image effects of endogenous chemicals…

2. compare relative SENSITIVITIES of MRS and PET

3. Not clear if MRS observations of NAA indicate increased glial activity or something else… possible contradictions on pages 8 & 9

4. can’t we make images from MRS… not just spectra

5. could use MRS to look at exogenous alcohol.

6. PET/SPECT require injection of radiotracers

7. A little overstatement: “series of images taken at appropriate intervals provides stop-action record of a drug’s movement into and out of the brain”

8. can you find the mistake in figure 5… F18 replaces OH not F19

questions (3)

1. Figure 5 legend leaves out a key step…”annihilation”

2. is there a difference between imaging dopamine receptors and dopamine transporters?

a. how ‘bout dopamine receptors and dopamine? How would you do it?

b. is there a difference between imaging cocaine effects on dopamine system and cocaine effects on mu-opioid system? What?

3. there are inherent ambiguities in PET data … such as the inability (in most cases) to separate the effects of change in affinity of receptor for ligands vs change in number of receptors.

a. how do people deal with such ambiguities?

4. we want to “exacerbate nicotine-induced dopamine dysregulation… how should we do it? Give MAO inhibitors that are present in tobacco smoke? If so, why is selegiline (MAO inhibitor) used (tried) as a smoking cessation treatment?

5. what imaging work has actually affected design/development of smoking and other addiction treatments?

6. “dopamine spikes underlie drug euphoria” has this ever been proved?

7. Treatment strategies. Paper by Kreek is cited to support: “third strategy… utilizes a medication that activates the same neurotransmitter system as an abused drug, but produces no shart dopamine spike”… this sounds like Chantix. Authors claim it is methadone and bupremorphine.

8. detox’d methamphet users who stayed abstinent for 9 months recovered dopamine transporters. but they did not recover the same degree of cognitive and motor function. why not?