Antonio P. Strafella M.D. Ph.D. FRCPC Dept. Medicine/Neurology, UHN. Toronto Western Research Inst., UHN PET Imaging Center, CAMH. University of Toronto HBM 2014- Educational Course: Brain Stimulation: Past, Present and Future Session on Modelling and imaging of the brain effects of stimulation: Combining TMS/PET
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HBM 2014- Educational Course Stimulation...VMAT DAT PET Scanning Striatal Uptake Uptake . Dopamine D2/D3 Receptor Imaging Agent in Striatum [11C]raclopride [123I]IBZM PET agent Affinity
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Antonio P. Strafella M.D. Ph.D. FRCPC
Dept. Medicine/Neurology, UHN. Toronto Western Research Inst., UHN
PET Imaging Center, CAMH.
University of Toronto
HBM 2014- Educational Course: Brain Stimulation: Past, Present and Future
Session on Modelling and imaging of the brain effects of stimulation: Combining TMS/PET
OBJECTIVES o To describe different PET radiotracers used to image the dopaminergic system. o To learn about the effects of brain stimulation on the dopaminergic system. o To describe TMS effects on brain functions and
Effects of Electrical Stimulation of Prefrontal Cortex on Dopamine Release
Taber and Fibiger, J of Neuroscience,1995
microdialysis experiments
rTMS Sham
Dorsal Striatum
Keck et al., Neuropharmacology, 2002
Dop
amin
e Le
vels
(%
bas
elin
e)
rTMS Effect on Dopamine Release
microdialysis experiments
Dorsal Striatum
rTMS Effect on Dopamine Release
Kanno et al. J. Neurol Sci. 2004
microdialysis experiments
Neuro-receptor Imaging
Ohnishi et al., 2004
rTMS & Striatal Dopamine
Macaque Monkeys
TMS and [11C] raclopride PET
0 -30 -15 30 60
11C-rac rTMS – 10 Hz PET scanning
X
dorsolateral PFC
X
occipital
Strafella et al., 2001
150 150 150
10’ 3’
X= -56, Y= -58, Z=-3
X= -40, Y= 32, Z=30
X
occipital
X
Primary motor cortex
X= -31, Y= -22, Z=52
X= -56, Y= -58, Z=-3
Strafella et al., 2003
rTMS & Striatal Dopamine -Stimulation of DLPFC-
Strafella et al., J of Neuroscience, 2001
Mean Δ%BP = -7.3%
Yeterian and Pandya J. Comp. Neurol. 1991
rTMS & Striatal Dopamine -Stimulation of motor cortex-
Strafella et al., Brain, 2003
Mean Δ%BP = -9.5%
Takada et al., Exp Brain Res. 1998
0,45
0,47
0,49
0,51
0,53
0,55
0,57
0,59
rTMS challenge d-amphetamine challenge
spec
ific
str
iata
l [12
3I]
IBZ
M r
atio
pre-challenge
post-challenge
Figure: Mean specific striatal IBZM-binding (striatal-occipital/occipital) before and after rTMS (left) and d-amphetamine (right) challenge.
- 9.6 % (± 6.2)
- 8 % (± 2.9)
Pogarell et al., Psychiatry Res , 2007
Striatal dopaminergic effects TMS versus amphetamine challenge
• rTMS effect on behaviors and possible clinical relevance.
[11C]FLB 457
-3
-6 t
Reductions [11C] raclopride BP Symptomatic Hemisp. Asymptomatic Hemisp.
TMS-induced release of dopamine in PD
• Reduction in [11C] BP in
ipsilateral putamen
• 12.9 % reduction in
asymptomatic hemisphere
• 9.45 % reduction in
symptomatic hemisphere
Strafella et al., EJN 2005
Reduction [11C] raclopride BP
70
560
113
904
• 61.4 % increase in
cluster size
-3
-6 t
Symptomatic Hemisp. Asymptomatic Hemisp.
Strafella et al., EJN 2005
Loss of functional segregation
Normal Nigrostriatal degeneration
• Because of loss of re-uptake sites, released dopamine diffuses out to more distant regions of the receptor populat ion in the dopamine-denervated striatum > loss of functional segregation
Zigmond et al. TINS 1990
• The loss of functional segregation may favor the de-arrangement of the selective facilitation/surround inhibition pattern leading to impaired inhibition of competing motor patterns.
• The neuroanatomical arrangement of the cortico-striatal system in a center-surround inhibitory pattern is thought to facilitate activity in cortico-striatal loops involved in the current task with concomitant suppression of competing motor networks.
Functional implications for models of basal ganglia function in PD
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Cerebral Cortex
Striatum
GPi
STN
Thalamocortical and Brainstem Targets
Desired Motor Pattern
Competing Motor
Patterns
ExcitatoryInhibitory
Reduction of [123I]-IBZM binding following left prefrontal rTMS in major depression
p < .01, Wilcoxon -20
-15
-10
-5
0
1 2 3 4 5 6 7 8 9
%-c
hang
e IB
ZM-b
indi
ng
B. Change of striatal [123I]-IBZM-binding after rTMS
Pogarell et al. J Psychiatr Res 2006 0,0 0,2 0,4 0,6 0,8 1,0 1,2