TMS in animal models: Methods and Applications
Transcript of TMS in animal models: Methods and Applications
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TMS in animal models: Methods and Applications
Alexander Rotenberg, M.D., Ph.D. Director, Neuromodulation Program
Boston Children’s Hospital
CoilElectricfield
Magneticfield
Electriccurrent
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Conflict of Interest Disclosure
Current: Neuro’motion Inc. (technology for improving emotional control; co-founder) NeuroRex (medical advisor) Brainsway Inc. (research support [equipment and personnel]) Soterix Medical Inc. (research support [equipment]) Neuroelectrics Inc. (research support [equipment]) Journal of Central Nervous System Diseases (EIC) NIH NIMH, DoD, CIMIT, ERF, TRP (research grants)
Past: Neuropace Inc. (research grant and equipment) Nexstim Inc. (consultant) Sage Therapeutics Inc. (consultant) Fisher Family Fund and Fisher-Wallace Inc. (research support [unrestricted gift and equipment])
Alexander Rotenberg
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TMS in animals DO NOT COPY
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Why TMS studies in animals?
– Basic Science – Translational
Research
Poma et al., 2006
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Advantages of animal subject
• Subject homogeneity • Available histology • Genetic / disease models
Liebetanz et al., 2003
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Translational Relevance
• Disease modeling • TMS safety • Neuronal connectivity • Synaptic plasticity • Cortical organization
Charlet de Sauvage et al. 2007
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Induced dysfunction: neglect-like syndrome in cats
Valero Cabre et al., 2005
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Frequency-Dependent 14C-2DG uptake modulated in cat
Valero-Cabre et al. 2006
20 Hz off-line
20 Hz on-line
1 Hz on-line
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No injury after prolonged TMS
• Counter, 1995: – No deleterious effect on AEP after 1000 pulses at 1Hz n
rabbits • Nishikiori, 1996:
– No cortical or brainstem lesions after ~1 month of daily TMS in rabbits
• Liebetanz et al., 2003: – No MRS or histologic changes after 5 days of 1 Hz rTMS
• Charlet de Sauvage et al., 2007 – No DNA damage after 2000 TMS pulses
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Most translational research is with rodents
• Well-described disease models • Inexpensive • Experiments may be translated to clinical care • TMS effect can be examined at multiple levels:
whole animal, brain slice, single cell, etc. Kistsen et al.,
in progress
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Disadvantages of rat model – Compromised stimulus focality – Slightly more difficult EEG – Required restraint or anesthesia
Luft et al., 2001
Kamida et al., 1998
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Stimulation protocols
Frye, Rotenberg, et al. Child Neurol 2007
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Off-Center Coil
Rotenberg et al., 2009
EMG EMG
Ground
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Lateralized brachioradialis MEP
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Lateralized TMS in Rats
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Stimulation protocols
Frye, Rotenberg, et al. Child Neurol 2007
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1
Conditioning TMS
2 Test TMS
Control
SICI; 2 ms ISI
ICF; 12 ms ISI 0.5 mV
25 ms
LICI; 200 ms ISI
0.5 mV
50 ms Rotenberg and Pascual-Leone, 2010
Measures of Cortical Excitability by Paired-Pulse TMS (ppTMS) DO NOT COPY
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Paired-Pulse Inhibition in rats
Vahabzadeh et al., 2011
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Inhibition in rats preserved with anesthesia
Vahabzadeh et al., 2011
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Inhibition lost with GABA-A antagonist / seizures
Vahabzadeh et al., 2011
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A
B
PTZ Effects on MEP Inhibition by ppTMS
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MMG (Mechanomyography)
Detection of cortical inhibition by MMG and ppTMS in unanesthetized rats
Accelerometer
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EMG v.s MMG
MM
G (V
)
-0.15
-0.10
-0.05
0.00
0.05
0.10
0.15
50ms
60%MO 70%MO 80%MO 90%MO 100%MO
MMG
Input–output curve of MMG
EMG (Tibia anterior m.)
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MMG testing during TMS
Awake rat
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• reduced inhibition with PTZ and increased inhibition with PB
GABAA-mediated cortical inhibition following pentobarbital (PB) and pentylenetetrazole (PTZ)
200ms ISI
ConditionPre P10 P60 Pre P10 P60 Pre P10 P60
% o
f unc
ondi
tione
d M
MG
20
40
60
80
SalinePBPTZ
Left Right Ave (L+R)***
*
***
*
***
*
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TMS in Experimental Epilepsy
• Diagnostic – Measure of cortical excitability – Assessment of drug (or other intervention) effect
• Therapeutic – Anticonvulsant (seizure termination) – Antiepileptic (seizure prevention)
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Fluid Percussion Injury: a post-traumatic epilepsy model
Nature Protocols, 2011
McIntosh et al., 1989
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• Rats with TBI show less ppTMS-MMG inhibition relative to sham-TBI controls 6 weeks after injury, when post-traumatic epilepsy develops.
Reduced cortical inhibition in TBI: a marker for epileptogenesis?
50ms ISIL R L R L R
% o
f unc
ondi
tione
d M
MG
0
20
40
60
80
100
120 Normal ratsChronic TBI rats
100ms ISI 200ms ISI
** ** *
2mm
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Gradual decrease in LICI reaches significance at 1 week after TBI as compared to pre-values. More detailed data compared between sham and TBI group in LICI at 100 ms (C) and 200 ms ISI (D) following TBI. (*p<0.05, **p<0.01)
100ms ISI
Time
Pre 1WK 2WKS 3WKS 4WKS 5WKS 6WKS
Rat
io
0.0
0.2
0.4
0.6
0.8
1.0Sham controlTBI
*** *
*200ms ISI
Time
Pre 1WK 2WKS 3WKS 4WKS 5WKS 6WKS
Rat
io0.0
0.2
0.4
0.6
0.8
1.0Sham controlTBI
*** *
*
**
Hsieh et al., ECCN 2011 abstr.
Loss of cortical inhibition after TBI DO NOT COPY
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4 2 Sham control TBI (lesion)
4 2 6 6 NeuN
4 2 TBI (contra-lesion)
6 I
II/III
V
VI
General cortical architecture was not affected by TBI
Layer V thickness NeuN
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Gonchar et al., 2007, Front Neuroanat.
Parvalbumin (PV) interneurons are the major sub-type of cortical inhibitory neuron…
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4 2 Sham control Post-TBI (peri-lesion)
4 2 6 6 PV
4 2 Post-TBI (contra-lesion)
6 I
II/III
V
VI
* ***
*** * n.s. n.s.
Peri-lesion Contra-lesion
Gradual loss of parvalbumin (PV)-cells after TBI
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8-oxo-dG I
II/III
V
VI
4 2 Sham control Post-TBI (peri-lesion)
4 2 6 6 4 2 Post-TBI (contra-lesion)
6
n.s.
*** ***
** n.s.
n.s. Peri-lesion Contra-lesion
Delayed increase in oxidative stress after TBI
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Implications for Therapy
TBI
Epileptic seizure
PTE
Antioxidant (N-acetylcysteine)
Oxidative stress
Loss of PV-cells
↓ Perineuronal nets ↓ Otx2 Impaired inhibition
Neuroprotection (Otx2)
Lee et al., 2013
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Ceftriaxone treatment prophylaxes against posttraumatic seizures DO NOT COPY
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ppTMS as a biomarker in TBI treatment
ppTMS-MMG at 200ms ISI
TimePre 1W 2W 3W 4W 5W 6W
Ratio
of u
ncon
ditio
ned
MM
G
0.0
0.2
0.4
0.6
0.8
1.0
1.2
SalineCTX
n=7 (saline)n=7 (CTX)
n=3 (saline)n=3 (CTX)
p=0.07
p=0.04p=0.05
p=0.002
n=7 (saline)n=6 (CTX)
Hameed et al., 2014
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Stimulation protocols
Frye, Rotenberg, et al. Child Neurol 2007
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Therapeutic TMS
• Three potential targets: – Seizure – Epilepsy – Epileptogenesis
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Rat TMS-EEG methods
Rotenberg, et al., 2005 Ives et al., 2006
EKG EEG
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Spike Provocation by TMS in Rats
Rotenberg, Brain Topogr 2010
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Rat “deep” TMS during seizure
EEG analysis (seizure detection)
coil electric current
magnetic field
electric field
torso strap restraints
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Kainate (KA) Model Status Epilepticus
• Three-Stage Effect: – Acute 2-3 hour prolonged seizure – Subacute 6-9 week seizure-free period – Chronic daily recurrent seizures
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Terminated KA seizure
Ives, Rotenberg et al., Clin Neurophys2006
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Refractory KA Seizure
5 sec
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rTMS during KA seizure
Rotenberg et al., Clin Neurophys 2008
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rTMS during KA seizures R
elat
ive
Aver
age
Seiz
ure
Dur
atio
n (%
unt
reat
ed c
ontr
ol)
0.25 Hz
0%
25%
50%
75%
100%
125%
150%
0.5 Hz
*
0.75 Hz untreated sham active
*
untreated sham active untreated sham active
Rotenberg et al., 2008
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Reduced c-Fos expression (and excitotoxicity?)
with 0.5 Hz rTMS
KA only Control KA + TMS
Rotenberg et al., AES abstr 2005
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Mixed results in controlled trials – Theodore et al., Neurology 2002
• N=24; 1 Hz X 900 BID X 1 week • Mild and short-lived seizure reduction
– Fregni et al., Annal Neurol 2006 • N=21; 1 Hz X 1200 X 5 days • Significant seizure reduction and EEG improvement
– Cantello et al., Epilepsia 2007 • N=43; 0.3 Hz X 1000 X 5 days • Significant EEG improvement; no change in seizures
– Sun et al., Epilepsia 2012 • N=64; 0.5 Hz X 1500 X 14 days • Significant seizure reduction and EEG improvement
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Better effect with 1 Hz
0.3 0.5 1
-100
-50
0
50
100
150
change
Hz
Rotenberg et al., unpublished data
% reduction in Seizure Frequency After rTMS DO NOT COPY
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Frequency-response in vitro LTD approximates rTMS data
Nakano et al., 2004
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Molecular Basis: Does rTMS induce LTP/LTD?
Kandel, 2001
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Kandel, 2001
rTMS mechanisms DO NOT COPY
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Muller et al., PLOS One 2014
*
1 0.5 0.25 S1 S0.5 S0.25 Stimulation Condition (Hz)
MEP depression by rTMS in anesthetized rat
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Kandel, 2001
rTMS mechanisms DO NOT COPY
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CREB phosphorylation by 20 Hz rTMS
0%
50%
100%
150%
200%
250%
300%
20 Hz rTMS Sham
pCR
EB (%
con
trol
)
20 Hz rTMS Sham
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Kandel, 2001
rTMS mechanisms DO NOT COPY
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BDNF expression after rTMS
anesthetized
awake
Gersner et al., J. Neursci 2011
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Gersner et al., J. Neursci 2011
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Follow-up
Work in Progress:
Time (min) 0
10 20 30 -10
Baseline Anesthesia
Kainic acid injection
rTMS/Sham
-70 -85 Lorazepam Follow-up Sham/rTMS
/Lorazepam
Gap in knowledge: how to combine neurostimulation with AEDS? DO NOT COPY
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Spike suppression by 20 Hz rTMS
A Sham rTMS
30 sec
Baseline
Treatment
Follow-up
0
0.5
1
1.5
2
2.5
Baseline Treatment Follow-up
Nor
mal
ized
spi
ke fr
eque
ncy
(aut
o-co
unt)
Baseline Treatment Follow-up ***
**
B
C
Time (sec)
*
*
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The effect of Lorazepam and rTMS combination treatment on spike frequency
LZP + Sham LZP + LZP LZP + rTMS
2nd treatment
Baseline
LZP
Follow-up
30 sec
0
0.2
0.4
0.6
0.8
1
1.2
1.4
BL 1st 2nd FU
Nor
mal
ized
spi
ke fr
eque
ncy
(aut
o-co
unt)
Baseline LZP Follow-up 2nd Treatment
** ***
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Can we model TMs in rodents without magnetic coils?
Hsieh et al., work in progress
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LTP-like potentiation after electrical iTBS
Hsieh et al., work in progress
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