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Transcranial Magnetic Stimulation - TMS
Diagnostic Applications
• Central Motor Conduction• Cortical Output Mapping• Cortical reactivity• Intracortical E/I Balance• Cortical Plasticity• Metaplasticity• Functional Connectivity
o Cortico-corticalo Cortico-subcortical
Therapeutic Applications
• Medication Refractory Depressiono Lancet 1995o FDA Approval, Neuronetics, 2008
• Parkinson’s Diseaseo Neurology 1994o MJFF Multicenter Study
• Paino Neurolieve – Migraine o Cerephex – Fibromyalgia
• Neurorehabilitationo Nexstim – Stroke
• Epilepsy….
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Brain Behavior Relations
Genetic Defect Environmental Factors Acquired Insult
Pathology
Brain Adaptation/ Compensation
Pattern of Brain Activity
BehaviorSymptoms of Disease
Change in Cognitive Strategy
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TMS
• Focal Interference with Brain Activity– Adding causal information to brain
imaging findings• Modulation of a Specific Neural
Network– Therapeutic potential in ‘circuit
disorders’
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rTMS: Lasting Modulation of Cortical ActivityModulation Depends on Pattern of Stimulation
ShamTMS
TMS
1 HzTMS
20 HzTMS
Valero-Cabré et al. Exp Brain Res 2005 & 2006
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Splenial visual area
Area 19Area 17
Valero-Cabré et al. Exp Brain Res 2005 & 2006
rTMS: Modulation of a Neural NetworkModulation Depends on Neural Connectivity
Cingulate visual area
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FDA approved for the treatment of medication-resistant depression.
FDA approved forcortical brain mapping
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TMS Terminology• Single pulse TMS
• single stimulus every 5-10 sec
• Paired pulse TMS• Two stimuli separated by 1-20 msec• Same coil or different coils
• Repetitive TMS (rTMS)• trains of stimuli to one brain area• slow = low frequency• fast (high freq) > 1 Hz• Asynchronous trains (eg theta burst
stimulation)
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TMS: Central Conduction Time
Kobayashi et al Lancet Neuro
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Motor Cortical Output Mapping
Nagib et al. Neurosurg Clin 2011
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Motor Cortical Output MappingComparing Noninvasive and Invasive Mapping
Nagib et al. Neurosurg Clin 2011
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TMS: Paired-Pulse
Kobayashi et al Lancet Neurol 03
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Characterizing Neural NetworksTMS and EEG
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Characterizing Neural NetworksTMS and fMRI
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Cortical Reactivity
Theta Burst Stimulation (TBS)
Cortical Reactivity
cTBS
iTBS
Cortical Plasticity
Frontiers Synaptic Plasticity 2011
Measuring LTP/LTD in Humans
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Frontiers Synaptic Plasticity 2011
Cortical Reactivity
Theta Burst Stimulation (TBS)
Cortical ReactivityCortical Plasticity
Measuring LTP/LTD in Humans
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Pascual-Leone et al Lancet 1996O’Reardon et al Biol Psych 2007 • Janicak et al J Clin Psych 2008
FDA approved Treatment for Medication-Resistant Depression
Oct 2008
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Therapeutic Applications of rTMS
(1) Modulate cortical excitability (increase or decrease it) to normalize abnormal level of activity in the targeted brain region - Depression, Dystonia
(2) Suppress activity in the targeted brain region and induce paradoxical behavioral facilitations through distant effects -Neglect, Aphasia
(3) Induce distributed modulation of brain activity resulting in network-specific release of neurotransmitters and activity modulation - PD, Depression, Prefrontal function
(4) Induce release of neurochemical agents with generalized neuromodulatory effects - Epilepsy
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rTMS in Dystonia1 Hz rTMS to suppress cortical excitability
Patients Controls
Siebner et al. 1999
Patients Controls
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Interhemispheric inhibition and neglect
Transcallosal inhibitory connections may subserve rival networks between the two hemispheres, the dynamic balance of which permits normal redirection of attention. (Kinsbourne, 1977)
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Interhemispheric inhibition and neglect
Two-lesion case studies• Sprague (1966): Neglect from cortical
lesion can be reversed by contralateral superior colliculus lesion.
• Vuilleumier et al. (1996): In humans with one lesion, a contralateral second lesion may attenuate neglect.DO N
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Therapeutic modulation of interhemispheric connections
Fregni & Pascual-Leone (2007)
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Contralesional TMS attenuates neglect
• 5 subjects with neglect (3 right brain injury; 2 left brain injury)
• Stimulation over right and left parietal cortex
• 10 pulses of TMS at 25 Hz, synchronous with stimuli
Oliveri et al., 2001
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Extended rTMS may lead to sustained improvement
• 3 patients; right brain injury with neglect
• rTMS to left parietal cortex– 900 Pulses– 1 Hz (inhibitory)– Every other day x 2
weeks• Improvement
persisted 15 days after completing TMS
Pre-rTMS Post-rTMS
Brighina et al., 2003
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Extended rTMS may lead to sustained improvement
• 14 Patients: 7 treatment, 7 control
• 0.5 Hz, 90% MT, 15 min, twice daily x 2 weeks
• Left P3 stimulated• Testing 2 weeks prior, start
of treatment, end of treatment, and two weeks later
• No control site, task, or sham
Song et al., 2009
Line Cancellation
Line BisectionDO N
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• Two chronic neglect patients• Six rTMS sessions over two weeks• 900 pulses to P5 per session• 0.9 Hz, 95% MT• Behavioral Inattention Test (BIT) administered at baseline, 2, 4, and
6 weeks.
Extended rTMS may lead to sustained improvement
Shindo et al., 2006
Subject 1 Subject 2
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Reduction of parietal hyperexcitability correlates with behavioral benefit
Koch et al., 2008
• Twin-coil TMS test of PPC-M1 influences.
• 12 RH patients with neglect, 10 without, 8 healthy controls
• MEP amplitude after conditioning pulse correlated with neglect severity.
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Reduction of parietal hyperexcitability correlates with behavioral benefit
Koch et al., 2008
• MEP amplitude in neglect patients reduced after 600 pulses of 1 Hz TMS (90% MT)
• Stimulation of right PPC also temporarily improved neglect symptoms of visual chimeric test (Sarri et al., 2006)
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Therapeutic Applications of rTMS
• Increase or Decrease cortical excitability in the targeted brain region to normalize abnormal level of activity
• Decrease cortical excitability in the targeted brain region to release inhibition on distant area and achieve paradoxical functional facilitation DO N
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∂% in MEP areapre/post rTMS
-100
-50
0
50
100
150
200
1Hz 10Hz 15Hz 20Hz-20
-10
0
10
20
30
40
rTMS condition
Modulation of Cortical Excitability•Inter-individual variability•Dependency on baseline cortical excitability
Maeda et al, 2000
rTMS: 240 stimuli at 90% of motor threshold
1Hz 10Hz 15Hz 20Hz
rTMS conditionrTMS: 240 stimuli at 90% of motor threshold
∂% in MEP areapre/post rTMS
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Therapeutic Applications of rTMS
• Stimulate the release of neurotransmitters or other substances with neuromodulatory effects
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Antiepileptic Property of the CSF after Exposure to rTMS
Anschel, Holmes, Pascual-Leone 200210 Hz 1 Hz
Flurothyl seizure model
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1994
MASTER-PD5 yr Multicenter Study
Univ Florida • Cleveland ClinicUCLA• Univ Toronto
Parkinson’s Disease
R. J. Goldberg FoundationNIH
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Therapeutic Applications of rTMS
• Induce distributed modulation of brain activity resulting in network-specific release of neurotransmitters and activity modulation
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TMS in Parkinson’s Disease
Fregni et al 2005
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TMS in Parkinson’s Disease
Wu et al 2008
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Depression in PDTMS vs Fluoxetine
Fregni et alJNNP 2004
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Depression in PDTMS vs Fluoxetine
Fregni et alJNNP 2004
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Depression in PDTMS vs Fluoxetine
Fregni et al JNNP 2004
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Depression in PDTMS vs Fluoxetine
Fregni et al Neurology 2006
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Depression in PDTMS vs Fluoxetine
Fregni et al Neurology 2006
After rTMS After Fluoxetine
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NICETM
Non Invasive Cortical EnhancerNeuronix ®
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Identify Brain Target
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NeuronavigationReliable Targeting of a Given Brain Region
NeuronavigatedNon-navigated
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Bashir et al. Brain Topography 2010
Neuronavigation: Enhanced Behavioral (Therapeutic) Effects
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Current shunting by damaged tissueModeling Current Distribution in Subject’s Brain
IEEE 2005; Neuroimage 2006Wagner et al.
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0.5 mV
20 ms
Normal Recovery from Stroke
Integrity of outputs?Network reorganization?
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0.5 mV
20 ms
L FDI(TMS of R affected M1)
R FDI(TMS of L unaffected M1)
Establish Integrity of Output
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0%
20%
40%
60%
80%
100%
120%
0 5 7 8 9 10 12 15 20
Interstimulus interval (ms)
Perc
enta
ge o
f ME
P (%
)L
Stroke
Conditioning Stimulus
Test Stimulus
L FDI
Paired Pulse TMS Measures Hemispheric Interactions:Patients after stroke have excessive interhemispheric inhibition
Normal controls
Stroke patients
Characterize Network Dysfunction
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Before After rTMS
Promoting Stroke Recovery
Fregni et al. 2005 • Boggio et al. 2006, 2007Hummel et al. 2005, 2006 • Schlaug et al 2011
Mansur et al. Neurology 2005
Khedr et al. Neurology 2005
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Martin et al. 2005Naeser et al. 2006, 07
Aphasia: Language Circuit - Rt. Pars Triangularis
Modulation of Neural Networks as Therapeutic Strategy
Pars Triangularis
Pars Opercularis
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R
Anterior Pars TriangularisPosterior Pars TriangularisPars Opercularis
R
Ventral Premotor CortexArcuate Fasciculus
Seed for Arcuate FasciculusDO N
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Before After rTMS
Aphasia: Language Circuit - Rt. Pars Triangularis
Modulation of Neural Networks as Therapeutic Strategy
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Martin et al. 2005Naeser et al. 2006, 07
Aphasia: Language Circuit - Rt. Pars Triangularis
Modulation of Neural Networks as Therapeutic Strategy
Pars TriangularisPars Opercularis
After rTMS
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Martin et al. 2005Naeser et al. 2006, 07
Aphasia: Language Circuit - Rt. Pars Triangularis
Modulation of Neural Networks as Therapeutic Strategy
Pars TriangularisPars Opercularis
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Therapeutic Applications of TMS• Depression• Autism• Acute Mania• Bipolar Disorder• OCD• PTSD• Schizophrenia• Auditory Hallucinoses• Pain
– Visceral pain– Neuropathic pain– Phantom pain
• Fibromyalgia• Migraine
• PD• Alzheimer’s Disease• Focal dystonia• Epilepsy
– Myoclonic epilepsy– Focal status epilepticus
• Stuttering• Tics• Neurorehabilitation
– Neglect– Aphasia– Hand weakness
• Addiction– Cocaine– Nicotine– Gambling– Food
Fregni & Pascual-LeoneNature Clinical Neurology 07
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Therapeutic Applications of TMS• Depression• Autism• Acute Mania• Bipolar Disorder• OCD• PTSD• Schizophrenia• Auditory Hallucinoses• Pain
– Visceral pain– Neuropathic pain– Phantom pain
• Fibromyalgia• Migraine
• PD• Alzheimer’s Disease• Focal dystonia• Epilepsy
– Myoclonic epilepsy– Focal status epilepticus
• Stuttering• Tics• Neurorehabilitation
– Neglect– Aphasia– Hand weakness
• Addiction– Cocaine– Nicotine– Gambling– Food
Fregni & Pascual-LeoneNature Clinical Neurology 07
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