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….

DO NOT C

OPY

Brain Behavior Relations

Genetic Defect Environmental Factors Acquired Insult

Pathology

Brain Adaptation/ Compensation

Pattern of Brain Activity

BehaviorSymptoms of Disease

Change in Cognitive Strategy

DO NOT C

OPY

TMS

• Focal Interference with Brain Activity– Adding causal information to brain

imaging findings• Modulation of a Specific Neural

Network– Therapeutic potential in ‘circuit

disorders’

DO NOT C

OPY

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

DO NOT C

OPY

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

DO NOT C

OPY

FDA approved for the treatment of medication-resistant depression.

FDA approved forcortical brain mapping

DO NOT C

OPY

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)

DO NOT C

OPY

TMS: Central Conduction Time

Kobayashi et al Lancet Neuro

DO NOT C

OPY

Motor Cortical Output Mapping

Nagib et al. Neurosurg Clin 2011

DO NOT C

OPY

Motor Cortical Output MappingComparing Noninvasive and Invasive Mapping

Nagib et al. Neurosurg Clin 2011

DO NOT C

OPY

TMS: Paired-Pulse

Kobayashi et al Lancet Neurol 03

DO NOT C

OPY

Characterizing Neural NetworksTMS and EEG

DO NOT C

OPY

Characterizing Neural NetworksTMS and fMRI

DO NOT C

OPY

Cortical Reactivity

Theta Burst Stimulation (TBS)

Cortical Reactivity

cTBS

iTBS

Cortical Plasticity

Frontiers Synaptic Plasticity 2011

Measuring LTP/LTD in Humans

DO NOT C

OPY

Frontiers Synaptic Plasticity 2011

Cortical Reactivity

Theta Burst Stimulation (TBS)

Cortical ReactivityCortical Plasticity

Measuring LTP/LTD in Humans

DO NOT C

OPY

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

DO NOT C

OPY

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

DO NOT C

OPY

rTMS in Dystonia1 Hz rTMS to suppress cortical excitability

Patients Controls

Siebner et al. 1999

Patients Controls

DO NOT C

OPY

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)

DO NOT C

OPY

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

OT COPY

DO NOT C

OPY

DO NOT C

OPY

DO NOT C

OPY

DO NOT C

OPY

Therapeutic modulation of interhemispheric connections

Fregni & Pascual-Leone (2007)

DO NOT C

OPY

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

DO NOT C

OPY

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

DO NOT C

OPY

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

OT COPY

• 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

DO NOT C

OPY

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.

DO NOT C

OPY

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)

DO NOT C

OPY

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

OT COPY

∂% 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

DO NOT C

OPY

Therapeutic Applications of rTMS

• Stimulate the release of neurotransmitters or other substances with neuromodulatory effects

DO NOT C

OPY

Antiepileptic Property of the CSF after Exposure to rTMS

Anschel, Holmes, Pascual-Leone 200210 Hz 1 Hz

Flurothyl seizure model

DO NOT C

OPY

1994

MASTER-PD5 yr Multicenter Study

Univ Florida • Cleveland ClinicUCLA• Univ Toronto

Parkinson’s Disease

R. J. Goldberg FoundationNIH

DO NOT C

OPY

Therapeutic Applications of rTMS

• Induce distributed modulation of brain activity resulting in network-specific release of neurotransmitters and activity modulation

DO NOT C

OPY

DO NOT C

OPY

TMS in Parkinson’s Disease

Fregni et al 2005

DO NOT C

OPY

TMS in Parkinson’s Disease

Wu et al 2008

DO NOT C

OPY

DO NOT C

OPY

Depression in PDTMS vs Fluoxetine

Fregni et alJNNP 2004

DO NOT C

OPY

Depression in PDTMS vs Fluoxetine

Fregni et alJNNP 2004

DO NOT C

OPY

Depression in PDTMS vs Fluoxetine

Fregni et al JNNP 2004

DO NOT C

OPY

Depression in PDTMS vs Fluoxetine

Fregni et al Neurology 2006

DO NOT C

OPY

Depression in PDTMS vs Fluoxetine

Fregni et al Neurology 2006

After rTMS After Fluoxetine

DO NOT C

OPY

NICETM

Non Invasive Cortical EnhancerNeuronix ®

DO NOT C

OPY

Identify Brain Target

DO NOT C

OPY

NeuronavigationReliable Targeting of a Given Brain Region

NeuronavigatedNon-navigated

DO NOT C

OPY

Bashir et al. Brain Topography 2010

Neuronavigation: Enhanced Behavioral (Therapeutic) Effects

DO NOT C

OPY

Current shunting by damaged tissueModeling Current Distribution in Subject’s Brain

IEEE 2005; Neuroimage 2006Wagner et al.

DO NOT C

OPY

0.5 mV

20 ms

Normal Recovery from Stroke

Integrity of outputs?Network reorganization?

DO NOT C

OPY

0.5 mV

20 ms

L FDI(TMS of R affected M1)

R FDI(TMS of L unaffected M1)

Establish Integrity of Output

DO NOT C

OPY

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

DO NOT C

OPY

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

DO NOT C

OPY

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

DO NOT C

OPY

R

Anterior Pars TriangularisPosterior Pars TriangularisPars Opercularis

R

Ventral Premotor CortexArcuate Fasciculus

Seed for Arcuate FasciculusDO N

OT COPY

Before After rTMS

Aphasia: Language Circuit - Rt. Pars Triangularis

Modulation of Neural Networks as Therapeutic Strategy

DO NOT C

OPY

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

DO NOT C

OPY

Martin et al. 2005Naeser et al. 2006, 07

Aphasia: Language Circuit - Rt. Pars Triangularis

Modulation of Neural Networks as Therapeutic Strategy

Pars TriangularisPars Opercularis

DO NOT C

OPY

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

DO NOT C

OPY

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

DO NOT C

OPY