Transcranial Magnetic Transcranial Magnetic Stimulation Stimulation Alvaro Pascual- -Leone, M.D., Ph.D. Leone, M.D., Ph.D. Alvaro Pascual
Michael Faraday (1831) Michael Faraday (1831)
d’ ’Arsonval Arsonval d
A.T. Barker A.T. Barker 1984 1984
TMS TMS
TMS Terminology TMS Terminology • • Single pulse TMS Single pulse TMS • • single stimulus every 5- single stimulus every 5 -10 sec 10 sec • • Paired pulse TMS Paired pulse TMS • • subthreshold stim stim. then . then suprathreshold suprathreshold stim stim. . subthreshold • • stimuli separated by 1- -20 20 msec msec stimuli separated by 1 • • Repetitive TMS (rTMS) Repetitive TMS (rTMS) • • trains of stimuli to one brain area trains of stimuli to one brain area • • slow = low frequency slow = low frequency • • fast (high freq) > 1 Hz fast (high freq) > 1 Hz
Equipment Equipment Repetitive Stimulators Repetitive Stimulators QuickTime™ and a Photo - JPEG decompressor are needed to see this picture.
Stimulation Coils Stimulation Coils
Induced Current Induced Current • Depends of coil geometry • Depends of coil geometry • Decay with square of distance • Decay with square of distance
Mechanism of action Mechanism of action
Mechanisms of action: Mechanisms of action: Interaction between induced current and axons Interaction between induced current and axons
Mechanism of action: Mechanism of action: Interindividual variability Interindividual variability
Modulation of Cortical Excitability Modulation of Cortical Excitability •Inter Inter- -individual variability individual variability • •Dependency on baseline cortical excitability Dependency on baseline cortical excitability • ∂ % in MEP area ∂ % in MEP area pre/post rTMS pre/post rTMS 40 200 30 150 20 100 10 50 0 0 -50 -10 -100 -20 1Hz 10Hz 15Hz 20Hz 1Hz 10Hz 15Hz 20Hz rTMS condition rTMS condition rTMS: 240 stimuli at 90% of motor threshold rTMS: 240 stimuli at 90% of motor threshold Maeda et al, 2000 Maeda et al, 2000
BEWARE OF INTER- - BEWARE OF INTER INDIVIDUAL VARIABILITY INDIVIDUAL VARIABILITY • ? different subject populations • ? different subject populations (Gangitano Gangitano et al) ( et al) • ? genetics • ? genetics
Reproducibility of Reproducibility of Modulatory Effects of rTMS Modulatory Effects of rTMS 40 30 20 10 ∂ % in MEP area 0 pre/post rTMS -10 -20 Day1 Day2 1 Hz 10 Hz 20 Hz -30 rTMS conditions
IS REPEATED APPLICATION IS REPEATED APPLICATION SAFE? SAFE? • Ethics of studies in normal subjects • Ethics of studies in normal subjects • Is primed- -1 Hz or theta burst pattern 1 Hz or theta burst pattern • Is primed stimulation ethical? stimulation ethical?
Different brain areas Different brain areas Robertson et al. J. Cog. Robertson et al. Neurosci 2003 2003 J. Cog. Neurosci
DO WE NEED MOTOR DO WE NEED MOTOR THRESHOLD? THRESHOLD? • Safety guidelines need rewriting • Safety guidelines need rewriting • Setting intensity by: • Setting intensity by: – Output of the device? – Output of the device? – Induced current density? – Induced current density? – Behavioral marker? – Behavioral marker?
Scalp to Brain Relation Scalp to Brain Relation
Scalp ≠ ≠ Brain Scalp Brain Pascual- Pascual -Leone et al., Leone et al., Trans. R. Phil. Soc. Trans. R. Phil. Soc. 1999 1999
Frameless Stereotaxy Stereotaxy Frameless Brainsight Brainsight - - Rogue Research Inc. Rogue Research Inc.
Topographic Precision Topographic Precision Scalp markers Stereotaxy Scalp markers Stereotaxy Gugino Gugino et al. Clin et al. Neurophysiol 2000 2000 Clin Neurophysiol
FRAMELESS STEREOTAXY FRAMELESS STEREOTAXY • What about the value of functional • What about the value of functional resolution? resolution? • Is projection of main vector good • Is projection of main vector good enough? enough? – BEWARE OF ‘ ‘PRETTY PICTURES PRETTY PICTURES’ ’ – BEWARE OF
Magnitude of Induced Current Magnitude of Induced Current A/cm 2 2 Humans: measured 12µ µA/cm Humans: measured 12 1 cm from coil 1 cm from coil 7% of max. output intensity 7% of max. output intensity Wagner et al., Neurosci Neurosci Lett Lett 2003 2003 Wagner et al.,
A More Realistic Head Model • MRI Guided CAD Design • Included: Skin, Skull, CSF, Gray Matter, and White Matter • Distinct Electrical Properties Assigned to Each Tissue
Induced Current Density
Evaluating the effect of pathologies • To account for the effects of a cortical stroke a cut was made in the gray matter and replaced with CSF
Induced Current Density 5kHz10 4 ε Solution- Normalized to Gray Matter
Induced Current Density 5kHz10 4 ε Solution- Normalized to Gray Matter
Tissue Boundary Effects
Stroke Case vs. Healthy Model Stroke Healthy
Stroke Case- Tissue Boundaries
Stroke Modeling Stimulate Here Focus Here
Summary • Tissues clearly have an influence in the current distribution – TMS is not the same as stimulation in a surgical environment with the cortex exposed • Strokes – Near centimeter perturbation – CSF shunts current • Alterations in the cortical geometry and/or electrical characteristics can alter the predicted site of stimulation – Ignored by current tracking systems
Where to Go From Here? • Integration of field solver with frameless stereotaxic system non TMS TMS • Validation of theories in animal models 20 Hz – Cat studies 1 Hz
DSI Guided TMS • Effects of TMS represent an interaction between the characteristics of the applied TMS pulse and those of the tissue stimulated. • Brain tissue is not homogeneous. • Enhanced knowledge about the characteristics of the tissue affected by TMS will allow to adjust the TMS parameters in order to maximize spatial resolution. • Diffusion spectrum imaging (DSI) can provide the required information and be used to guide TMS for optimized spatial resolution.
Diffusion MRI - Diffusion Spectrum Imaging Cerebral Neurography -Tractography
Diffusion MRI - Diffusion Spectrum Imaging Mapping Cortical Cytoarchitectonics
DSI-Guided TMS Computed TMS interaction with cerebral white matter - circular 10 cm TMS coil over vertex - DTI of cerebral white matter orientation, coronal slab - induced axonal EMF’s computed with “ antenna ” model: d< E , s >/ ds red +, blue -
EFFECTS OF TMS ARISE EFFECTS OF TMS ARISE FROM THE INTERACTION OF FROM THE INTERACTION OF A NON- -PHYSIOLOGIC PHYSIOLOGIC A NON STIMULUS WITH THE TISSUE STIMULUS WITH THE TISSUE (AND ITS ONGOING (AND ITS ONGOING ACTIVITY) ACTIVITY)
Topographic precision Topographic precision Siebner Siebner et al. 2001 et al. 2001
Topographic resolution Topographic resolution
TURN TOPOGRAPHIC TURN TOPOGRAPHIC RESOLUTION INTO AN RESOLUTION INTO AN EXPERIMENTAL QUESTION EXPERIMENTAL QUESTION
Temporal resolution Temporal resolution
TURN TEMPORAL TURN TEMPORAL RESOLUTION INTO AN RESOLUTION INTO AN EXPERIMENTAL QUESTION EXPERIMENTAL QUESTION
Neurophysiologic Effects of Neurophysiologic Effects of 1 Hz off- -line line rTMS rTMS 1 Hz off Before rTMS After 1 Hz rTMS Waechter, Ashe, Pascual , Ashe, Pascual- -Leone Leone Waechter
Mechanism of action: Mechanism of action: Studying the effects of TMS on neuronal Studying the effects of TMS on neuronal activity in the visual cortex of cats activity in the visual cortex of cats Moliadze Moliadze et al. et al. J. . 2003 2003 J. Physiol Physiol.
Effects of TMS on spontaneous Effects of TMS on spontaneous neuronal activity neuronal activity
Effect of TMS on neuronal activity Effect of TMS on neuronal activity modulated by visual stimuli modulated by visual stimuli Visual + TMS (late) Visual + TMS TMS alone (early)
rTMS: : rTMS Lasting Modulation of Cortical Activity Lasting Modulation of Cortical Activity TMS Sham Sham TMS TMS 1 Hz 1 Hz TMS TMS 20 Hz 20 Hz TMS TMS Valero et al. 2002 Valero et al. 2002
Area 17 Area 19 Superior Colliculus LPl PUL LPi L G N L G N * M G N M G N Splenial visual area Lateral Post. Complex
*
EFFECTS OF TMS ARISE EFFECTS OF TMS ARISE FROM THE INTERACTION FROM THE INTERACTION WITH THE ACTIVITY IN A WITH THE ACTIVITY IN A DISTRIBUTED NETWORK DISTRIBUTED NETWORK
Repetitive TMS: Online Repetitive TMS: Online 20 10 1 0.5 mV 1 mV 1 mV 1 mV 20 ms TMS 1 Hz 10 Hz 20 Hz 5 Hz
Repetitive TMS: Offline Repetitive TMS: Offline TMS train 10 pulses, 20 Hz, 150% 0.2 Hz, 90% 40 41 1 1 100 µV 60 21 20 20 10 ms
Modulation of Cortical Modulation of Cortical Excitability Excitability High frequency High frequency rTMS increases rTMS increases CBF CBF Low frequency Low frequency rTMS decreases rTMS decreases CBF CBF Pascual- -Leone et al, 1998 Leone et al, 1998 Pascual
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