introduction to transcranial magnetic stimulation …gestaltrevision.be/pdfs/lss2014/tms lecture...

INTRODUCTION TO

TRANSCRANIAL MAGNETIC

STIMULATION FOR THE STUDY OF

BRAIN-BEHAVIOUR

RELATIONSHIPS

CAITLIN MULLIN

PERCEPTUAL ORGANIZATION SUMMER

SCHOOL 2014

*This presentation contains images taken from the internet for which I do

not hold the copyright.

OUTLINE

• History

• Nuts and bolts

• Aspects of the technique

• Experimental design

• Parameter selection

• Safety and ethical considerations

• [TMS with neuroimaging]

WHAT IS TMS?

TMS is a non-invasive tool for the electrical stimulation of

neural tissue.

TECHNIQUE ON THE RISE

Rossi., Hallett, Rossini, & Pascual-Leone (2009)

d’Arsonval(1896/1911)

Thompson, 1910

Magnusson &

Stevens, 1911

FUNNY PICTURES

Faraday, 1831

TRUST ME, I’M A DOCTOR

Barker, 1984

MODERN STIMULATOR

NUTS AND BOLTS

TMS coil current

8kA

Magnetic field pulse 2.5T

Rate of change of

magnetic field

30kT/s

Induced tissue current

15mA/cm2

Induced electric field

500v/m

HOW IT WORKS:

SEQUENCE OF EVENTS

WHAT CAN TMS DO FOR YOU

AS A RESEARCHER?

• Virtual Patients: causal link between brain activity and

behavior

Occipital TMS disrupts braille reading

in early blind, but not control subjects

Cohen et al., 1997.


AS A RESEARCHER?

• Chronometry: timing the contribution of focal brain

activity to behavior

Hamilton & Pascual-Leone, 1998

Role of “visual” cortex in tactile information processing in early

blind subjects


AS A RESEARCHER?

• Functional connectivity: relate behavior to the

interaction between elements of a neural network

TELL US WHAT WE REALLY

WANT TO KNOW ABOUT

TMS

• How are the neurons activated?

• How precise does the localization get?

• How deep can you stimulate?

• How long does the effect last?

It depends...

• Biophysical mechanisms influenced by TMS are still not fully understood.

• Prevailing hypothesis: Axons!

• The flow of ions brought about by the electric field induced in the brain alters the electric charge stored on both sides of cell membranes

• Any part of the cell membrane interrupting this motion of the charges becomes depolarised or hyperpolarised.

HOW NEURONS ARE

STIMULATED?

uniform current along the axon,

no change from the resting state gradient activation due to non uniform field

across the axon, resulting in action potential

bent axon in uniform electric field

causes action potential

depolarization caused by transverse activation of the neuron change in activation at the axon terminal

EXCITATION? INHIBITION?

IT’S ALL NOISE TO ME!

Hmmm?

NEUROPHYSIOLOGICAL

MECHANISMS?

Pa

ire

d a

sso

cia

tion

stim

ula

tion (

PA

S)

LTP

LTD

Increase in synaptic strength

Decrease in synaptic efficacy

STATE/RHYTHMIC TMS

EFFECTS

Romei, Driver, Schyns, & Thut, 2011 Dugué, Marque, & VanRullen, 2011

SUMMARY: SO HOW DOES

TMS EFFECT NEURONS?

Depends on:

•The spatial derivations of neurons underlying the coil

•The kind of stimulation protocol used (high vs. low

frequency)

•The preliminary state of the activity in the region

SPATIAL RESOLUTION

OF TMS

• Exact resolution cannot be measured in cm or mm

• The geometry of the coil determines the focality of the

magnetic field and of the induced current - hence also of

the targeted brain area.

SPATIAL RESOLUTION

OF TMS

Phosphenes can be elicited with a resolution

of 1-2 degrees of visual angle

Muscles that are segregated by as

little as 1 to 2 cm on the cortex can

be selectively stimulated in motor

cortex

Behavioural dissociations in spatially adjacent regions in the cortex

DEPTH OF

STIMULATION

SUMMARY: SPATIAL

RESOLUTION OF TMS

• Resolution depends on parameters of stimulation, coil

type, etc.

• But we can infer resolution from a number of observations

• Evidence from studies using these kinds of inferences

correspond with an effective spatial resolution of 1-2cm

THE TEMPORAL

RESOLUTION OF TMS

cycle of a single pulse of TMS is approximately 1ms

The duration of

the effect in the

cortex is difficult

to determine

because the

neurons

stimulated by the

field may take

time to recover

their normal

functional state

Thus the most important

consideration when

designing TMS experiments

is the duration of the

impairment to the

behavioural performance

being measured

KINDS OF PULSES

Single pulse TMS

• single stimulus every 5-10 sec

Repetitive TMS (rTMS)

• trains of stimuli to one brain area

Patterned TMS

• Theta-burst

• E.g. 100 triple-pulses at a

frequency of 5Hz with the

triple-pulse frequency of

50Hz

EXPERIMENTAL

DESIGN FOR TMS

THE QUESTION

CHOOSING PARAMETERS

• Where to stimulate

• Task/Dependent variables

• Methods for identifying your target site

• Coil localization

• Control conditions

• Choosing the best stimulation parameters

• - Intensity

• - Frequency

• - Type of stimulation

• - Duration

WHERE TO STIMULATE?

• Informed by:

• Patient studies

• Neuroimaging literature

• Do your own neuroimaging

WHERE TO STIMULATE?

THE BRAIN REGIONS

Zaretskaya, Anstis & Bartels, 2013

DEPENDENT VARIABLES


Percent of time in global vs. local percept

global local

Eye movement maps under both percepts

How to measure the effects of TMS

IDENTIFYING TMS

TARGET SITES

Find functional effect

- hand twitch (MEP)

- moving phosphenes

Find anatomical landmark

inion/nasion-ear/ear vertex

EEG 10/20 system

MRI/fMRI co-registration

IDENTIFYING TMS

TARGET SITES

Sack, Kadosh, Schuhmann, Moerel, Walsh, & Goebel, (2009)

IT’S ALL ABOUT THE POWER!

n = 5 fMRI

n = 9 MRI

n = 13 Tal coordinates

n = 47 EEG

10-20 system

IDENTIFYING TMS TARGET

SITES IN REAL TIME

Real

Sham

Different hemisphere

Different site

Different

effect or

no effect

Or interleave TMS with no TMS trials

CONTROL CONDITIONS

CONTROL CONDITIONS


Motor Threshold

INTENSITY

Phosphene Threshold

Bartels uses 80% of each individuals active motor threshold

FREQUENCY AND TYPES

OF STIMULATION

On-line:

Stimulation occurs while the subject

performs a task and the effects last for

approximately the duration of

stimulation.

• Good for chronometrics

• How many pulses?

Off-line:

Stimulation occurs without a task and

the length of effect is typically

measured in minutes.

• Low frequency stimulation

• Theta burst

FREQUENCY AND TYPES

OF STIMULATION

Dayan, Censor, Buch, Sandrini, & Cohen, (2013)

RECAP SO FAR?

• Where to stimulate:

• Task/Dependent variables:

• Methods for identifying your target site:

• Coil localization:

• Control conditions:

• Choosing the best stimulation parameters

- Intensity

- Frequency

- Type of stimulation

- Duration

RH aIPS & SPL – based on individual fMRI

Percent of time spent in each

local/global percept

fMRI localizer

Individual fMRI with stereotaxy

Vertex stimulation & baseline performance

80% active motor threshold

Continuous thetaburst stimulation: 48 s of

three pulses at 50 Hz repeated

every 0.2 s, resulting in 600 pulses in total

REPRESENTATIVE

RESULTS dura

tion p

ost-

TM

S/p

re-T

MS


CAUSAL

CONCLUSIONS

“Our results point to aIPS as a potential source of this high-level

grouping signal because it was most strongly activated during the

“global” compared with “local” perceptual state and because it

was causally involved in forming the global percept.”

WHAT ABOUT

TIMING?

We just walked through a virtual lesion study

- TMS protocol – straight forward

What about the chronometrics?

- Many of the decisions will remain the same

• Pascual-Leone et al. (1993), Safety of transcranial magnetic stimulation in normal volunteers.

Electroencephalogr Clin Neurophysiol, 89(2):120-130

• Chen et al. (1997), Safety of different inter-train intervals for repetitive transcranial magnetic

stimulation and recommendations for safe rages of stimulation parameters.

Electroencephalogr Clin Neurophysiol 105(6):415-421

• Wassermann. (1998), Risk and safety of repetitive transcranial magnetic stimulation: report

and suggested guidelines from the International Workshop on the Safety of Repetitive

Transcranial Magnetic Stimulation. June-5-7, 1996. Electroencephalogr Clin Neurophysiol

108(1):1-16

• Machii, et al. (2006). Safety of rTMS to non-motor cortical areas in healthy participants and

patients. Clinical Neurophysiology. 117, 455-471.

• Rossi, S., Hallett, M., Rossini, P. M., & Pascual-Leone, A. (2009). Safety, ethical

considerations, and application guidelines for the use of transcranial magnetic stimulation in

clinical practice and research. Clinical neurophysiology,120(12), 2008-2039.

SAFETY AND SIDE

EFFECTS

Side effect Single-pulse TMS

Paired-pulse TMS

Low frequency

rTMS

High frequency rTMS

Theta burst

Seizure induction Occasional Not reported Occasional (usually

protective effect)

Possible (1.4% crude risk

estimate in epileptic patients;

less than 1% in normals)

Not reported

Transient acute hypomania induction

No No Rare Possible following left prefrontal stimulation

Not known

Syncope Possible as epiphenomenon (i.e, not related to direct brain effect) Not reported

Transient headache, local pain, neck pain, toothache, paresthesia

Possible Likely possible, but not

reported/addressed

Frequent (see para. 3.3)

Frequent (see para. 3.3)

Not reported

Transient hearing changes or tinnitus

Possible Likely possible, but not reported

Possible Possible (avoid rTMS in

cochlear implants)

Not known

Transient cognitive/ neuropsychologial changes

Not reported No reported Overall negligible

(see para. 3.5)

Overall negligible (see para. 3.5)

Not known

Burns from scalp electrodes

No No Not reported Occasionally reported

Not known, but likely possible

Induced currents in electrical circuits

Theoretically possible, but described malfunction only if TMS is delivered in close proximity with the electric device

(pace-makers, brain stimulators, pumps, intacardiac lines)

Structural brain changes

Not reported Nor reported Inconsistent Inconsistent Not known

Histoxicity No No Inconsistent Inconsistent Not known

Other biological transient effects

Not reported Not reported Not reported Transient hormone changes

(Prolactine, TSH)

Not known


SEIZURES

• Hypersynchronized discharges of groups of neurons in

gray matter

• -Imbalance between inhibitory and excitatory activity

• -Alterations of ion gradients in nerve cells

• -Factors leading to spread between cortical areas

• Two factors to take into consideration:

• -Parameters used

• -Individual receiving TMS stimulation

EXCLUSIONARY

CRITERIA

SAFETY GUIDELINES


SIDE EFFECTS

• Most common adverse effects reported, and more common with rTMS (Loo et al 2007):

• -Headache: ~20% with single pulse; ~29% with rTMS

• -Neck pain or discomfort: up to 39% in rTMS

• Factors other than TMS also important!!: Headband, Swim cap, Neck posturing

• Prophylaxis and Treatment measures

• -Responds well to analgesics

• -Topical anesthetics have been tried

• -shorter blocks; frequent breaks

ETHICAL

CONSIDERATIONS

Although the risk is small, it is always present, so there is

an obligation on the experimenter to always consider the

value of a given experiment

• How can you minimize risk & discomfort?

• What is the minimal stimulation necessary?

• Is the TMS information clear and consent

informed?

• Are subjects always screened?

• Are the experimenters safety trained?

• Are emergency procedures clear & in place?

• Would YOU do this experiment?

Major limitations summary • Only regions on cortical surface can be stimulated

• Can be unpleasant for subjects

• Risks to subjects and esp. patients

• Stringent ethics required (can’t be used by some institutions)

• Localisation uncertainty

• Stimulation level uncertainty

Major advantages summary • Reversible lesions without plasticity changes

• Repeatable

• High spatial and temporal resolution

• Can establish causal link between brain activation and behaviour

• Can measure cortical plasticity

• Can modulate cortical plasticity

• Therapeutic benefits

TMS: YAY OR NE?

introduction to transcranial magnetic stimulation …gestaltrevision.be/pdfs/lss2014/tms lecture...

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