My collaboratorsNeurology: DALE ROBERTS, JORGE OTERO-MILLAN, PREM JAREONSETTASIN

Otolaryngology: BRYAN WARD, JOHN CAREY, CHARLES DELLA SANTINA,

GRACE TAN, MICHAEL SCHUBERT

Magnetic Vestibular Stimulation (MVS): An Update

DalePremBryan

Grace

DSZ Jorge

DSZ

Michael

NO CONFLICTS OF INTEREST

Take home messages about MVS (magneto

vestibular stimulation)

– EVERYBODY (humans, mice, zebra fish) develops nystagmus (or postural

abnormalities) in an MRI machine from the magnetic field itself (no imaging

needed) due to static magneto-hydrodynamic (Lorentz) forces acting on the ion-

carrying endolymph within the inner ear semicircular canals.

– MVS is a simple, safe, comfortable tool to elicit a sustained vestibular imbalance

and study

• The functional anatomy of vestibular stimulation and visual-vestibular

interaction

• Mechanisms of vestibular adaptation as a model of motor learning (“set-

point” or “bias” adaptation)

• Mechanisms of vestibular perception

• Effects of drugs and other therapies, genetic manipulations, development,

etc., on vestibular function

• A potential rehabilitative technique, for balance as well as for higher level

cognitive disorders such as neglect

• BEWARE effects on functional MRI and resting state connectivity

How do we normally sense head

rotation? Fluid flow, cupula

movement, hair cells bending,

neural discharge

1 Canals respond to head acceleration

2. Position of the cupula signals head velocity

3. Constant acceleration needed to keep cupula deviated and hence to produce a constant slow-phase velocity.

Carey, Della Santina

Marcelli, Vincenzo, otolaryngologist

Spatio-temporal pattern of vestibular information processing after

brief caloric stimulation. (1.5T magnet)

European Journal of Radiology 70 (2009) 312–316

“… spontaneous nystagmus (jerking of the eyes induced

by excitation of the labyrinth) preceding the injection (of

water) …

The beginning in 2010 with a

conversation in Siena, Italy

Marcelli speculated this was due to the magnetic field itself!

Il Campo Il Palio

7T magnet at Kennedy-Krieger Institute

Why were people getting dizzy in and near these strong magnets?

First key in solving this problem: Eliminate fixation to bring out a

peripheral vestibular nystagmus by using infrared video goggles.

Remember: Fixation mechanisms that hold the eyes still use

unwanted motion of images across the retina as the “error signal” to

trigger a response and is the first line of defense against any

unwanted movement of the eyes.

Hallmark clinical dictum: peripheral vestibular nystagmus is

suppressed by fixation (Romberg sign of the vestibulo-ocular reflex)

Nystagmus induced by exposure to a magnetic field

(magneto-vestibular stimulation (MVS))

Eye Position Plot of Nystagmus

Horizontal

Eye

Position

Slow

Phase

Quick

Phase

Slope of the slow phase (Δ

position / Δ time) gives one the

SLOW-PHASE VELOCITY

Time(1 sec)

Enter Bore

MVS nystagmus in the magnet

“Search Coil”

Induced Voltage shown

on Green trace,

Tesla/second*10

Peak Velocity

Slow rise to

a sustained

peak (like

response to

a rotation of

the head that

was of a

constant

acceleration)

REMEMBER: SCC respond to ACCELERATION but transduce (by the position of the cupula and bending of hair cells) VELOCITY

Enter Bore

Exit Bore

Reversal

phase

(adaptation

after-effect)

MVS nystagmus in the magnet

“Search Coil”

Induced Voltage shown

on Green trace,

Tesla/second*10

Peak Velocity

Adaptation

Slow rise to

a sustained

peak (like

response to

a rotation of

the head that

was of a

constant

acceleration)

MVS Nystagmus in the magnet

500 1000 1500-10

-5

0

5

10

Slo

w P

hase E

ye V

elo

cit

y(d

eg

rees/s

eco

nd

)

Time (seconds)

Secs

Deg/sec

24 min

Reversal

phase

ADAPTATION

reflected in

decrease of

nystagmus in

the magnet and

reversal of

nystagmus

when out of

magnet

(adaptation

aftereffect).

Enter

Adaptation

Exit

MVS effect produces a force that is an acceleration-like stimulus that

pushes the cupula of the semicircular canal to a new position which

produces a constant-velocity slow-phase nystagmus response.

Note: Marked dissociation between nystagmus (which endures) and

misperception of rotation which is transient (< 1 minute)

No MVS nystagmus in two patients (two different head

positions) with acquired loss of labyrinthine function

In Magnet

Out of Magnet

What is the mechanism of Magneto-Vestibular Stimulation (MVS)?

• (Dia-, Para-, Ferro-) Magnetic Susceptibility (MS)

• Electromagnetic Induction (dB/dt) (Faraday) – Dynamic

• MHD (Magneto-Hydrodynamics, interaction of ion currents

in fluids and magnetic fields)

– Dynamic

– Static (Lorentz forces)

How might magnetic fields affect biological tissues?

PHYSICS!

100 200

-10

0

10

20

100 200 100 200

100 200-20

-10

0

10

100 200 300

50 100 150 200-10

-5

0

5

10

MVS is STATIC (continuous, head movement not required)

MVS not related to subject velocity

MVS Magnitudeproportional to

Static Field Magnitude

7 Tesla 3 Tesla

500 1000 1500-10

-5

0

5

10

Slo

w P

hase E

ye V

elo

cit

y(d

eg

rees/s

eco

nd

)

Time (seconds)

Nystagmus persists in bore, stops quickly

on bore exit

No reverse peak on exit for short durationNystagmus peaks afterinduced voltage peak.

Long 25-minute duration

Short 40-second duration

1T/sec 2T/sec 3.5T/sec

100 200 300 400-10

0

10

50 100 150

MVS is Sensitive to Polarity

Front of magnet Back of magnet

This rules out Magnetic Susceptibility, which is not polarity sensitive.

Magnetic Vestibular Stimulation is:

• Static - continuous, not related to transiently induced voltages (e.g., electromagnetic induction, Faraday forces)

• Polarity Sensitive – Reversing the magnetic field vector reverses the nystagmus direction, therefore not do to magnetic susceptibility properties of tissues.

Current flowing vertically through the liquid experiences

a force (F = hJ x B) along the

tube as shown.

The answer is Static MHD(magneto-hydrodynamics, effects of magnetic fields on

fluids in which there is a current flowing)

Fluid

CurrentMagnetic

Field

Force Lorentz force

Zeeman effect

FLUID (ENDOLYMPH) WITHIN

THE INNER EAR IN WHICH

HEAD MOTION IS SENSED

Endolymph is the key

• Endolymph: a potassium rich fluid that fills the vestibular labyrinth and serves a dual purpose:

– It transmits ionic current into hair cells in the utricle and in the crista ampullaris to sustain their resting discharge.

– It transmits force, as pressure onto the cupula (the ear’s rotational sensor) within the semicircular canal.

SCC is a conduit that channels the Lorentz force in the endolymph onto the cupula. Direct excitation of the utricle is NOT the mechanism, it is the cupula movement.

CURRENTin endolymph

fluid FORCEin endolymph fluid

CUPULA

•What is the source and path by which a horizontal nystagmus could be produced?

•Are MHD forces sufficient to cause

nystagmus?

Two Key Questions

SOURCE AND PATH

Are MHD Forces Sufficient to Cause Nystagmus?

How many hair cells? ~33,000 in Utricle

~7,000 in each ampulla

How much current? Each hair cell has a resting current of about 10-100pA

How much cupula pressure in a 7 Tesla magnet?

0.0023-0.023 pascals (Utr.)

0.0005-0.005 pascals (Amp)

How much cupula pressure 0.0001 pascalsYES: MHD forces are sufficient to generate nystagmus.

To Summarize:

• Strong MAGNETIC FIELDS interact with weak, naturally occurring IONIC CURRENTS flowing into vestibular hair cells to produce a CONSTANT FORCE in the endolymph fluid.

• This force pushes on the cupula, just as during a sustained rotational acceleration of the head, and will cause constant nystagmus if fixation is removed (subject in darkness).

CurrentField

Force

The Lorenz forces are sufficient,

but are the directions correct?

Must explore the geometrical relationships between the

orientation of the semicircular canals and the utricle in

the head and the position of the head relative to the

direction of the magnetic field in the bore.

One Subject, Different Static Head Pitches in

the Magnet

NULL

• All subjects have a “null” head pitch position in which there is no

horizontal nystagmus, but the range is quite wide.

• Nystagmus direction reverses when null is crossed.

MHD Geometry/Directions are Correct

Looking down onto top of head at horizontal canals and utricles

MHD Geometry/Directions are correct

The horizontal nystagmus amplitude and direction varies with head pitch. As the

utricle current vector (green arrow) pitches up and down it crosses the magnetic

field vector (yellow arrow) and the pressure changes direction (red arrow).

With the chin pitched up (head back), the pressure is going to the left, producing

leftward slow phases (stimulating right and inhibiting left lateral canal).

With the chin pitched down (head forward), the pressure is going to the right,

producing rightward slow phases (stimulating left and inhibiting right lateral

canal).

Conclusion: Nystagmus in the MRI bore is

explained by the effects of magnetic fields on

the labyrinth, specifically Lorenz forces

Roberts, DC, Marcelli, V, Gillen, JS, Carey, JP, Della Santina, CC, Zee,

DS, MRI magnetic field stimulates rotational sensors of the brain,

Current Biology, 2011

BPPV (benign paroxysmal

positional vertigo)

Ward et al. (2015)

CSF leak (after

endonasal surgery

for a pituitary

adenoma) opened

by vomiting induced

in MRI magnetic

field

A few clinical implications

– Unilateral loss vestibular patients (UVL)

• Parsing out which parts of the labyrinth are

affected based on the pattern of MVS

– AS PREDICTED: UVL patients show a vertical slow-

phase component and the direction depends on

which labyrinth is affected

– This is due to the proximity of the opening of the

superior (anterior) canal as well as the lateral canal

to the utricle

FURTHER SUPPORT FOR MVS

MECHANISM

SOURCE AND PATH

In bore, significant upward beating component to the nystagmus.

Patient with left unilateral labyrinthine loss

Lateral and anterior

canals:

In each pair, one is

excited and the

other inhibited

Geometric Model

Ewald’s First Law: Eyes (head) rotates in a plane parallel to that of rotation of the head

(detected by the SCC in that plane) and so stabilizes gaze (eye in space) around all three

axes of head rotation.

Ewald’s Second Law. The lateral SCC are stimulated relatively better by ampullopetal

(excitation) than by ampullofugal (inhibition) fluid flow.

Ewald’s Third Law: The vertical SCC are stimulated relatively better by ampullofugal

(excitation) than by ampullopetal (inhibition) fluid flow.

19th Century Giants

What happens when you stimulate an

individual semicircular canal

Arrows indicate

direction of slow

phase with

stimulation

Ewald Flourens Breuer

Lorentz forces excite one

lateral SCC (usually right)

and inhibit the other SCC

(usually left) = net

horizontal nystagmus,

usually slow phase left

Lorentz forces excite

left anterior SCC and

inhibit right anterior

SCC. Vertical

components cancel

and torsion

components add.

Ward et al. Frontiers Neuro-

otology, 2014

Ewald’s Laws explains the patterns of nystagmus in normal

subjects (except WHY did we not see torsion initially?)

Geometric Model +

Canal Stimulation

Pattern of nystagmus in the magnet (normal subject, head first) TORSION is present

Mix horizontal and torsional

LEFT-SIDED

LOSS, inhibition

of remaining

right anterior

SCC = upbeat

nystagmus

RIGHT-SIDED

LOSS, excitation

of remaining left

anterior SCC =

downbeat

nystagmus

Ewald’s Laws explain the patterns of

nystagmus in unilateral loss patients

Animal models

Mice (genetic mutants) and Zebra fish (ototoxicity)

Mouse model

The Lorentz Force model correctly predicts that animals with a smallervestibular system will experience vestibular stimulation equivalent to a larger head acceleration.

The Lorentz force scales with the first power of the canal size, and head rotation force scales with the second power (square) of the canal size.

Zebra fish in an 11T magnet

Zebra fish are an excellent biological model to study brain

development, connectivity, ototoxicity and function using

optogenetic imaging and genetic manipulation. Now we

have an elegant behavioral assay of the vestibular system

using MVS. Grace Tan

Jareonsettasen et al., Multiple Time Courses of

Vestibular Set-Point Adaptation Revealed by

Sustained Magnetic Field Stimulation of the

Labyrinth, Current Biology, 26:1359-66, 2016

WHAT IS NEW?

USING MVS TO STUDY SET-POINT (BIAS) ADAPTATION

How does the brain rid itself of a sustained, unwanted,

spontaneous nystagmus, so we can see clearly when the

head is still?

How does the brain restore normal balance between

vestibular nuclei on either side of the brain stem?

Using MVS to study vestibular adaptation

MVS produces a sustained nystagmus (many minutes) in normal subjects, similar to an acute vestibular imbalance such as occurs after a viral or ischemic lesion that destroys function in one labyrinth.

This is an attractive (and painless) model for studying longer time courses of vestibular adaptation to unwanted spontaneous nystagmus.

More practical than using a rotating chair (which must continuously accelerate to induce a sustained response), calorics (cold and hot water irrigation of the ear), galvanic vestibular stimulation at the mastoid or patients with acute lesions.

Mechanism of vestibular adaptation

• RECALL, the vestibular system works in push-pull, around a tonic level of activity so that both an increase in activity on one side and a decrease in activity on the other can be used to transduce the motion of the head.

• This optimizes dynamic behavior but puts the organism at risk for an unwanted imbalance between the two sides, resulting in spontaneous nystagmus that compromises vision when the head is at rest and can bias the dynamic response when the head is moving.

Carey, Della Santina

The early lines of defense against a spontaneous nystagmus

• VISUAL fixation mechanisms to suppress a spontaneous nystagmus• Limited velocity range so does not do well for high

velocities of spontaneous nystagmus

• Not as effective for suppression of torsional or vertical nystagmus

• Short-term vestibular adaptation• Reversal phases of rotational, caloric, post head

shaking nystagmus and includes pathological periodic alternating nystagmus (PAN)

Classical studies (Malcomb and Melvill-Jones, 1970)

Constant head velocity (velocity STEP) Constant head acceleration (velocity RAMP)

ADAPTATION ADAPTATION

EARLY MODELS: Feedforward or feedback adaptation (one time constant only)

Classical studies (Malcomb and Melvill-Jones 1970)

DATA MODEL

Constant head velocity (step of velocity)

Constant head acceleration (ramp of velocity)

Using MVS for 90 minutes to elicit adaptation over a

longer time scale

Jareonsetassen et al., 2016

Constant acceleration responses: MVS and chair rotations elicit similar adaptation responses

Malcomb, Melvill-Jones, 1970 Jareonsetassen et al., 2016

TWO NEW IDEAS• Adaptation operators are variably leaky integrators (modifiable leak and tc

parameters)• Multiple adaptation operators with progressively different dynamics (Ta3 >

Ta2 > Ta1)

The best fit: Three adaptation time constants

Take home messages about MVS (magneto

vestibular stimulation)

– EVERYBODY (humans, mice, zebra fish) develops nystagmus (or postural

abnormalities) in an MRI machine from the magnetic field itself (no imaging

needed) due to static magneto-hydrodynamic (Lorentz) forces acting on the ion -

carrying endolymph of the inner ear semicircular canals.

– MVS is a simple, safe, comfortable tool to elicit a sustained vestibular imbalance

and study

• The functional anatomy of vestibular stimulation and visual-vestibular

interaction

• Mechanisms of vestibular adaptation as a model of motor learning (“set-

point” or “bias” adaptation)

• Mechanisms of vestibular perception

• Effects of drugs and other therapies, genetic manipulations, development,

etc., on vestibular function

• A potential rehabilitative technique, for balance as well as for higher level

cognitive disorders such as neglect

• BEWARE effects on functional MRI and resting state connectivity