Magnetic Vestibular Stimulation (MVS): An Update

Transcription

1 Magnetic Vestibular Stimulation (MVS): An Update My collaborators Neurology: DALE ROBERTS, JORGE OTERO-MILLAN, PREM JAREONSETTASIN Otolaryngology: BRYAN WARD, JOHN CAREY, CHARLES DELLA SANTINA, GRACE TAN, MICHAEL SCHUBERT DSZ Prem Dale Bryan Grace DSZ Jorge Michael NO CONFLICTS OF INTEREST

2 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 ioncarrying 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 ( setpoint 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

3 How do we normally sense head rotation? Fluid flow, cupula movement, hair cells bending, neural discharge Carey, Della Santina 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.

4 The beginning in 2010 with a conversation in Siena, Italy Il Campo Il Palio Marcelli, Vincenzo, otolaryngologist Spatio-temporal pattern of vestibular information processing after brief caloric stimulation. (1.5T magnet) European Journal of Radiology 70 (2009) spontaneous nystagmus (jerking of the eyes induced by excitation of the labyrinth) preceding the injection (of water) Marcelli speculated this was due to the magnetic field itself!

5 7T magnet at Kennedy-Krieger Institute

6 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)

7 Nystagmus induced by exposure to a magnetic field (magneto-vestibular stimulation (MVS))

8 Eye Position Plot of Nystagmus Horizontal Eye Position Quick Phase Slow Phase Time (1 sec) Slope of the slow phase (Δ position / Δ time) gives one the SLOW-PHASE VELOCITY

9 MVS nystagmus in the magnet Enter Bore REMEMBER: SCC respond to ACCELERATION but transduce (by the position of the cupula and bending of hair cells) VELOCITY Slow rise to a sustained peak (like response to a rotation of the head that was of a constant acceleration) Peak Velocity Search Coil Induced Voltage shown on Green trace, Tesla/second*10

10 MVS nystagmus in the magnet Enter Bore Adaptation Slow rise to a sustained peak (like response to a rotation of the head that was of a constant acceleration) Peak Velocity Search Coil Exit Bore Reversal phase (adaptation after-effect) Induced Voltage shown on Green trace, Tesla/second*10

11 MVS Nystagmus in the magnet Slow Phase Eye Velocity (degrees/second) Deg/sec Enter Adaptation Time (seconds) Secs Exit Reversal phase 24 min ADAPTATION reflected in decrease of nystagmus in the magnet and reversal of nystagmus when out of magnet (adaptation aftereffect). 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)

12 No MVS nystagmus in two patients (two different head positions) with acquired loss of labyrinthine function In Magnet Out of Magnet

13 What is the mechanism of Magneto-Vestibular Stimulation (MVS)? How might magnetic fields affect biological tissues? (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) PHYSICS!

14 (degrees/second) MVS is STATIC (continuous, head movement not required) Long 25-minute duration Time (seconds) 7 Tesla 3 Tesla Nystagmus persists in bore, stops quickly on bore exit MVS Magnitude proportional to Static Field Magnitude T/sec 2T/sec 3.5T/sec Short 40-second duration MVS not related to subject velocity No reverse peak on exit for short duration Nystagmus peaks after induced voltage peak.

15 MVS is Sensitive to Polarity 10 Front of magnet Back of magnet This rules out Magnetic Susceptibility, which is not polarity sensitive

16 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.

17 The answer is Static MHD (magneto-hydrodynamics, effects of magnetic fields on fluids in which there is a current flowing) Current flowing vertically through the liquid experiences a force (F = hj x B) along the tube as shown. Magnetic Field Current Fluid Force Lorentz force Zeeman effect

18 FLUID (ENDOLYMPH) WITHIN THE INNER EAR IN WHICH HEAD MOTION IS SENSED

19 Endolymph is the key CURRENT in endolymph fluid FORCE in endolymph fluid CUPULA 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.

20 Two Key Questions What is the source and path by which a horizontal nystagmus could be produced? Are MHD forces sufficient to cause nystagmus?

21 SOURCE AND PATH

22 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 pA How much cupula pressure in a 7 Tesla magnet? pascals (Utr.) pascals (Amp) YES: MHD forces are sufficient to generate nystagmus.

23 To Summarize: Force Field Current 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).

24 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.

25 One Subject, Different Static Head Pitches in the Magnet NULL

26 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.

27 MHD Geometry/Directions are Correct Looking down onto top of head at horizontal canals and utricles

28 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).

29 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

30 A few clinical implications Ward et al. (2015) CSF leak (after endonasal surgery for a pituitary adenoma) opened by vomiting induced in MRI magnetic field BPPV (benign paroxysmal positional vertigo)

31 FURTHER SUPPORT FOR MVS MECHANISM 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 slowphase 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

32 SOURCE AND PATH

33 Patient with left unilateral labyrinthine loss In bore, significant upward beating component to the nystagmus.

34 Lateral and anterior canals: In each pair, one is excited and the other inhibited Geometric Model

35 19 th Century Giants What happens when you stimulate an individual semicircular canal Ewald Flourens Breuer Arrows indicate direction of slow phase with stimulation 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.

36 Ward et al. Frontiers Neurootology, 2014 Geometric Model + Canal Stimulation 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. Ewald s Laws explains the patterns of nystagmus in normal subjects (except WHY did we not see torsion initially?)

37 Pattern of nystagmus in the magnet (normal subject, head first) TORSION is present Mix horizontal and torsional

38 Ewald s Laws explain the patterns of nystagmus in unilateral loss patients LEFT-SIDED LOSS, inhibition of remaining right anterior SCC = upbeat nystagmus RIGHT-SIDED LOSS, excitation of remaining left anterior SCC = downbeat nystagmus

39 Animal models Mice (genetic mutants) and Zebra fish (ototoxicity)

40 Mouse model The Lorentz Force model correctly predicts that animals with a smaller vestibular 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.

41 Zebra fish in an 11T magnet

42 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

43 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? Jareonsettasen et al., Multiple Time Courses of Vestibular Set-Point Adaptation Revealed by Sustained Magnetic Field Stimulation of the Labyrinth, Current Biology, 26: , 2016

44 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.

45 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. Carey, Della Santina 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.

46 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)

47 Classical studies (Malcomb and Melvill-Jones, 1970) Constant head velocity (velocity STEP) Constant head acceleration (velocity RAMP) ADAPTATION ADAPTATION

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

49 Classical studies (Malcomb and Melvill-Jones 1970) DATA MODEL Constant head velocity (step of velocity) Constant head acceleration (ramp of velocity)

50 Using MVS for 90 minutes to elicit adaptation over a longer time scale Jareonsetassen et al., 2016

51 Constant acceleration responses: MVS and chair rotations elicit similar adaptation responses Malcomb, Melvill-Jones, 1970 Jareonsetassen et al., 2016

52 TWO NEW IDEAS Adaptation operators are variably leaky integrators (modifiable leak and tc parameters) Multiple adaptation operators with progressively different dynamics (Ta3 > Ta2 > Ta1)

53 The best fit: Three adaptation time constants

54 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 ( setpoint 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