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Laurent Goffart, PhD

CNRSINT, Marseille, France

A meeting honoring our memory of late David A. RobinsonMay 26-27, 2017Baltimore, USA

Cerebellar control of saccades by the size of the active population

in the caudal fastigial nucleus

Fastigio-reticular projections and the cerebellar control of visual saccades

Motoneurons(ABD)

Ponto-medullaryReticular

Formation(EBN, IBN)

Corticaleye

fields(LIP, FEF, SEF…)

DeepSuperiorColliculus

Thalamus Caudal Fastigial Nuclei

Visualcorticalareas

Lobules VIc-VII

Pontine Nuclei,NRTP, cMAO

Neck proprioception

Vestibular input

NPH

Extra-ocular muscle proprioception

EBNIBN

MN agonist

EBN IBN

For every saccade (horizontal, oblique or vertical), the left and right cFN regulate the dynamic balance of activity

between the excitatory and inhibitory input (from EBNs and IBNs)to the motor and internuclear neurons in the abducens nucleus.

(Goffart, Chen & Sparks Journal of Neurophysiology 2004)

Bilateral hypothesis

midline

contracFN

ipsicFN

EBNIBN

MN agonist

EBN IBN

Electrical microstimulation evokes a contralateral saccade

STIM

contracFN

ipsicFN

midline

Quinet J & Goffart L. Journal of Neurophysiology 2015 (head fixed monkey)

Cogdell B, Hassul M & Kimm J. Archives of Otolaryngology 1977

Noda H, Murakami S, Yamada J, Tamada J, Tamaki Y & Aso T. Journal of Neurophysiology 1988

Quinet J & Goffart L. Journal of Neurophysiology 2009 (head free monkey)

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EBNIBN

MN agonist

EBN IBN

STIM

contracFN

ipsicFN

EBNIBN

MN agonist

EBN IBN

STIM

contracFN

ipsicFN

highcurrent

smallcurrent

larger number ofexcited neurons

WORKING HYPOTHESIS : the cerebellar control of saccade dynamics consists of

regulating the size of the population of active prem otor burst neurons

EBNIBN

MN agonist

EBN IBN

cFN inactivation does not suppress contralateral saccades,but reduces their horizontal velocity and amplitude

contracFN

midline

muscimol

ipsicFN

Goffart L & Pélisson D. Journal of Neurophysiology 1994, 1998 (head free cat)

Ohtsuka K, Sato H & Noda H. Journal of Neurophysiology 1994

Robinson FR, Straube A & Fuchs AF Journal of Neurophysiology 1993

Goffart L, Chen LL & Sparks DL. Journal of Neurophysiology 2004

Quinet J & Goffart L. Journal of Neurophysiology 2005, 2007 (head free monkey)

EBNIBN

MN agonist

EBN IBN

contracFN

ipsicFN

midline

muscimol

cFN inactivation also affects ipsilateral saccades, making their horizontal amplitude hypermetric

Goffart L & Pélisson D. Journal of Neurophysiology 1994, 1998 (head free cat)

Ohtsuka K, Sato H & Noda H. Journal of Neurophysiology 1994

Robinson FR, Straube A & Fuchs AF Journal of Neurophysiology 1993

Goffart L, Chen LL & Sparks DL. Journal of Neurophysiology 2004

Quinet J & Goffart L. Journal of Neurophysiology 2005, 2007 (head free monkey)

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“planning noise” = “all noise sources that contribute to the variability of the planned saccade amplitude” (page 3)i.e., “non-motor noise affecting sensory processing, target selection, and cortical representations of the initial motor error” (page 3)

Fastigio-reticular projections and the cerebellar control of saccades

Motoneurons(ABD)

PremotorNeurons

(EBN, IBN)Cortical

eyefields

(LIP, FEF, SEF…)

DeepSuperiorColliculus

Thalamus Caudal Fastigial Nuclei

Visualcorticalareas

Lobules VIc-VII

Pontine Nuclei,NRTP, cMAO

Neck proprioception

Vestibular input

NPH

Extra-ocular muscle proprioception

Microstimulation (100Hz)

Horizontal position (deg) Horizontal position (deg)V

ertic

al p

ositi

on (

deg)

Evidence for an intrasaccadic, not planning disorder

ControlMuscimol

ControlStimulation

32

24

16

8

0

-8

-16

-24

-32-32 -24 -16 -8 0 8 16 24 32-32 -24 -16 -8 0 8 16 24 32

Muscimol injection

Right cFN (rebound saccades removed)

SEE ALSO : Goffart L, Chen LL & Sparks DL. Annals NY Academy of Sciences 2003

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Increased variability of starting positionsNOT EXACT

x 3.

Is the endpoint variance increasedfor ipsilesional saccades ?

Not position but amplitude !

InactivationControl

Increased variability of starting positions due to :- shifted centroid of positions AND- horizontal dysmetria of fixational saccades

Is the endpoint variance increasedfor ipsilesional saccades ?

NOT EXACTNot position

but amplitude !

x 3.

Hor

izon

tal l

andi

ng p

ositi

on (

°)

Trial #

16DOWN

16UP

HOR

10

0

-20

-10

10

20

0-10-20 20

Horizontal position (°)

Ver

tical

pos

ition

(°)

A26jun15_5

POST

POST

Other possible target locations(+/-8,0); (0,+/-8); (+/-8,+/-8)

A26jun15_5

POSTPRE

PREflashed target (100 ms)gap = 200 ms

No increase of endpoint variance for ipsilesional saccades

10

0

-20

-10

10

20

0-10-20 20

A26jun15_5

POSTPRE

POSTPRE

left cFN

Larger hypermetria

A09oct15_5

POSTPRE

Smaller hypermetria

0

-20

-10

10

20

100-10-20 20

Searching for symmetry

Horizontal position (°)

Ver

tical

pos

ition

(°)

Horizontal position (°)V

ertic

al p

ositi

on (

°)

right cFN

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5

10

0

-20

-10

10

20

0-10-20 20

A26jun15_5

POSTPRE

POSTPRE

left cFN

Increased endpoint variabilityfor contralesional saccades !!!

A09oct15_5

POSTPRE

100-10-20 20

0

-20

-10

10

20

Searching for symmetry

Horizontal position (°)V

ertic

al p

ositi

on (

°)Horizontal position (°)

Ver

tical

pos

ition

(°)

right cFN

100

0

-20

-10

10

20

0 300

right cFN

A09oct15_5

500200 400

0

-20

-10

10

20

-10-20

Trial #

100 20

POSTPRE

A09oct15_5

Other possible target locations(+/-8,0); (0,+/-8); (+/-8,+/-8)

Hor

izon

tal l

andi

ng p

ositi

on (

°)

Ver

tical

pos

ition

(°)

Horizontal position (°)

100

0

-20

-10

10

20

0 300 500200 400

Trial #

Other possible target locations(+/-8,0); (0,+/-8); (+/-8,+/-8)

A09oct15_5

right cFN

Weak time-dependence

Strong time-dependence

Time-dependent endpoint variability for contralesional saccades

0

-20

-10

10

20

-10-20 100 20

POSTPRE

A09oct15_5

Hor

izon

tal l

andi

ng p

ositi

on (

°)

Ver

tical

pos

ition

(°)

Horizontal position (°)

100

0

-20

-10

10

20

0 300 500200 400

Trial #

1000 300 500200 400

Trial #H

oriz

onta

l lan

ding

pos

ition

(°)

Hor

izon

tal l

andi

ng p

ositi

on (

°)

0

-20

-10

10

20

A02oct15_5A09oct15_5

right cFN

Strong time-dependence

Weak time-dependence

Stability

Stability

injection A7 injection A6

NOYES

Time-dependent endpoint variability for contralesional saccades depends upon the experiment

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For some injection, the magnitude of hypometria incre ases with the trial number.

The drug diffuses with the trial number.

As the drug diffuses, the number of inactivated neurons increases = the numbe r of active neurons diminishes

Reduced number of active neurons reduced peak velocityinsufficient duration enhanced hypometria

EBNIBN

MN agonist

EBN IBN

midline

EBNIBN

MN agonist

EBN IBN

midline

EBNIBN

MN agonist

EBN IBN

midline

muscimol

contracFN

ipsicFN

0

0

-30

-10

10

30

-10-20-30 20

Horizontal position (°)

Ver

tical

pos

ition

(°)

B02avr14

POSTPRE

POSTPRE

left cFN

10

-20

20

Trial #

Hor

izon

tal l

andi

ng p

ositi

on (

°)

-40

-30

-20

-10

0

10

20

-402000 300 400100

Time-dependent endpoint variability also possible for only ipsilesional saccades

POSTPRE

time-dependence

stability

EBNIBNEBN

OPN

contracFN

midline

EBNIBN

MN agonist

EBN IBN

ipsicFN

midline

muscimol

EBNIBN

MN agonist

EBN IBN

midline

MN agonist

IBN

Enhanced duration is due to : - desinhibited residual input from descending commands- due to prolonged inhibition of OPN by the agonist drive

Reduced number of active neurons enhanced duration

unchangedenhanced

enhanced hypermetriapeak velocity

As the drug diffuses, the number of active neurons diminishes

reduced feedback gainduring ipsilesional saccades longer H duration longer V duration

VERTICAL GENERATOR

HORIZONTAL GENERATOR

1+∆g2

1-∆g1

Goffart, Koene & Quinet SFN abstr . 2005

Goffart, Koene & Quinet 2005 rejected

Saccade duration and the local feedback control

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25 muscimol injections in the cFN of 4 monkeys

Oblique saccades

enhancedVduration

<

CONCLUSION

1. BOTH cFN contribute to accelerate AND decelerate the horizontal component of any saccade

reduccedH peakvelocity

enhancedH peakvelocity

1. BOTH cFN contribute to accelerate AND decelerate the horizontal component of any saccade2. The NUMBER of active neurons in BOTH cFN matters in the specification of saccade dynamics

EBNIBN

MN agonist

EBN IBNEBNIBN

MN agonist

EBN IBNEBNIBN

MN agonist

EBN IBN

muscimol

contracFN

ipsicFN

CONCLUSION : the bilateral mass hypothesis

EBNIBN

MN agonist

EBN IBN

contracFN

EBNIBN

MN agonist

EBN IBNEBNIBN

MN agonist

EBN IBN

ipsicFN

Saccade time course

activelate

active early

CONCLUSION : the bilateral mass hypothesis

1. BOTH cFN contribute to accelerate AND decelerate the horizontal component of any saccade2. The NUMBER of active neurons in BOTH cFN matters in the specification of saccade dynamics

3. The late burst of some neurons in the ipsilateral cFN is the signature of a RECRUITMENTOhtsuka K & Noda H. Journal of Neurophysiology 1991

Kleine JF, Guan Y & Büttner U. Journal of Neurophysiology 2003 Fuchs AF, Robinson FR & Straube A. Journal of Neurophysiology 1993

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1. BOTH cFN contribute to accelerate AND decelerate the horizontal component of any saccade2. The NUMBER of active neurons in BOTH cFN matters in the specification of saccade dynamics

3. The late burst of some neurons in the ipsilateral cFN is the signature of a RECRUITMENT4. Different evolutions of ipsi/contra-lesional dysmetria suggest DISTINCT ROUTES to EBN/IBNs

Trial #

Hor

izon

tal l

andi

ng p

ositi

on (

°)

-30

-20

-10

0

10

20

-402000 300 400100

Strong time-dependence ofIpsilesional dysmetria

stability

100

0

-20

-10

10

20

0 300 500200 400

Trial #A09oct15_5

Weak time-dependence

Strong time-dependence ofcontralesional dysmetria

Hor

izon

tal l

andi

ng p

ositi

on (

°)

CONCLUSION : the bilateral mass hypothesis

1. BOTH cFN contribute to accelerate AND decelerate the horizontal component of any saccade2. The NUMBER of active neurons in BOTH cFN matters in the specification of saccade dynamics

3. The late burst of some neurons in the ipsilateral cFN is the signature of a RECRUITMENT4. Different evolutions of ipsi/contra-lesional dysmetria suggest DISTINCT ROUTES to EBN/IBNs

5. Between the topographical and temporal "codes", the NEURONAL MASS "code"

TOPOGRAPHICAL "code" (e.g. deep Superior Colliculus)

TEMPORAL "code"(e.g. motoneurons)

NEURONALMASS"code"

Cerebello-reticularnetwork

neuronal mass = the number of active neurons contributing to the agonist burst

CONCLUSION : the bilateral mass hypothesis

Gratefulness and thanks for their support

Julie QUINET

Edward L. KELLER

Longtang L. CHEN

Ziad M. HAFED

Rich J. KRAUZLIS

Patrick CAVANAGH

POSITION (P. Cavanagh)

Clara BOURRELLY

Lorenzo GUERRASIO

Ulrich BÜTTNER

David L. SPARKS

Albert F. FUCHS

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