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Chapter 9
SUPRANUCLEAR CONTROL OF GAZE AND INTERCONNECTIONS

Key Words: Vestibular nuclei, PPRF, MLF, riMLF , integrators- Cajal, Prepositus, Vestib Nuclei, tonic cells, phasic (pause and bursters), DLPN, Supraoculomotor nucleus, Edinger Westfall, NRTP, PIN, Vert and Horiz representation, Saccades, Pursuits, Convergence, Accommodation, VOR, OKN, gaze palsies and various ophthalmoplegias

Outline
VII.  Premotor Nuclei (contí):  Interconnections and Gaze Control

  • MLF: Interconnections between nuclei and cranial nerves
    Medial longitudinal fasciculus interconnects V & H premotor to motor nuclie
     
  • Vestibular Nuclei: control of pursuits & saccades
    Primary input- vestibular; Secondary inputs- visual, muscle proprioception, somatosensory
    Binocular yoking and monocular reciprocal innervation
    Conversion of velocity to position signals for VOR, OKN, pursuits
    Velocity storage for VOR
    Adaptable gain adjustment for OKN and VOR
    Lesions produce jerk nystagmus with fast phase to contralateral side
     
  • PPRF: Horizontal Saccades
    Horizontal yoking and reciprocal innervation - Abducens nucleus and interneurons to contralateral III
    Reciprocal inhibition - PPRF inhibits contralateral PPRF and vestib nucleus
    Lesions in PPRF cause horizontal gaze palsy for saccades only
     
  • Rostral interstitial nucleus MLF (riMLF): Vertical Saccades
    Binocular yoking and monocular reciprocal innervation
    Vertical step derived from integral of burst in cajal in MRF-eye and head
    Parinauds syndrome- Anterior (caudal) MLF lesions
     
  • Shaping of Saccades
    Triggering, velocity, amplitude (position), and breaking
    Types of burst - Pause, long-medium & short bursters, tonic cells
    Pulse-step components of saccades
    Saccade velocity (burst frequency)
    Saccade amplitude (burst duration) (main sequence curve)
    Neural Integration of Saccades - Transform velocity to position for horizontal tonic cells
    (Horizontal Step derived from integral of burst)
     
  • Horizontal & Vertical Pursuits
    MST to dorsal lateral pontine nuclie DLPN
    Projects to flocculus and vermis of the cerebellum and then vestibular nuclei
     
  • Near Response- vergence accommodation and pupil
    Supraoculomotor nucleus - vergence and accommodation
    Edinger-Westphal nucleus- motor nucleus - pupil and accommodation
    Nucleus reticularis tegmentis pontine (NRTP) vergence and accommodation
    Posterior interposed nucleus (PIN) vergence and accommodation in Cerebellum
     
  • Lesions and Anomalies
    Gaze paulsies (Foville, Parinaud)
    Lesion in interneuron projection to contra III - internuclear ophthalmoplegia
    Posterior INO - horizontal gaze palsy for all types of movements
    Anterior INO - adduction of III limited
    1 1/2 syndrome
     
  • Video
    Internuclear Ophthalmoplegia


Interconnections between pre-motor and motor nuclei:
Medial Longitudinal Fasciculus (MLF)
(See chapter 10, especially pp 432-438 in Zee)
The various motor nuclei that send axons via the cranial nerves to the body musculature receive instructions from premotor nuclei.  The interneurones making up the communication lines between premotor nuclei and the final common pathway is called the Medial Longitudinal Fasciculus (MLF).  Programmed responses for horizontal and vertical components orchestrated by the pre-motor nuclei are conveyed to a variety of motor nuclei via a parallel set of axons that run caudal to rostral along the brainstem.  Some of these fibers decussate and others remain on one side of the brain stem.  A section later in this chapter describes various neurological syndromes that result from lesions of the MLF.

 

 

Fig 9.1
Location of Motor and Premotor Nuclei.

Note the location of the Medial Longitudinal Fasciculus (MLF) relative to nuclei.

Vestibular Nuclei: Slow-Conjugate Eye Movements
(See pp. 54-56 of Zee)  The vestibular nucleus received its name because it is the main target of axons from the vestibular canals via the auditory, or vestibular, nerve (VIII).  However it also plays a major role in controlling almost all slow visually driven conjugate eye movements like pursuits and OKN.  In addition vestibular nuclei receive afferents for visual, oculomotor, neck proprioception and somatosensory. 

The vestibular neuron is the second in a three-neuron reflex arc that includes the vestibular sensory bipolar cells in the canals, the vestibular nuclei and the oculomotor nuclei.  This short path has a transmission time of only 10 msec.  The role of the vestibular nuclei is to convert a velocity signal to a position signal that projects to the oculomotor nuclei.  (The appropriate stimulus for the semicircular canals is angular head acceleration.  In order to obtain the eye position related signal found in oculomotor neurons, a twofold integration has to take place.  One integration is determined mechanically in the canal which transforms endolymph acceleration to velocity.  The vestibular nuclei perform the second integration.)

Binocular yoking and monocular reciprocal innervation
Different eye muscle pairs are activated by different canals.  (See fig 2-6 p 35, Zee.)  From the vestibular nuclei, direct excitatory and inhibitory pathways project to the motoneurons of specific extra-ocular muscle pairs lying closest to a canal pair.  The horizontal canal responds to horizontal head rotation towards the side of the canal.  The VOR causes the eyes to rotate to the side opposite to the stimulated canal.  The canal projects to the ipsilateral VN which then projects to the contralateral abducens.  Interneurons projected from the abducens cross back to the stimulated side and synapse with the medial rectus portion of the oculomotor (III) nucleus.  The same canal causes inhibition of the abducens and interneuron controlling gaze in the opposite direction.

 

 

Fig 9.2
VOR (Vestibulo-ocular reflex) during head rotation to the left.

The left horizontal canal stimulates the left VN which stimulates the contralateral (right) abducens nucleus while inhibiting the left abducens nucleus.

Also note interneurons projected from the abducens nuclei to oculomotor (III) nuclei.
 

For the vertical canals, the excitatory connections synapse on vestibular cells on the crossed side of the brainstem.  Inhibitory connections are uncrossed.  The anterior canal is activated by downward head rotation.  The resulting VOR causes contraction of the ipsilateral SR and contralateral IO.  It also inhibits the ipsilateral IR and contralateral SO.  (Activation of both anterior canals results in upward movement of both eyes, holding gaze steady.)  The posterior canal, on the other hand, is activated by upward head rotation.  The resulting VOR causes contraction of the ipsilateral SO and contralateral IR, and inhibition of the ipsilateral IO and contralateral SR.  (Allowing downward eye movement to hold gaze steady.)

Fig 9.3  Excitatory VOR pathways for, A) the anterior canal (downward head rotation), B) the horizontal canal (head rotation to left), and C) the posterior canal (upward head rotation).

III, oculomotor nucleus; IV, trochlear nucleus; VI, abducens nucleus; YG, y group region; VN, vestibular nucleus; MV, medial vestibular nucleus; BC, brachium conjunctivum; FLM, medial longitudinal fasciculus. (Also see Fig. 13.8
in chapter 13.)

Table 9.1  Vestibular Canals and Paired Yoked Muscles- Excitatory Projections

Canal

Nuclei

Ipsi muscle

Contra muscle

HORIZONTAL

Contra VI

MR

LR

ANTERIOR VERT.

Contra III

SR

IO

POSTERIOR VERT.

Contra IV and III

SO

IR

Table 9.2  Vestibular Canals and Paired Yoked Muscles- Inhibitory Projections

Canal

Nuclei

Ipsi muscle

Contra muscle

HORIZONTAL

Ipsi VI

LR

MR

ANTERIOR VERT.

Ipsi III and IV

IR

SO

POSTERIOR VERT.

Ipsi III

IO

SR

Velocity to position integration
The vestibular nuclei also transform velocity signals for driving VOR and OKN to position signals.  The VOR responds to acceleration of the head.  As stated above, this signal must be integrated twice to become a position signal.  The first integration occurs in the hair cells of the vestibular sensor of head rotation.  The second integration occurs in the vestibular system.  The OKN stimulus is field velocity.  The velocity signal is relayed to the vestibular nuclei from the retina via the accessory optic tract via the nucleus of the optic tract (NOT).  This signal is integrated to a position signal by the medial vestibular nuclei.   Finally, pursuit signals are coded for velocity in the cortex area MST.  These signals eventually reach the vestibular nuclei where they are integrated to position signals that vary in time.

Velocity storage
Both OKN and the VOR continue responding in darkness after their stimulus has ceased.  This demonstrates a persistance of the VOR after the stimulus (head acceleration) ceases.  Normally if we rotate at a constant velocity, the VOR is activated when rotation begins, but the stimulus ceases when we reach a constant velocity.  The VOR continues however and operates like a spinning top which continues to rotate after a single torque has been applied.  This continued response is the result of a neurological velocity storage mechanism that lies in the vestibular nucleus.   The vestibular nuclei act as a flywheel for reflex following movements.  A flywheel analogy uses momentum to maintain rotation.  It captures momentum of eye and continues eye rotation without stimulation for 20 seconds.

This aftereffect compensates for motion adaptation of the sensory system. This persistence is referred to as a velocity storage mechanism and it works for the reflex image stabilization responses.  It results from an interaction between the nodulus (posterior extremity of the inferior vermis of the cerebellum) and a region in the vicinity of the vestibular nuclei.   This compensates for motion adaptation to constant velocity for VOR and motion adaptation in general for OKN.  Examples of motion adaptation occur while driving a car for long periods of time.  For example, when you exit a freeway you may feel you are driving slower than you really are.  The adapted visual stabilization reflexes help keep the optic flow pattern of the retinal image stabilized even though you are less sensitive to motion than when you first began to drive on the freeway.

 

Fig 9.4
Persistence of the VOR with sustained rotation.

(Relationship among vestibular nystagmus, optokinetic nystagmus, and optokinetic after-nystagmus.)

Variable gain adaptation
The vestibular nucleus is adaptable in that it can change the gain of the VOR.  If you wear glasses, try shaking your head sideways without your glasses and you will see the world move opposite to your head rotation if you're myopic.  No motion is seen while shaking your head with the glasses on.  The VOR has been adjusted to the minified image size caused by the glasses and this adjustment has occurred in the vestibular nuclei and its interactions with the flocculus of the cerebellum.  We will see later that this adjustment is made by inhibitory influences of Purkinje cell projections from the cerebellum to the vestibular nuclei.  Lesions to the vestibular nuclei result in spontaneous nystagmus and positional nystagmus.

 
PPRF and Horizontal Saccades
The first function of the supranuclear premotor areas is to orchestrate coordinated actions of groups of muscles.  The lateral gaze center in paramedian pontine reticular formation (PPRF) is responsible for cordinating horizontal saccades.  A caudal region of the Pons contains nuclei that cause a conjugate saccade to the ipsilateral or same side as the stimulus.  This region projects to the ipsilateral abducens nucleus but not the contralateral medial rectus.  The abducens contains both motoneurons whose axons innervate the lateral rectus and internuclear neurons or interneurons that cross the midline and excite medial rectus motoneurons in the contralateral oculomotor nucleus.

 

Fig 9.5
Schematic representaton of the PPRF (paramedian pontine reticular formation) and its relation to motor nuclei.

Thus the PPRF drives the abducens and an interneuron near the abducens which travels via the medial longitudinal fasciculus to the contralateral oculomotor nucleus.   The PPRF also sends inhibitory connections to the contralateral PPRF and vestibular nucleus to reduce innervation of the antagonist.

 
riMLF and Vertical Saccades
The triggering or gating of vertical saccades is initiated by pause cells in the PPRF which projects directly to the rostral interstitial nucleus of the MLF (riMLF).  The PPRF is located in the pons and the riMLF (rostral interstitial MLF) is located rostrally in the mesencephalon, anterior to III.  (See Fig 9.6 above.)  The riMLF only participates in the formation of saccades.  A lesion in this area will not ablate vertical slow movements such as pursuits, OKN or the VOR.  These slower movements originate from the Pons and vestibular nuclei and involve projections to a mesencephalic region called the nucleus of Cajal which is responsible for integrating velocity signals into position signals.  Cells in the riMLF innervate the ipsilateral trochlear nucleus (IV) and the vertical recti subnuclei of both oculomotor nerves (III).  The riMLF innervates the contralateral SO via the ipsilateral IV nucleus and it innervates the ipsilateral IR via the ipsilateral III nucleus.  The ipsilateral IR is innvervated via the contralateral III and the contralateral IO is innervated by the contralateral III.

 

Fig 9.6
Connections of the riMLF

riMLF - rostral intersitial nucleus of MLF
PC - Posterior Commisure
VC - Ventral Commisure
INC - interstitial Nucleus of Cajal
III - Oculomotor Nucleus
IV - Trochlear Nucleus
rip - nucleus Raphe Interpositus
VN - Vestibular Nucleus

Table 9.3  Vertical Saccade Pathways originating from the riMLF to the III and IV Nuclei

Nucleus

Muscle

 

(Down Movers:)

Ipsi IV

Contra SO

Ipsi III

Ipsi IR

 

(Up Movers:)

Contra III

Ipsi SR

Contra III

Contra IO

Shaping of Saccades
The second function of the PPRF and riMLF is to shape the innervation controlling onset, velocity, amplitude and duration of a saccade.  This is a complex problem for saccades because they have high velocities ranging up to nearly 1000 deg/sec.  The viscosity of the eye muscles and orbital connective tissue require great amounts of force to achieve high velocities.  This is accomplished with three general classes of neurons called pause, burst, and tonic. 

 

Fig 9.7
Pause, burst, and integration circuit.

Pause neurons act like a car clutch.  They engage the saccade by releasing their inhibition of the burst cells.  The burst cells produce a brief pulse of innervation which is followed by a constant step of innervation produced by the tonic cells.  The pulse innervation produced by the burst controls the velocity of the saccade, and the step of innervation produced by the tonic cell controls the final position of the eye upon completion of the saccade (page 180-183 Zee).  The pulse is needed to overcome the viscosity of the eye-orbit and the step is needed to overcome the elastic restoring forces of the eye muscles and orbit.  Normally the pause cells prevent saccades by constantly inhibiting bursters.  The pause cell discharges continuously except immediately prior to and during saccades when they pause.  This is when they release their inhibition.  The same pause cells inhibit saccades in all directions.  If we were to have a lesion that disturbed these cells there would be no inhibition of saccades and eye movements would occur uncontrollably in all directions of gaze.

Types of Burst Cells
There are three general types of burst cells (short lead excitatory burst neurons SLBN, long lead burst neurons LLBN and inhibitory burst neurons IBN).  The LLBN discharge up to 0.2 second before the saccade.  The long-lead neurons project to the short lead to evoke the saccade. The SLBN  begin discharging at a high frequency (300-400 spikes/sec) immediately at the beginning of the saccade and throughout the duration of the saccade.  These SLBN are referred to as medium lead burst neurons in Adler's text (p 145-146).  Duration of SLBN activity ranges from 10 to 80 msec.  The pulse innervation controls the velocity and amplitude of the saccade.  Velocity is controlled by the frequency and amplitude is controlled by the duration of the burst activity.  This duration is gated by the pause cell.  There is a strict relationship between the saccade amplitude to both its velocity and duration that results from the mechanical properties of the eye and orbit.  Saccade amplitude can be predicted knowing either the duration of the pulse or its velocity.  This relationship is described as the main sequence diagram, which was borrowed from astronomy by Stark and Bahill.

Neural Integrators
Upon completion of the saccade, the new eye position is held by the discharge step of the tonic cell.  The discharge rate of the tonic cell is thought to be derived directly from the pulse innervation.  The step is derived by integrating the pulse.  At least two sites are known to integrate horizontal pulses, these are the medial vestibular nuclei and the prepositus. Vertical pulses are integrated in the nucleus of Cajal. 

Fig 9.8
Locations of burst and integrator regions.

Vert. Burst: riMLF
V Integrator: iC (interstitial nucleus of Cajal)

Horiz. Burst: PPRF
H Integrator: ppH (prepositus Hypoglossi) and medial vestibular nuclei (not shown)

The Flocculus of the cerebellum is also involved in integrating the velocity signals to position signals controlling eye movements.  Some anomalies occur that appear to result from lesions of the integrator.  In these cases the eyes make a saccade and then drift back to primary position.  In addition the patients are unable to hold fixation away from primary position and a jerk gaze nystagmus develops in which the eyes slow-phase drift is toward primary position and fast-phase saccades are away to the desired position.

Horizontal and vertical pursuits
Smooth following eye movements resulting from cortical motion signals are processed in the dorsal lateral pontine nuclei DLPN.  Velocity signals are projected from here to the floccular region and to the vermis lobules VI and VII of the cerebellum.  The flocculus is thought to maintain pursuit during steady constant tracking while the Vermis is important when the target velocity changes or when initiating pursuit.  The role of the cerebellum is to sort out eye and head rotations in the tracking process and to sort out the ocular pursuit signal from visual and eye-head motor inputs.  From here, activity passes via parts of the vestibular nuclei which performs the necessary neural integration of the velocity signal to a position signal that is sent to the eye muscle motoneurons.  (page 156-158 in Zee).  There is a great deal about the pursuit pathways that is yet to be understood, especially for the generation of vertical pursuit.

Near response
The near response refers to the combined oculomotor actions that occur as a visual target changes distance from the observer.  These actions are vergence, accommodation, and pupillary reflex.  Several supranuclear regions are associated with these actions:

The nucleus reticularis tegmenti ponti (NRTP), located just ventral to the rostral portion of the PPRF (in the pons), receives projections from the frontal eye fields and the superior colliculus.  The NRTP projects to the cerebellum, and appears to be associated with vergence and accommodation.  The posterior interposed nucleus (PIN) of the cerebellum projects to supraoculomotor regions.  The supraoculomotor nucleus contains both burst and tonic neurons.  Excitatory connections of the supraoculomotor nucleus project to the oculomotor nucleus, driving the medial recti.  Inhibitory connections project to the abducens nucleus to inhibit the abducens.  As a result, the supraoculomotor nucleus is associated with vergence. 

 

Fig 9.9
Innervation of horizontal recti muscles from oculomotor and abducens nuclei.

The Edinger-Westphal nucleus, located at the rostral portion of the midbrain at the oculomotor nucleus, contains parasympathetic motor neurons projecting to the ciliary muscle, driving accommodation.  Each hemisphere of the Edinger-Westphal nucleus projects to one eye, resulting in individual control.  Parasympathetic outflow of the Edinger-Westphal nucleus also results in miosis (pupillary contraction).  Inhibition of the Edinginer-Westphal nucleus causes pupil dilation.
 
Lesions and Disorders
Any lesion that disrupts these fibers disconnects the pre-motor from the motor nuclei and are referred to as ophthalmoplegia.  Deficits caused by lesions of the MLF depend on the size and location of the lesion in this pathway (Also see table 10-13 on p. 433 of Zee).

Fig 9.10  Various lesions (ophthalmoplegia) and resulting symptoms.  (Bars above eyes indicate approximate range of motion.)

1) Oculomotor Ophthalmoplegia
2) Abducens palsy
3) Unilateral INO (InterNuclear Ophthalmoplegia)
4) One-and-a-half syndrome
5) Fovilleís Syndrome (Posterior INO)

Lesions that occur in the MLF are called supranuclear ophthalmoplegia as opposed to complete ophthalmoplegia which results to lesions of the oculomotor nucleus III.  Unilateral lesions of the MLF produce weakness of movement to the side of the lesion.  Internuclear ophthalmoplegia (INO) refers to an adduction failure caused by disruption of interneuron pathways from premotor nuclie to motor neuron nuclei of the III nerve nucleus.  In these cases the affected eye is unable to move to the contralateral side and the eye drifts temporalward.  Convergence is still normal in these patients which distinguishes this lesion from disruption of the abducens nucleus. Often these patients develop a convergence nystagmus in an attempt to bring the exotropic eye into primary gaze.  Internuclear ophthalmoplegia is usually caused by multiple sclerosis in young adults or by occlusion of the basilar artery near the circle of Willis later in life.  It is called Anterior INO if only adduction of one eye is affected and Posterior INO if both adduction of one eye and abduction of the other eye are affected.  One-and-a-half Syndrome is caused by a lesion of the abducens (affecting the ipsilateral lateral rectus) and both interneurons (affecting the ipsilateral and contralateral medial recti).

Foville's syndrome is a unilateral lesion at or near the abducens nucleus (p. 323 in Zee) which causes conjugate gaze palsy, contralateral limb paralysis, and ipsilateral facial paralysis.  If only saccades are affected, the lesion is in the PPRF, and is called lateral gaze palsy. Lesions in the PPRF lead to horizontal gaze palsies to the ipsilateral side.  Only horizontal saccades are effected in lesions of the PPRF (p. 198 in Zee) whereas lesions of the abducens affect both saccades and the VOR.  This is because the abducens is the final common pathway for all lateral eye movements.  Lesions in either the PPRF or abducens nucleus prevent movement of either eye to the ipsilateral side because the interneurons projecting form the abducens to the contralateral oculomotor nucleus are also effected.

Lesions rostral to III cause paralysis of vertical gaze (Parinaud's syndrome) and failure of convergence, but retention of normal lateral gaze ability.  It occurs in the vicinity of the superior colliculi and affects all vertical eye movements including saccades.  It often results from tumors of the Pineal gland that compress the superior colliculi and pretectal structures. Lesion caudal to III  cause exotropia and failure of adduction while normal vergence ability is retained.  Thus the patient cannot adduct either eye while attempting conjugate lateral gaze but can converge both eyes easily to a near stimulus.  Unilateral lesions may also cause skew deviations in which there is a vertical hyper deviation of one eye.  Unilateral lesions can also cause unilateral nystagmus where the affected eye has a slow upward drift and fast downward saccade (down beat nystagmus).  Symmetrical caudal lesions will produce problems of lateral gaze involving both the medial and lateral recti.


Review Questions:

  1. List the gaze centers that are specialized for the control of horizontal and vertical saccades and pursuits.
  2. What pathway interconnects premotor and motor nuclei?
  3. Describe the cranial nerves excited and inhibited by the various vestibular canals.
  4. What structures in the brain stem transform velocity to eye position?
  5. What are the sites of lesions that produce the following:
    a.  Foville's syndrome,  b.  Parinaud's syndrome,  c. Internuclear ophthalmoplegia (anterior and posterior),  d.  One and a half syndrome, e.  VI nerve palsy

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