S2: Neuroscience : 1:00-2:00Scribe: Andrew Treece

Wednesday, February 25, 2009Proof: Sally Hamissou

Dr. GamlinOculomotorPage1 of 6

Abbreviations: MLF= medial longitudinal fasciculus, EOM= extra-ocular muscles, VOR= vestibulo-ocular reflex,

PPRF= paramedian pontine reticular formation, riMLF= (rostral interstitial nucleus of the medial longitudinal fasciculus)

Introduction [S1]: The Top Ten Things You Should Know About The Oculomotor System
Movements of the eyes are produced by six extra-ocular muscles [S2]
The first thing you should know about the eye movement system is that movements of the eyes are produced by six EOMs, and if they or the neural pathways controlling them aren’t functioning normally, then eye movements are abnormal. As we will see, the neural control pathways for eye movements involve midbrain, brainstem, cerebellum, cortex, and they are very precise movements and so damage too many parts of the brain will produce eye movement abnormalities.
In addition when people talk about the eye movement system they usually refer to the EOMs, but we are also going to discuss accommodation which is produced by the ciliary muscle which is a smooth muscle controlled by the autonomic nervous system and pupillary responses which are controlled by the parasympathetic and sympathetic systems.
Video1: This is an example of Dwayne’s syndrome. These are abnormal eye movements. The left eye is unable to abduct normally, which is usually due to the fact that the sixth nerve developed abnormally in the innervation of the lateral rectus. So that is usually a peripheral explanation.
Video2: This is an example of opsoclonus where the patient makes rapid eye movements back to back. This is also abnormal. Notice the abnormal eye movements that move back and forth in a shaking manner. This may indicate a tumor, but clearly an indicator of abnormality.
Take home message: Studying the eyes and understanding neural pathways may help diagnose problems that cannot be shown through MRI structurally. In many cases the MRI may not show anything, but neurologically signs will.
Meet the muscles [S3]
Let’s briefly talk about the muscles and nomenclature of the eye.
Medial rectus (adduction or A-D-duction toward the midline) and lateral rectus (abduction or A-B-duction away from the midline) move the eye horizontally.
Superior rectus (elevation) and inferior rectus (depression)
Superior oblique (intorsion where the tops of the eyes rotate in towards the nose) and inferior oblique (extorsion where the tops of the eyes rotate outward)
Today’s focus is on horizontal eye movements.
Meet the muscles (cont) [S4]
These are intraocular muscles.
Ciliary muscle produces positive accommodation, in other words the lens focuses for near and unusually it does not have an antagonistic muscle. This is an unusual arrangement, because its antagonist is the suspensory ligaments that it acts against. No push pull system, just a single muscle
For pupil control the sphincter constricts the pupil and the dilator dilates the pupil.
The stretch reflex is absent. [S5]
The other thing you should know about is that in contrast of skeletal muscle that has a well-developed stretch receptor system, the stretch reflex at least in a moment to moment basis is absent for eye movements.
If you close one eye and press on the other eye you will see the whole world jump around because you do not have a moment to moment proprioceptive feedback from the EOMs. This means that for the brain to keep track of where the eyes are, it has to keep track of the signals that are sent to the motor neurons and base the position on the signals that are going to the motor neurons, and this is known as an efference copy or corollary discharge.
So you don’t use proprioceptive feeback from the eye muscles, instead you keep track of the signals you send to those muscles and that’s how you keep track of where your eyes are.
Except for changes in viewing distance, normal eye movements are yoked [S6]
In humans and non-human primates, the eye movements are usually yoked (which is not true for chameleons which can move their eyes independently).
Human eyes usually move both eyes the same amount in the same direction. So when the left eye goes up the right eye usually goes up the same amount, and if you don’t you get a vertical diplopia. When one eye goes left the other eye goes left, and if it doesn’t you get a horizontal diplopia.
When the eyes are not well-aligned the person will see double and have what is called diplopia.
This can also come from imbibing too much alcohol.
The yoking between the left and right eye is ensured by the fact that projections from the abducens nucleus to the medial rectus neurons, about 40% of the neurons in the abducens nucleus are not motor neurons but instead they are internuclear neurons that project by way of the MLF (medial longitudinal fasciculus) to the contralateral medial rectus, and it’s this abducens to medial rectus pathway through the MLF that ensures the yoking between the two eyes.
The only problem for that is when you want to converge your eyes, the eyes move in equal but opposite directions so the system that ensures your eyes move together normally for perfect eye movements actually works against you when you want to converge and diverge your eyes. But we will see that the nervous system has evolved to have a separate vergence control system that bypasses the MLF, because the MLF wants to yoke the eye movements.
Diagram [S7]
Just to go over this pathway, this is a schematic of the sixth nerve nucleus, left and right.
DO NOT memorize the neurotransmitters here. The main point is that there are lateral rectus motor neurons, that project to the lateral rectus muscle, and there are abducens internuclear neurons which project to the contralateral medial rectus motor neurons of the oculomotor nucleus. Only half of this pathway is shown.
The other thing about this diagram you should note is that there is a vergence signal to converge the eyes that is coming into the oculomotor nucleus independent of this pathway. Damage to this pathway produces a syndrome called internuclear ophthalmoplegia.
This MLF pathway is heavily myelinated, and is susceptible to damage in cases of multiple sclerosis. So in internuclear ophthalmoplegia what happens is that these abducens internuclear neurons become demyelinated or damaged for other reasons such as stroke, and the signal from this nucleus to the medial rectus is damaged so that when the lateral rectus contracts on this side the signal to the medial rectus to contract is not present.
Video3: What you normally see with internuclear ophthalmoplegia is that one eye is not adducting normally (not moving towards the nose properly), it can abduct but the signal to the medial rectus motor neurons is not present or reduced because of damage to the MLF. Notice it doesn’t adduct.
If you were to ask this same person to converge their eyes, this eye would then be able to move towards the midline. It would converge normally, but it will not move towards the midline for what are called conjugate eye movements.
So internuclear ophthalmoplegia is defined by the inability to adduct the eye towards the midline for saccadic movements, smooth pursuit movements, and vestibular responses but you can adduct the eye for convergence.
Eye movements are controlled by distinct neurological subsystems [S8]
Now the next thing to note is that eye movements are controlled by distinct neurological subsystems with some overlap, but overall there are specific regions of the brain that control different types of eye movements.
The first thing we can do is break up eye movements into two broad categories:
There are involuntary eye movements which stabilize the image on the retina, so for example if you look at your thumb there are involuntary eye movements such as the VOR that will stabilize the image.
There are also voluntary eye movements that allow you to look at new, novel objects of interest.
Functional classes of eye movements [S9]
The ones that are yoked normally and the signals go through the MLF are all of these except for vergence and the vergence signals do not travel in the MLF.
So what about these two broad categories.
The first is vestibular responses that hold the image of the world on the retina during head movements, and then the optokinetic system which holds images of the world steady on the retina during sustained rotations. If you continue to rotate for a long time, the vestibular responses adapt and it’s the optokinetic responses that continue to move your eyes. These are reflexive eye movements mainly.
We are not going to talk about visual fixation too much except that it exists.
We will talk about the eye movements you can make under voluntary control, smooth pursuit allows you to track this laser pointer across the screen.
Saccadic eye movements are ones that you make to look rapidly around a room, and interestingly they have the same characteristics of the quick phases of nystagmus that are present in just about all vertebrates. Saccades as we know them as we bring our fovea on objects of interest are particularly well-developed in humans and non-human primates.
Finally, vergence of eye movements are the ones you can make to look at objects at different distances.
Functional classes of eye movements (cont.) [S10]
Also accommodation which is able to focus the image on the fovea unless you are older and presbyopic and the lens gets harder and you can no longer focus objects on the fovea as well.
The pupillary light reflex controls illumination of the retina. It also controls depth of focus of the image but we won’t worry about that.
Vestibular responses [S11]
If you don’t have intact VOR it is hard to even read because of head movements due to heartbeat and other spontaneous movements.
Specifically, if your head turns in one direction with a specific velocity, your eyes will turn an equal and opposite amount in the opposite direction. If the gain, or relationship, between head movement and eye movement is 1, which means that for a 10 degree head movement you get a 10 degree eye movement.
The other thing you should not is that there is this head movement that causes a signal from the vestibular apparatus which is a velocity signal that reaches the motor neurons, but the other thing is that after you have made this head movement, your head is stationary at a new position but your eyes don’t drift back to primary position. Your eyes move and stay there, so the brain has to generate a signal to hold the eyes in a new position, and so a tonic signal which is proportional to the mathematical integral of the eye velocity (a position signal). The neuronal population will take the velocity signal and turn it into a position signal to hold the eyes in the appropriate new position. So the eye movement system for VOR is a little more complicated than generating an eye velocity signal, it generates an eye velocity signal to move the eyes in the orbit, and then there is a tonic signal to hold the eyes in that new position.
So both a velocity and a tonic signal, and we will see which neurons in the brain are responsible for generating those signals.
[S12] skipped
Sinusoidal oscillation in the dark [S13]
You can put a person in a chair and rotate them left and right instead of having them move their head and if you look at the chair velocity (bottom wave) you will see that it does this and if you look at the eye velocity (middle wave) you will see that it does the equal and opposite thing. 180 degrees out of phase.
The input is head velocity and the output is eye velocity which is 180 degrees out of phase, and the relationship between the eye velocity and chair velocity is called the gain. So if the peak eye velocity matches the peak chair velocity that would be a gain of one. On the other hand if the eye velocity was about 0.5 that of the chair velocity, the gain would be 0.5 so you can measure how effective the gain of the VOR is under certain circumstances.
In many cases for normal rapid head movements, the gain is close to one.
VOR gain is low at low frequencies [S14]
But, for very slow head movements, as the frequency of the head movement gets lower, the gain drops.
As long as the head movement is relatively quick the gain is fine, but if it slows down the gain reduces.
It therefore needs to be compensated for by a different system.
Vestibulo-ocular reflex [S15]

a. To reiterate, the VOR is what for rapid head turns ensures that the eyes move in the equal and opposite direction.

b. Last lecture, we went through the idea that there is an increase in firing rate in this case for rightward head turns. This is the projection to the medial vestibular nucleus and it is showing an inhibitory connection to the ipsilateral abducens nucleus and excitatory connection to the contralateral abducens nucleus, so that when there is an increase in firing in the vestibular apparatus on one side there is a net increase in firing in the lateral rectus motor neurons on the left and on the medial rectus motor neurons on the right, and a decrease firing for the lateral rectus motor neurons on the right and a decrease firing for the medial rectus motor neurons on the left resulting in a head turn to the right producing eye movements to the left.

Sagittal section of brain [S16]
This is a sagittal section through a Rhesus monkey brain showing the MLF, cerebellum, the sixth nerve nucleus with the sixth nerve coming out, and the third nerve nucleus.
There are important regions of the brain that are involved in specific control of horizontal eye movements and those are shown, and vertical eye movements, but mainly this is to emphasize where the sixth nerve nucleus is and the MLF and oculomotor nucleus.
We will now talk a little about the second system that stabilizes the eye before we come back and fill out the details on this diagram.
Functional classes of eye movements [S17]
So the other system that is important in addition to the vestibular system is the optokinetic system which stabilizes your eyes when your vestibular system has adapted or your responses of the head movements are really slow.
Optokinetic responses. The world drifts without them. [S18]
Basically, when large field stimuli moves, the eyes tend to follow along. Like in an IMAX theater where the visual world moves up and you feel as if you are falling, those were optokinetic response.
Normally when the whole world moves up, you are falling or moving down, so you interpret whole-field stimuli as being movements of the world down, but your eyes tend to follow those whole-field movements.
So in the vestibular system when you move your head left and right, if the vestibular system is not causing the appropriate compensatory eye movements then the visual world will tend to move. So when you look at the wall and shake your head, the wall is not moving because the VOR gain is about one, but if the gain was low, every time you turned your head the wall would move back and forth.
So if the VOR gain is not one, when you move your head a certain amount in one direction, the whole world appears to move in the opposite direction, and that’s not good so what will happen is that your eye movements will tend to detect any of the whole-field movement and generate compensatory eye movements.
Brain diagram [S19] skipped
Dots demonstration [S20, S21]
Dots are moving from left to right.
When the dots stop moving and disappear, the fixation cross looks as if it is moving to the left.
What was happening is that your eyes were tracking the flow field slightly and that is a typical optokinetic response.
Vestibular nucleus neuron [S22]
It turns out that the vestibular responses that come from the vestibular apparatus are combined with the optokinetic responses in the vestibular nuclei. So this diagram, if you record from the vestibular nucleus neuron during a sustained rotation in the dark, so shown is a brief acceleration and there is a continual velocity for about 60 seconds. If you continue to spin with a constant velocity for about 60 seconds, what happens is that the initial response to the acceleration is there because in the semicircular canals the fluid is pushing on the cupula and during the initial surge you will get a signal from the vestibular nerve and there is going to be a strong vestibular signal in the nucleus.
Now as you maintain that rotation, the system adapts and everything settles back down because there is no acceleration occurring even though you are going at a constant velocity, and because there is no acceleration the vestibular system adapts back down.
If you spin around for 60 seconds and then stop, you would see the eyes moving in the opposite direction, nystagmus in the opposite direction. Your eyes cannot do a 360 degree rotation in the orbit, so as head rotates your eyes will do an equal and opposite turn in the other direction, then once they get to a certain position they will do a fast reset, which is the quick phase, and then they will come back because they need to quickly reset then follow then quickly reset then follow. So you see this characteristic movement during a sustained rotation which slowly decays and at this point if you were rotating after about 60 seconds the eyes would no longer be moving in the orbit the VOR would nearly be absent at this point. But after you stopped spinning the eyes go back in the equal and opposite direction and show this post-rotatory nystagmus.
Even though you have stopped spinning the eyes keep moving, which is not great for normal vision but that is just the characteristics of rotation in darkness.
BUT if you take the individual and rotate them in light, then what happens is that their vestibular response jumps up during the rotation and it stays there for the entire duration of the rotation. It turns out that is because in the light the visual world can be seen to be moving and it contains the optokinetic responses for the whole 60 seconds of the spinning. And you can show that these cells in the vestibular nuclei receive these optokinetic stimuli because in this case there is no rotation, the animal was sitting stationary but the whole world flowed (like the IMAX experience). The reason you get the sensation of falling when the whole world moves up is that the neurons in your vestibular nucleus are actually activated by optokinetic stimuli and it feels as though the vestibular system is being stimulated and it gets this sensation of movement which is what the IMAX directors rely on.
So those signals are actually combined in the vestibular nuclei: vestibular and optokinetic.
Vestibular-optokinetic interactions [S23]
NOT RESPONSIBLE FOR THIS SLIDE
When you are rotating in the dark, that response is called a rotatory nystagmus: the eye movements will be moving to try to compensate for the movements then resetting, moving then resetting.
After that rotation, there is a phenomenon called post-rotatory nystagmus. So the post-rotatory nystagmus means that after you have been spinning in the dark, imagine you are chasing someone in a dark room, and you suddenly stop and your eyes keep moving. The optokinetic system interestingly produces optokinetic responses, where right after the optokinetic stimulus ends there is optokinetic after-nystagmus. That is due to visual field motion, and when these two signals are combined in the vestibular nucleus, the net result is that your eyes move appropriately during the movement and stop when the head motion isn’t occurring.
So the after-nystagmus is there to offset the post-rotatory nystagmus, and the reason for that is pretty straight forward, it’s just mechanical. As you continue to spin the fluid in the semicircular canals stops putting pressure on the cupula, and then when you stop it goes back in the other direction just a purely mechanical phenomenon, so this system is set up to compensate for basically the characteristics of the semicircular canal, just basic physics.

SQ: If you chase someone at night what happens?