TMS Perturbs Saccade Trajectories and Unmasks an Internal Feedback Controller for Saccades

Author(s): Minnan Xu-Wilson, Jing Tian, Reza Shadmehr, David S. Zee

Summary: Transcranial magnetic stimulation (TMS) centrally perturbs saccades and these saccades are corrected for the perturbation within the movement providing further support for internal feedback control of saccadic eye movements.

Question(s): Can we observe online correction of saccadic eye movements after a central perturbation via TMS?

Abbreviations: Postinhibitory Rebound (PIR)

• Introduction
• Saccades are known to be highly variable beasts.
• However, they generally arrive on target (+- 1.0 deg)
• Motor commands may depending on any or all of the following, but are not limited to:
• Stimulus content
• Stimulus predictability
• Whether or not the stimulus covaries with the target of a reaching movement
• Motivation
• While arm movements can be perturbed via a force-field, it has been difficult to perform an analogous procedure on eye movements.
• Current Methods (and their drawbacks)
• Facial Stimulation
• Painful
• Loud Noise
• Uncomfortable
• Shows habituation
• Let's use TMS!
• Preliminary findings
• "When a single pulse is applied immediately before or during a saccade, it engages a startle-like neural reflex that briefly alters the ongoing oculomotor commands, slowing or even transiently stopping the eye movement."
• "Despite this perturbation, the movement is corrected with commands that arrive later in the same saccade, accurately steering the eyes close to the target even when the target stimulus is no longer visible."
• Materials and Methods
• n = 5, 3 M
• Visually guided saccades
• Materials
• Saccades
• Bite-bar (annoying)
• Scleral search coil (probably painful)
• f_s = 1000 Hz
• Filters
• Low-pass 90 Hz Butterworth on eye position signals
• 3rd order Savitzky-Golay applied to position signals to derive velocity and acceleration signals
• 0.2 deg red laser beam projected 1 meter away from subjects
• Used 500 Hz frame rate video and an EyeLink 1000 to corroborate findings from search coils
• TMS
• 2.2 Tesla
• Stimulation strength: 50% - 60%
• Stimulated Cz (using EEG 10-20 system coordinates)
• Methods
• 16 deg/s criteria for saccades
• Exclusion criteria
1. Amp < 67% of target displacement
2. 100 ms > saccade reaction time > 500 ms
3. Abnormal trajectories due to blinks
• Pause criteria
• 2 clear peaks in velocity profile
• Local minima < 50 deg/s
• Experiment 1: Saccade Onset
• Fixate for 1500-2300 ms
• TMS triggered when 30 deg/s velocity threshold reached
• happened only on 67% of trials (determined probabilistically)
• Confound? Only three out of five subjects were tested to determine whether the sound alone elicited a peturbation. Why not all five when in the introduction they state that this is a commonly used method to achieve the same end goal as their experiment?
• Experiment 2: During the Saccade
• Determine how timing of TMS affects saccade trajectories
• Used oblique saccades because these would provide a larger time window for TMS to take effect.
• Given on 70% of trials
• at 5, 15, 25, 35, 45 and 55 ms after saccade onset (i.e., velocity threshold reached).
• Experiment 3: Before the saccade
• Assumed 180 ms saccade latency
• Triggered TMS w.r.t. target onset randomly at 40, 60, or 80 ms before the expected saccade onset.
• Analysis:
• Grouped trials into bins according to the actual time of TMS before saccade onset.
• Modeling
• Ramat et al., 2005
• Components
• "Two coupled excitatory burst neuron (EBN) and inhibitory burst neuron (IBN) pairs..."
• "Burst neurons fired at a rate that depends on the size of hte difference between the current estimate of eye position and the target position..."
• "Motor error calculated by integrating the velocity output from the burst neurons and then subtracting this estimate of current eye position from the desired goal of the movement--the integration served as a state estimator, providing an ongoing internal feedback to the system..."
• "The burst neurons' membranes were modeled as high-pass filters with adaptation"
• Results

• Experiment 1
• In 74% of trials the TMS perturbed the saccade trajectory regardless of where the brain was stimulated
• Always in the form of a pause in the velocity profile
• Effected persisted for 32 ms before the eyes reaccelerated
• No difference in slowing time of vertical and horizontal components of oblique saccades.
• No habituation over sets of trials (a friend pointed out to me that this is like asking whether there was habituation of curare, but the authors reported the statistics used to test this effect so it seems like it's relevant somehow...)
• Paused Saccades
• The size of the compensatory movement was highly correlated with the remaining distance to the target.
• Visual condition (whether target was blanked on saccade) made NO difference in the time it took for resumed movement to start nor the quality of compensation for error during the pause
• Interestingly, the final amplitude of a perturbed saccade was, on average, larger than a control saccade by 0.83
• Oddities
• No-pause saccades (26%) elicited the following 2 properties:
• Their amplitudes were generally smaller than control saccades by 0.84 degrees
• Amplitudes were generally l.10 deg larger than the initial amplitudes of saccades that paused and resumed
• Anti-saccades were tested because the effect may have been due to the involuntary nature of so-called "pro" saccades
• During horizontal saccades no effect of eyelid perturbation was found on eye trajectory, thus the perturbation in the eye was caused by TMS not some interaction between the TMS and the eyelid.
• Lid saccade pauses and eye saccade pauses are highly correlated
• No evidence for head motion causing the observed effect
• Experiment 2
• TMS applied late in the time course of a saccade could stop the saccade altogether

Why are so few subjects used in this line of research? There are only 5 subjects in the study and most saccade studies do not have any more than that. In an experiment that a colleague of mine and I are working on we have 5-6 subjects per condition and that still seems low to me.

Interestingly, these guys found that saccades that were perturbed were slower yet hypermetric when compared with non TMS'ed saccades. They account for this by suggesting that during the pause period, the burst neurons are inhibited by reactivated OPNs, leading to greater firing rate of burst neurons after the pause period. This effect was not greater than the firing rates seen after saccades of the same size were made after a normal fixation. I don't really understand how the "inherent delay in the feedback loop does not allow for complete compensation of this overshoot" can account for the paradox of hypermetric saccades with smaller peak amplitudes than saccades not perturbed by TMS.

Phillip: Why is habituation not important?

Nate: It's possible that the authors are conflating the notion of stimulated the nervous system with TMS versus a stimulus evoking a response in the nervous system. Hmmm let's talk about this tomorrow.