Brainstem Neural Circuits Triggering Vertical Saccades and Fixation.

Neurons in the nucleus raphe interpositus have tonic activity that suppresses saccadic burst neurons (BNs) during eye fixations, and that is inhibited before and during saccades in all directions (omnipause neurons, OPNs). We have previously demonstrated via intracellular recording and anatomical staining in anesthetized cats of both sexes that OPNs are inhibited by BNs in the medullary reticular formation (horizontal inhibitory BNs, IBNs). These horizontal IBNs receive monosynaptic input from the caudal horizontal saccade area of the superior colliculus (SC), and then produce monosynaptic inhibition in OPNs, providing a mechanism to trigger saccades. However, it is well known that the neural circuits driving horizontal components of saccades are independent from the circuits driving vertical components. Thus, our previous results are unable to explain how purely vertical saccades are triggered. Here, we again apply intracellular recording to show that a disynaptic vertical IBN circuit exists, analogous to the horizontal circuit. Specifically, we show that stimulation of the SC rostral vertical saccade area produces disynaptic inhibition in OPNs, which is not abolished by midline section between the horizontal IBNs. This excludes the possibility that horizontal IBNs could be responsible for the OPN inhibition during vertical saccades. We then show that vertical IBNs in the interstitial nucleus of Cajal, which receive monosynaptic input from rostral SC, are responsible for the disynaptic inhibition of OPNs. These results indicate that a similarly functioning SC-IBN-OPN circuit exists for both the horizontal and vertical oculomotor pathways. These two IBN-mediated circuits are capable of triggering saccades in any direction.Significance Statement Saccades shift gaze to objects of interest, moving their image to the central retina, where it is maintained for detailed examination (fixation). During fixation, high gain saccade burst neurons (BNs) are tonically inhibited by omnipause neurons (OPNs). Our previous study showed that medullary horizontal inhibitory BNs (IBNs) activated from the caudal superior colliculus (SC) inhibit tonically active OPNs in order to initiate horizontal saccades. The present study addresses the source of OPN inhibition for vertical saccades. We find that OPNs monosynaptically inhibit vertical IBNs in the interstitial nucleus of Cajal during fixation. Those same vertical IBNs are activated by the rostral SC, and inhibit OPN activity to initiate vertical saccades.

Brainstem Circuits Triggering Saccades and Fixation.

Omnipause neurons (OPNs) in the nucleus raphe interpositus have tonic activity while the eyes are stationary ("fixation") but stop firing immediately before and during saccades. To locate the source of suppression, we analyzed synaptic inputs from the rostral and caudal superior colliculi (SCs) to OPNs by using intracellular recording and staining, and investigated pathways transmitting the inputs in anesthetized cats of both sexes. Electrophysiologically or morphologically identified OPNs received monosynaptic excitation from the rostral SCs with contralateral dominance, and received disynaptic inhibition from the caudal SCs with ipsilateral dominance. Cutting the tectoreticular tract transversely between the contralateral OPN and inhibitory burst neuron (IBN) regions eliminated inhibition from the caudal SCs, but not excitation from the rostral SCs in OPNs. In contrast, a midline section between IBN regions eliminated disynaptic inhibition in OPNs from the caudal SCs but did not affect the monosynaptic excitation from the rostral SCs. Stimulation of the contralateral IBN region evoked monosynaptic inhibition in OPNs, which was facilitated by preconditioning SC stimulation. Three-dimensional reconstruction of HRP-stained cells revealed that individual OPNs have axons that terminate in the opposite IBN area, while individual IBNs have axon collaterals to the opposite OPN area. These results show that there are differences in the neural circuit from the rostral and caudal SCs to the brainstem premotor circuitry and that IBNs suppress OPNs immediately before and during saccades. Thus, the IBNs, which are activated by caudal SC saccade neurons, shut down OPN firing and help to trigger saccades and suppress ("latch") OPN activity during saccades.SIGNIFICANCE STATEMENT Saccades are the fastest eye movements to redirect gaze to an object of interest and bring its image on the fovea for fixation. Burst neurons (BNs) and omnipause neurons (OPNs) which behave reciprocally in the brainstem, are important for saccade generation and fixation. This study investigated unsolved important questions about where these neurons receive command signals and how they interact for initiating saccades from visual fixation. The results show that the rostral superior colliculi (SCs) excite OPNs monosynaptically for fixation, whereas the caudal SCs monosynaptically excite inhibitory BNs, which then directly inhibit OPNs for the initiation of saccades. This inhibition from the caudal SCs may account for the omnipause behavior of OPNs for initiation and maintenance of saccades in all directions.

The unknown but knowable relationship between Presaccadic Accumulation of activity and Saccade initiation.

The goal of this short review is to call attention to a yawning gap of knowledge that separates two processes essential for saccade production. On the one hand, knowledge about the saccade generation circuitry within the brainstem is detailed and precise - push-pull interactions between gaze-shifting and gaze-holding processes control the time of saccade initiation, which begins when omnipause neurons are inhibited and brainstem burst neurons are excited. On the other hand, knowledge about the cortical and subcortical premotor circuitry accomplishing saccade initiation has crystalized around the concept of stochastic accumulation - the accumulating activity of saccade neurons reaching a fixed value triggers a saccade. Here is the gap: we do not know how the reaching of a threshold by premotor neurons causes the critical pause and burst of brainstem neurons that initiates saccades. Why this problem matters and how it can be addressed will be discussed. Closing the gap would unify two rich but curiously disconnected empirical and theoretical domains.

Source of high-frequency oscillations in oblique saccade trajectory.

Most common eye movements, oblique saccades, feature rapid velocity, precise amplitude, but curved trajectory that is variable from trial-to-trial. In addition to curvature and inter-trial variability, the oblique saccade trajectory also features high-frequency oscillations. A number of studies proposed the physiological basis of the curvature and inter-trial variability of the oblique saccade trajectory, but kinematic characteristics of high-frequency oscillations are yet to be examined. We measured such oscillations and compared their properties with orthogonal pure horizontal and pure vertical oscillations generated during pure vertical and pure horizontal saccades, respectively. We found that the frequency of oscillations during oblique saccades ranged between 15 and 40 Hz, consistent with the frequency of orthogonal saccadic oscillations during pure horizontal or pure vertical saccades. We also found that the amplitude of oblique saccade oscillations was larger than pure horizontal and pure vertical saccadic oscillations. These results suggest that the superimposed high-frequency sinusoidal oscillations upon the oblique saccade trajectory represent reverberations of disinhibited circuit of reciprocally innervated horizontal and vertical burst generators.

Acute vertical pendular nystagmus: eye-movement analysis and review of the literature.

Vertical pendular nystagmus (PN) rarely occurs with acute pontine lesions. To hypothesize a pathophysiology for acute vertical PN, we analyzed the clinical characteristics and quantitative eye-movement recordings of one new case with acute vertical PN and an additional 11 patients from the literature. Most patients had extensive pontine lesions causing either the locked-in syndrome or unresponsiveness, but two conscious patients had focal lesions restricted to the paramedian caudal pontine tegmentum. All patients presented a complete or partial horizontal gaze palsy, and about half showed ocular bobbing before or during the appearance of vertical PN. The vertical oscillations were conjugate at a frequency of 1-5 Hz, and the amplitudes were variable, ranging from 0.2° to 40°. The peak velocities were asymmetric in some patients, faster with downward movements. About half of the patients developed palatal tremor several weeks or months after presenting with acute vertical PN. Based on the location of the lesions and results of eye-movement recordings, we suggest two possible mechanisms for acute vertical PN; oscillations originating in the inferior olives due to disruption of the central tegmental tract or low-velocity saccadic oscillations caused by omnipause neuron damage.

Rituximab improves not only back stiffness but also "stiff eyes" in stiff person syndrome: Implications for immune-mediated treatment.

OBJECTIVE: Stiff person syndrome (SPS) is usually characterized by truncal muscle rigidity and episodic painful spasms, but it sometimes appears with ocular symptoms called "stiff eyes". We recorded saccade movements in an SPS patient manifesting with "stiff eyes" conditions with slow saccade velocity and evaluated the effect of immunotherapy including rituximab on saccade parameters. METHODS: We repeatedly conducted saccade eye recordings using video-based eye tracking system on a 42-year-old male SPS patient with slow saccade. The velocity and onset latency of visual guided saccades (VGS) were measured at each recording. Because VGS velocity is affected by saccade amplitude, estimated peak velocity (Vmax) was also calculated by taking the relationship between the velocity and the amplitude of saccade into account. RESULTS: The mean VGS velocity improved significantly after two courses of rituximab administration compared with its lowest value. The estimated Vmax decreased as the clinical manifestations worsened, but it increased after rituximab administration. Other neurological symptoms in this patient such as muscle rigidity and gait instability also improved after the treatment. CONCLUSION: Slow saccade in a "stiff eyes" patient improved after rituximab administration. Our study also indicated that the saccade eye recording is useful for evaluating the clinical condition of SPS when it is complicated with ocular symptoms.

Brainstem neural circuits for fixation and generation of saccadic eye movements.

We review neural connections of the superior colliculus (SC) and brainstem saccade-related neurons in relation to saccade generation mechanism. The caudal and rostral SC play a role in saccade generation and visual fixation, respectively. This functional differentiation suggests that different connections should exist between these two SC areas and their brainstem target neurons. We examined synaptic potentials evoked by stimulation of the rostral and caudal SC in inhibitory burst neurons (IBNs) and omnipause neurons (OPNs) in anesthetized cats. The caudal and rostral SC produced monosynaptic excitation and disynaptic inhibition in IBNs, respectively. Intracellular HRP staining showed that single IBNs sent their axons to abducens motoneurons, IBNs and OPNs on the opposite side. OPNs received monosynaptic excitation from the rostral SC, and disynaptic inhibition from the caudal SC via opposite IBNs. These neural connections are discussed in relation to the saccade triggering system and the model proposed by Miura and Optican.

What stops a saccade?

Rapid movements to a target are ballistic; they usually do not last long enough for visual feedback about errors to influence them. Yet, the brain is not simply precomputing movement trajectory. Classical models of movement control involve a feedback loop that subtracts 'where we are now' from 'where we want to be'. That difference is an internal motor error. The feedback loop reduces this error until it reaches zero, stopping the movement. However, neurophysiological studies have shown that movements controlled by the cerebrum (e.g. arm and head movements) and those controlled by the brain stem (e.g. tongue and eye movements) are also controlled, in parallel, by the cerebellum. Thus, there may not be a single error control loop. We propose an alternative to feedback error control, wherein the cerebellum uses adaptive, velocity feedback, integral control to stop the movement on target.This article is part of the themed issue 'Movement suppression: brain mechanisms for stopping and stillness'.