Saccadic Burst Neurons Research Articles

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.

Abstract 265: A Curious Case Of Acute Binocular Diplopia, Ischemic Stroke Of The Interstitial Nucleus Of Cajal

Introduction The nuclei in the periaqueductal gray of the midbrain are critical structures that coordinate and control vertical and torsional gaze, as well as crucial components of the vestibulo‐occular reflex. These structures are so fine that they may be missed on routine imaging however, they represent distinct localizations for the neurological exam, with lesions of these structures being important clinical considerations. The Interstitial Nucleus of Cajal (inC) coordinates signals from the saccadic burst neurons in the rostral interstitial nucleus of the medial longitudinal fasiculus (riMLF), vestibular projections (utricular and semicircular canal pathways from the vestibular nuclei via the MLF), and descending pursuit fibers, the paired interstitial nuclei of Cajal act as neural integrators for vertical gaze and torsion. These nuclei lie adjacent but dorsal and caudal to the riMLF, For upgaze, fibers from the inC cross via the posterior commissure, then connect to the contralateral superior rectus and inferior oblique subnuclei. For downgaze, fibers travel across the posterior commissure, then innervate the contralateral inferior rectus subnucleus and fourth nerve nucleus. Blood supply is derived from the terminal branches of the basilar artery. Lesions of these interstitial nuclei and their tracts may produce vertical and torsional gaze‐holding deficits such as impairments in the vertical vestibulo‐occular reflex, hypertropia, counter‐rolling of the eyes, superior oblique palsy, and see‐saw and torsional nystagmus. Methods Case report and review of literature Results 45‐year‐old, right‐handed woman with history of turner syndrome, anemia, nephrolithiasis, horseshoe kidney, premature ovarian failure on hormone replacement therapy (HRT), suspected adrenal mass of undetermined significant, and degenerative disk disease presented to the emergency department with complaints of acute binocular diplopia and dizziness clarified to be sensation of the ground/objects bobbing in visual field. Neurological exam significant for left hypertropia and exotropia in primary gaze, equal in right/left gaze and right/left head tilt, as well as large amplitude medium frequency (see‐saw) nystagmus characterized by upbeat nystagmus with intorsion on the right, and downbeat nystagmus with extorsion left. Visual fields were intact to finger count with binocular diplopia and oscillopsia noted in primary gaze. CT head and CT angiogram of the head and neck were unrevealing. Initial MRI brain negative for diffusion restriction but with flair hyperintensity in periaqueductal gray prompting repeat MRI brain without contrast with thin slices through the brainstem with showed infarct in periaqueductal gray within the region of the interstitial nuclei, with stroke etiology undetermined at the time of presentation but suspicion of small vessel disease vs hypercoagulability given propensity for thrombophilia in Turner syndrome and patient being on HRT. Full dose aspirin and high intensity statin therapy was initiated given presentation out of tPA window, and hypercoagulability workup initiated prior to discharge. Conclusion Acute ischemic stroke and lesions of the interstitial nuclei in the periaqueductal gray are important, under recognized considerations for the evaluation of binocular diplopia, that may represent an opportunity for thrombolytic administration if providers had a higher index of suspicion. Hypercoagulability and Turner syndrome are also unique qualifiers, underscoring a nuanced approach to determination of stroke diagnosis and etiology in cases of isolated ocular symptomology.

Opsoclonus Induced by Head-Shaking in Vestibular Migraine.

Opsoclonus refers to saccadic oscillations without an intersaccadic interval occurring in multiple planes. Opsoclonus mostly indicates dysfunction of the brainstem or cerebellum. We report opsoclonus induced by horizontal head-shaking without other signs of brainstem or cerebellar dysfunction in two patients with vestibular migraine (VM). The development of opsoclonus after horizontal head-shaking indicates unstable or hyperactive neural circuits between the excitatory and inhibitory saccadic premotor burst neurons in these patients with VM.

Saccadic premotor burst neurons and histochemical correlates of their firing patterns in rhesus monkey

Bursting behavior of brainstem premotor burst neurons (BNs) is essential for initiation of saccades and calibrating their metrics. Several ion channel families such as voltage-gated potassium (Kv) channels, low-voltage-activated calcium (Cav3) channels and hyperpolarization-activated cyclic nucleotide–gated (HCN) channels are major regulators of the bursting in neurons. Therefore, it was speculated that ion channels with rapid kinematics are essential for characteristic firing patterns of the BNs and rapid saccade velocities. However, the expression patterns of ion channels are yet to be confirmed. Confirmation would not only support the neuromimetic model predictions for saccade generation in brainstem, but also contemporary views that channelopathies can cause saccade disorders in humans. As proof of concept, we examined excitatory BNs in the rostral interstitial nucleus of medial longitudinal fasciculus (RIMLF, vertical saccades) and inhibitory BNs in nucleus paragigantocellularis dorsalis (PGD, horizontal saccades) histochemically in macaque monkeys. We found strong expression of Kv channels, which enable rapid-firing, as well as HCN1&2 and Cav3.2&3.3, which enable post-inhibitory rebound bursting, in both BN populations. Moreover, PGD was found to host multiple neuron groups in terms of calretinin immunoreactivity. Our results provide histochemical evidence that supports models proposing post-inhibitory rebound facilitates bursting in BNs. Furthermore, our findings support the notion that deductions can be made about electrophysiological firing properties by histochemical examination of functional groups within the brainstem saccadic circuitry. This development is an important building block supporting the concept of channelopathies in saccadic disorders. Future histological studies in humans will confirm this approach for saccadic disorders.

Ocular dipping movements in an electrocution cardiac arrest survivor

Background : Abnormal eye movements can occur in patients with neurological diseases. These have been described in unconscious patients due to anoxic coma and often disappear as the patient regains consciousness. Ocular dipping movements are rarely seen in practice in pediatric patients. Methods : A one year old male patient was brought unconscious with electrocution injury. With resuscitation, he became hemodynamically stable. He could not recognize his mother or respond to visual/auditory stimuli; and had generalized hypertonia. Cranial nerves were normal. He showed abnormal involuntary conjugate vertical saccadic eye movements, consisting of slow downward movement (for 1-2 seconds) followed by a relatively faster return to the primary mid-position. These persisted continuously for 48 hours at irregular intervals of 1-2 seconds. The patient was awake but non-responsive and not interested in surroundings. Results : These eye movements are called ocular dipping (OD) . In a normal person, saccadic movements are meant for stable fixation and are maintained by pause-cell neurons positioned in the pontine raphe. These prevent the occurrence of unwanted saccadic pulses by inhibiting the saccadic premotor burst neurons in the paramedian pontine reticular formation and midbrain. Injury to pause cells leads to extraneous saccades without fixation. It appears that cortical and basal ganglia malfunction causes ocular dipping. OD is mainly seen in anoxic coma and creuztfelt Jacob disease. A 53-year-old man developed ocular dipping following prolonged hypotension.Our patient was in vegetative state with normal respiratory and cardiac function suggesting that major midbrain and medullary centers were intact. Conclusion : The self limiting nature of OD suggests that these are caused by diffuse dysfunction rather than a single structural locus.

Velocity storage mechanism in zebrafish larvae

The optokinetic reflex (OKR) and the angular vestibulo-ocular reflex (aVOR) complement each other to stabilize images on the retina despite self- or world motion, a joint mechanism that is critical for effective vision. It is currently hypothesized that signals from both systems integrate, in a mathematical sense, in a network of neurons operating as a velocity storage mechanism (VSM). When exposed to a rotating visual surround, subjects display the OKR, slow following eye movements frequently interrupted by fast resetting eye movements. Subsequent to light-off during optokinetic stimulation, eye movements do not stop abruptly, but decay slowly, a phenomenon referred to as the optokinetic after-response (OKAR). The OKAR is most likely generated by the VSM. In this study, we observed the OKAR in developing larval zebrafish before the horizontal aVOR emerged. Our results suggest that the VSM develops prior to and without the need for a functional aVOR. It may be critical to ocular motor control in early development as it increases the efficiency of the OKR.

Ocular flutter in essential tremor: clinical course and response to primidone

Essential tremor (ET) is generally regarded as a benign monosymptomatic condition with tremor being the sole neurological manifestation. Structural brain abnormalities are not considered part of the syndrome. Over recent years, however, it has become increasingly clear that a cerebellar pathology might be involved in the disease process [1, 2]. Neuropathological studies associated Purkinje cell loss with ET [3], whereas brain imaging demonstrated in many cases atrophic changes in different lobules of the cerebellum [4]. It should be mentioned, however, that there are also studies which failed to show an association of ET and cerebellar pathology [5]. Reports on clinical cerebellar signs in ET are sparse [1, 6]. Here, we present an ET case exhibiting saccadic intrusions with features of ocular flutter (OF). A 74-year-old woman presented with gradual onset of hand tremor over the last three decades. The tremor worsened with stress or intense physical exercise and improved after ingestion of small amounts of alcohol. Her father had similar symptoms but never sought medical advice. She also complained of dizziness and oscillopsia lasting ‘‘a few seconds’’ many times a day for at least 10 years. On examination, a postural tremor of both hands, more pronounced on the left, was noted. Finger-to-nose test was slightly impaired, but heel–knee–shin was unremarkable. The eyes showed infrequent (1–2/min), rapid, conjugate, horizontal oscillations occurring in bursts, leading to the clinical diagnosis of OF. No other ocular motor abnormalities were noted. Recording of eye movements confirmed the clinical impression, showing bursts of fast phases without intersaccadic intervals (Fig. 1a). Intraburst frequency was 10 Hz, and interburst frequency was 0.5 Hz in a 4-min record. Surface electromyography (EMG) recordings of the wrist extensors revealed a postural tremor frequency of 6–6.5 Hz (Fig. 1c). We put the patient on primidone, slowly titrated up to a daily dose of 375 mg. Upon reexamination 2 months later, hand tremor had virtually disappeared (Fig. 1d), although the patient reported a mild tremor of the left hand during emotional excitement. Interestingly, ocular flutter was also absent both clinically and in a 7-min-long record (Fig. 1b). Importantly, she could not recall any oscillopsias in the last couple of weeks. OF is a pathological form of saccadic intrusions consisting of back-to-back horizontal saccades [7]. It is considered a subtype of opsoclonus, the former being characterized by multidirectional fast phases of varying amplitudes. The pathophysiology of OF and opsoclonus is still controversial. It is assumed that abnormal Purkinje cell activity in the cerebellum leads to reduced inhibition on the fastigial nucleus. This results in enhanced inhibition of brainstem omnipause neurons, which, in turn, renders saccadic burst neurons free to oscillate [8, 9]. Recent modeling, however, is based on a dysfunction of the brainstem saccadic generator while cerebellar abnormalities are believed to be secondary to brainstem oscillations [10]. Nonetheless, available functional neuroimaging data conform to the cerebellar hypothesis of OF genesis [11, 12]. The present case exhibited ocular flutter linked with mild oscillopsia for presumably more than 10 years. Thus, this long period largely rules out causes such as encephalitis or paraneoplastic disease. The fact that both tremor E. Anagnostou (&) E. Kararizou I. Evdokimidis Department of Neurology, Eginition Hospital, University of Athens, Vas. Sophias Avenue 74, 11528 Athens, Greece e-mail: granavan@yahoo.com

Isolated ocular flutter

A previously healthy 30-year-old man presented with gradually worsening oscillopsia 2 weeks after an unusual headache; there was ocular flutter on examination (video on the Neurology ® Web site at [www.neurology.org][1]) without other findings. Brain MRI was unremarkable. CSF showed mild pleocytosis (11 cells/mm3), but no evidence of active viral infections (herpes simplex virus, cytomegalovirus, varicella-zoster virus, Epstein-Barr virus, human herpesvirus 6, and measles). Serum antiganglioside antibodies (including anti-GQ1b antibody) were negative. The symptom resolved without treatment within 4 weeks. Ocular flutter is rare and may be isolated, although it is usually accompanied by generalized myoclonus or truncal ataxia.1,2 Brainstem (omnipause neurons in the paramedian pontine reticular formation3) or cerebellar dysfunction may contribute, as may abnormal pause cell control over saccadic burst neurons. [1]: http://www.neurology.org

Simple spatio-temporal transformation with sub-threshold integration in the saccadic system

Saccades are the fast eye movements dedicated to sight orientation toward targets. Robinson [1] suggested a model based on feedback control according to an internally estimated motor error relying on a integrator. Although supported by numerous behavioral studies, this principle is still in search of biological confirmation. Indeed, neurophysiological data has not yet uncovered all the details of the complex circuitry supporting saccade control. The displacement command is monitored by a brief pulse of activity emitted by saccadic burst neurons of the brain stem resulting in a stereotypic duration/velocity relationship (the main sequence). Burst neurons are under the control of the deep layers of the superior colliculus (SC) which encode saccade command as a focal burst of activity on a bidimensional retinotopic map. The transformation from bidimensional activity toward a precise burst is called the spatio-temporal transformation [2]. The many functional models that have been proposed [3] reproduce most of the robustness to perturbation observed, but lack in neuronal implementation details. Most of all, the integrator appears delicate to simulate with realistic neurons. Our proposition is that this integration component could simply rely on neuronal sub-threshold membrane integration with appropriate membrane time constant. The model we present is built with realistic spiking neurons (excitatory and inhibitory LIF neurons with reverse potentials - Damned simulator [4]). The general scheme is inspired from simple principles exposed in [5] suggesting that duration and velocity may be coded by two independent tracks from the colliculus (Dual path principle) [6]. The model comprise a complete SC topographic map and the path from the map to premotor burst neurons, including central mesencephalic reticular formation (cMRF) and omni-pause neurons (OPN). With appropriate projections, saccadic pre-motor activity is produced at the output of the system. Most of state-of-the-art properties are obtained :spatio-temporal transformation, component stretching, staircase saccades, etc. Our model also suggests distinct roles taken by ipsilateral and contralateral cMRF: contralateral cMRF could play the role of a gate silencing the OPN and allowing the burst neurons to start spiking, while ipsilateral cMRF would integrate the signal from SC and emit a brief burst of spikes at the end of saccade, as observed in [7].

The role of the medial longitudinal fasciculus in horizontal gaze: tests of current hypotheses for saccade-vergence interactions

Rapid shifts of the point of visual fixation between equidistant targets require equal-sized saccades of each eye. The brainstem medial longitudinal fasciculus (MLF) plays a cardinal role in ensuring that horizontal saccades between equidistant targets are tightly yoked. Lesions of the MLF--internuclear ophthalmoparesis (INO)--cause horizontal saccades to become disjunctive: adducting saccades are slow, small, or absent. However, in INO, convergence movements may remain intact. We studied horizontal gaze shifts between equidistant targets and between far and near targets aligned on the visual axis of one eye (Müller test paradigm) in five cases of INO and five control subjects. We estimated the saccadic component of each movement by measuring peak velocity and peak acceleration. We tested whether the ratio of the saccadic component of the adducting/abducting eyes stayed constant or changed for the two types of saccades. For saccades made by control subjects between equidistant targets, the group mean ratio (±SD) of adducting/abducting peak velocity was 0.96 ± 0.07 and adducting/abducting peak acceleration was 0.94 ± 0.09. Corresponding ratios for INO cases were 0.45 ± 0.10 for peak velocity and 0.27 ± 0.11 for peak acceleration, reflecting reduced saccadic pulses for adduction. For control subjects, during the Müller paradigm, the adducting/abducting ratio was 1.25 ± 0.14 for peak velocity and 1.03 ± 0.12 for peak acceleration. Corresponding ratios for INO cases were 0.82 ± 0.18 for peak velocity and 0.48 ± 0.13 for peak acceleration. When adducting/abducting ratios during Müller versus equidistant targets paradigms were compared, INO cases showed larger relative increases for both peak velocity and peak acceleration compared with control subjects. Comparison of similar-sized movements during the two test paradigms indicated that whereas INO patients could decrease peak velocity of their abducting eye during the Müller paradigm, they were unable to modulate adducting velocity in response to viewing conditions. However, the initial component of each eye's movement was similar in both cases, possibly reflecting activation of saccadic burst neurons. These findings support the hypothesis that horizontal saccades are governed by disjunctive signals, preceded by an initial, high-acceleration conjugate transient and followed by a slower vergence component.

Local Neural Processing and the Generation of Dynamic Motor Commands within the Saccadic Premotor Network

The ability to accurately control movement requires the computation of a precise motor command. However, the computations that take place within premotor pathways to determine the dynamics of movements are not understood. Here we studied the local processing that generates dynamic motor commands by simultaneously recording spikes and local field potentials (LFPs) in the network that commands saccades. We first compared the information encoded by LFPs and spikes recorded from individual premotor and motoneurons (saccadic burst neurons, omnipause neurons, and motoneurons) in monkeys. LFP responses consistent with net depolarizations occurred in association with bursts of spiking activity when saccades were made in a neuron's preferred direction. In contrast, when saccades were made in a neuron's nonpreferred direction, neurons ceased spiking and the associated LFP responses were consistent with net hyperpolarizations. Surprisingly, hyperpolarizing and depolarizing LFPs encoded movement dynamics with equal robustness and accuracy. Second, we compared spiking responses at one hierarchical level of processing to LFPs at the next stage. Latencies and spike-triggered averages of LFP responses were consistent with each neuron's place within this circuit. LFPs reflected relatively local events (<500 microm) and encoded important features not available from the spiking train (i.e., hyperpolarizing response). Notably, quantification of their time-varying profiles revealed that a precise balance of depolarization and hyperpolarization underlies the production of precise saccadic eye movement commands at both motor and premotor levels. Overall, simultaneous recordings of LFPs and spiking responses provides an effective means for evaluating the local computations that take place to produce accurate motor commands.

Opsoclonus-Myoclonus Syndrome in Patients With Locked-in Syndrome: A Therapeutic Porthole With Gabapentin

Patients with locked-in syndrome, although fully conscious, have quadriplegia, mutism, and lower cranial nerve paralysis. The preservation of vertical gaze and upper eyelid movements usually enables them to interact with the environment through an eye-coded communication. However, locked-in syndrome may be complicated by the development of an opsoclonus-myoclonus syndrome that may represent an additional impediment to communication. We evaluated whether off-label treatment with gabapentin could help patients with locked-in syndrome and opsoclonus-myoclonus symptoms regain voluntary control of full eye movements. A mechanism responsible for gabapentin-induced improvement has been also hypothesized. In this study, 4 patients presenting with locked-in syndrome complicated by opsoclonus-myoclonus syndrome were continuously treated with gabapentin up to 1200 mg/d. The treatment resulted in a rapid and long-lasting resolution of opsoclonus-myoclonus symptoms without adverse effects. After 2 weeks, patients showed voluntary attempts to communicate through eye blinking and thereafter regained voluntary control of full eye movements. This event enabled them to regain a communication channel with relatives and physicians and to start using eye-controlled brain-computer interfaces. Because of its effectiveness in restoring eye movement control, gabapentin opened a communicative porthole in the patients' lives. Since opsoclonus may be related to disorders of the inhibitory control of saccadic burst neurons by pontine pause cells, we hypothesize that gabapentin acts as a regulator of saccadic circuits.

Macaque Pontine Omnipause Neurons Play No Direct Role in the Generation of Eye Blinks

We recorded the activity of pontine omnipause neurons (OPNs) in two macaques during saccadic eye movements and blinks. As previously reported, we found that OPNs fire tonically during fixation and pause about 15 ms before a saccadic eye movement. In contrast, for blinks elicited by air puffs, the OPNs paused <2 ms before the onset of the blink. Thus the burst in the agonist orbicularis oculi motoneurons (OOMNs) and the pause in the antagonist levator palpabrae superioris motoneurons (LPSMNs) necessarily precede the OPN pause. For spontaneous blinks there was no correlation between blink and pause onsets. In addition, the OPN pause continued for 40-60 ms after the time of the maximum downward closing of the eyelids, which occurs around the end of the OOMN burst of firing. LPSMN activity is not responsible for terminating the OPN pause because OPN resumption was very rapid, whereas the resumption of LPSMN firing during the reopening phase is gradual. OPN pause onset does not directly control blink onset, nor does pause offset control or encode the transition between the end of the OOMN firing and the resumption of the LPSMNs. The onset of the blink-related eye transients preceded both blink and OPN pause onsets. Therefore they initiated while the saccadic short-lead burst neurons were still fully inhibited by the OPNs and cannot be saccadic in origin. The abrupt dynamic change of the vertical eye transients from an oscillatory behavior to a single time constant exponential drift predicted the resumption of the OPNs.

Oculomotor disorders in adult-onset Still’s disease

A patient with adult-onset Still’s disease (AOSD) developed periodic horizontal micro-saccadic oscillations and periodic rapid clockwise torsional eye movements followed by counterclockwise torsional drifts (see video). Neuroimaging studies were normal. Tests for paraneoplastic antibodies were negative. Details of the clinical presentation and experimental methods are presented in supplementary material 1. Horizontal saccades were faster than normal (supplementary material 2). There were bursts of horizontal saccadic oscillations without intersaccadic intervals (21.6 ± 0.4 Hz) and clockwise rapid torsional eye movement (top pole rotating towards the right ear) that had the same peak velocity-amplitude relationship as torsional quick phases of nystagmus (Fig. 1). These rapid torsional movements were followed by a drift (0.8 ± 0.2 deg/s) that brought the eyes to baseline. Low-frequency vertical and torsional oscillations were also seen (median: 3.4 and 3.1 Hz, respectively; Fig. 1b, d). The onset of rapid torsion and the horizontal saccadic oscillations were not always related (i.e., torsion did not trigger the horizontal oscillations or vice versa) (Fig. 2a). The median frequency of the pathological, spontaneous, horizontal saccadic oscillations during fixation (26.3 Hz) was not significantly different from the frequency of the physiological horizontal saccadic oscillations that are seen during orthogonal (vertical) saccades (21.9 Hz) (One-way ANOVA: p = 0.2) [6]. The median peak velocity of the pathological horizontal saccadic oscillations (14.8 deg/s) was significantly less than that of the corresponding horizontal saccadic oscillations during orthogonal (vertical) saccades (37.8 deg/s: One-way ANOVA: p 0.001; Fig. 2c). The median frequencies of the vertical (3.4 Hz) and torsional (3.1 Hz) pathological oscillations were lower than the corresponding frequencies of torsional (22.9 Hz) or vertical (21.6 Hz) oscillations during orthogonal (horizontal) saccades (One-way ANOVA: p 0.001; not shown in figure). A hypothesis to explain the pathophysiology of periodic saccadic oscillations in our patient is that saccadic burst neurons, excitatory burst neurons (EBN) and inhibitory burst neurons (IBN), comprise a reciprocally innervated premotor circuit. Their membranes contain ion channels that are important for the rebound increase in neural firing after transient external inhibition—post-inhibitory rebound (PIR) [4, 9]. Such reciprocal innervation and PIR make this neural circuit prone to oscillate [2, 3, 5–7]. We speculate that in our patient an immune mediated abnormal increase in the excitability of the burst neurons (either by reducing inhibition or increasing excitation) led to the bursts of pathological microsaccadic oscillations. Since the pattern of oculomotor dysfunction in our patient is not seen in all AOSD patients, just the presence of an immune mediated effect on burst neurons may not be sufficient to increase their excitability enough to cause oscillations. The patient might also need the appropriate genetic background (i.e., a Electronic supplementary material The online version of this article (doi:10.1007/s00415-009-5308-y) contains supplementary material, which is available to authorized users.

Ocular flutter associated with a lesion of the right upper pontine tegmentum

Ocular flutter is a relatively rare eye movement disorder characterized by intermittent bursts of conjugate horizontal saccades without an intersaccadic interval. Its anatomical and neurophysiological basis remains controversial. Here we present a case of ocular flutter in which the flutter declined as the clinical stage of the associated ailment declined, until it eventually disappeared. Radiological examination revealed a tiny lesion in the right upper pontine tegmentum that included areas of the reticular formation, superior cerebellar peduncle and locus ceruleus. Because the lesion occupied the upper part of the paramedian pontine reticular formation, it did not contain omnipause neurons, which would seem to contradict a previously hypothesized explanation for ocular flutter: loss of pause cell control over saccadic burst neurons. On the other hand, we found no lesion in the area of the deep cerebellar nuclei; instead, the lesion was in the path of the projection from the fastigial nucleus to the brainstem saccadic generator. This is consistent with the idea that, in this case, there is impaired control by the cerebellar fastigial nucleus, especially of the horizontal saccadic system.

Role of Glycinergic Inhibition in Shaping Activity of Saccadic Burst Neurons

The immediate premotor signals for saccades are created at the level of medium-lead burst neurons (MLBNs). During fixations, MLBNs receive tonic inhibition from omnipause neurons (OPNs), which use glycine as a neurotransmitter. To elucidate the role of this inhibition, we studied discharge patterns of horizontal MLBNs following iontophoretic application of strychnine, a glycine-receptor antagonist, in alert cats. Three-barrel micropipettes were used for extracellular recording and iontophoresis. After application of strychnine, MLBNs exhibited spontaneous discharge and visual responses during intersaccadic intervals. Spikes were evoked by single-pulse stimulation of the contralateral superior colliculus (SC). These results show that MLBNs receive substantial excitatory input during intersaccadic intervals and that inhibitory action of OPNs is indeed necessary to prevent MLBNs from firing. Strychnine also affected saccade-related activity of MLBNs. The burst of activity, as in normal conditions, declined rapidly before the end of saccades but was followed by low rate spike activity, which continued beyond the end of saccades. This suggests that in normal conditions, the termination of saccades is determined by resumed inhibitory action of OPNs and not by termination of excitatory input to MLBNs. In addition, the firing rate and the number of spikes during saccades increased after strychnine application, suggesting that MLBNs receive glycinergic inhibition of non-OPN origin as well. We conclude that glycinergic inhibition plays essential roles in the maintenance of stable fixation, the termination of saccades, and the regulation of saccade size and velocity.

Saccadic Burst Cell Membrane Dysfunction Is Responsible for Saccadic Oscillations

Saccadic oscillations threaten clear vision by causing image motion on the retina. They are either purely horizontal (ocular flutter) or multidimensional (opsoclonus). We propose that ion channel dysfunction in the burst cell membrane is the underlying abnormality. We have tested this hypothesis by simulating a neuromimetic computational model of the burst neurons. This biologically realistic model mimics the physiologic properties and anatomic connections in the brainstem saccade generator. A rebound firing after sustained inhibition, called post-inhibitory rebound (PIR), and reciprocal inhibition between premotor saccadic burst neurons are the key features of this conceptual scheme. PIR and reciprocal inhibition make the circuits that generate the saccadic burst inherently unstable and can lead to oscillations unless stabilized by external inhibition. Our simulations suggest that alterations in membrane properties that lead to an increase in PIR, a reduction in external glycinergic inhibition, or both can cause saccadic oscillations.

Dynamic Coding of Vertical Facilitated Vergence by Premotor Saccadic Burst Neurons

To redirect our gaze in three-dimensional space we frequently combine saccades and vergence. These eye movements, known as disconjugate saccades, are characterized by eyes rotating by different amounts, with markedly different dynamics, and occur whenever gaze is shifted between near and far objects. How the brain ensures the precise control of binocular positioning remains controversial. It has been proposed that the traditionally assumed "conjugate" saccadic premotor pathway does not encode conjugate commands but rather encodes monocular commands for the right or left eye during saccades. Here, we directly test this proposal by recording from the premotor neurons of the horizontal saccade generator during a dissociation task that required a vergence but no horizontal conjugate saccadic command. Specifically, saccadic burst neurons (SBNs) in the paramedian pontine reticular formation were recorded while rhesus monkeys made vertical saccades made between near and far targets. During this task, we first show that peak vergence velocities were enhanced to saccade-like speeds (e.g., >150 vs. <100 degrees/s during saccade-free movements for comparable changes in vergence angle). We then quantified the discharge dynamics of SBNs during these movements and found that the majority of the neurons preferentially encode the velocity of the ipsilateral eye. Notably, a given neuron typically encoded the movement of the same eye during horizontal saccades that were made in depth. Taken together, our findings demonstrate that the brain stem saccadic burst generator encodes integrated conjugate and vergence commands, thus providing strong evidence for the proposal that the classic saccadic premotor pathway controls gaze in three-dimensional space.

The Brain Stem Saccadic Burst Generator Encodes Gaze in Three-Dimensional Space

When we look between objects located at different depths the horizontal movement of each eye is different from that of the other, yet temporally synchronized. Traditionally, a vergence-specific neuronal subsystem, independent from other oculomotor subsystems, has been thought to generate all eye movements in depth. However, recent studies have challenged this view by unmasking interactions between vergence and saccadic eye movements during disconjugate saccades. Here, we combined experimental and modeling approaches to address whether the premotor command to generate disconjugate saccades originates exclusively in "vergence centers." We found that the brain stem burst generator, which is commonly assumed to drive only the conjugate component of eye movements, carries substantial vergence-related information during disconjugate saccades. Notably, facilitated vergence velocities during disconjugate saccades were synchronized with the burst onset of excitatory and inhibitory brain stem saccadic burst neurons (SBNs). Furthermore, the time-varying discharge properties of the majority of SBNs (>70%) preferentially encoded the dynamics of an individual eye during disconjugate saccades. When these experimental results were implemented into a computer-based simulation, to further evaluate the contribution of the saccadic burst generator in generating disconjugate saccades, we found that it carries all the vergence drive that is necessary to shape the activity of the abducens motoneurons to which it projects. Taken together, our results provide evidence that the premotor commands from the brain stem saccadic circuitry, to the target motoneurons, are sufficient to ensure the accurate control shifts of gaze in three dimensions.

A new familial disease of saccadic oscillations and limb tremor provides clues to mechanisms of common tremor disorders

Tremor disorders pose fundamental questions about disease mechanisms, and challenges to successful neurotherapeutics: What causes motor circuits to oscillate in disorders in which the central nervous system otherwise seems normal? How does inheritance 'determine' the clinical phenotype in familial tremor disorders? Here, we address these questions. Analogies between the neural circuits controlling rapid eye movements (saccades) and those controlling limb movements allow us to translate the interpretations from the saccadic systems to the limb movement system. Moreover, the relatively well understood neurophysiology of the ocular motor system offers a unique opportunity to test specific hypotheses about normal and abnormal motor control of both eye and limb movements. We describe a new familial disorder--'micro-saccadic oscillations and limb tremor (microSOLT)'--in a mother and daughter who had tiny saccadic oscillations of the eyes and tremor of the hands. This unique oscillatory movement disorder resembles other common tremor disorders (such as essential tremor) that occur in patients who have an otherwise normally functioning central nervous system. We hypothesize that microSOLT is caused by an inherited abnormality that results in abnormal membrane properties causing reduced external inhibition in the premotor neurons that generate the high-frequency discharge (burst) for saccades and for ballistic limb movements. To test this hypothesis, we recorded hand tremor and eye movements in two patients with microSOLT and particularly during natural circumstances when inhibition of the premotor saccadic burst neurons is removed (e.g. eye closure). We then simulated a conductance-based model for the premotor commands which included excitatory and reciprocally inhibitory burst neurons. The structure of this physiologically realistic model was based upon known cell types and anatomical connections in the brainstem (for saccades) and the thalamus (for limb movements). The physiological phenomenon of post-inhibitory rebound in premotor burst neurons makes the circuit inherently unstable and prone to oscillate unless prevented by external inhibition. Indeed, with simulated reduction of external inhibition (in this case glycinergic), saccadic oscillations and limb tremor were reproduced. Our results suggest that a single-inherited deficit can alter membrane properties, which impairs inhibition in an inherently unstable neural circuit causing the eye and limb oscillations in microSOLT. This concept has broad implications for understanding the mechanism and designing rationale pharmacotherapy for abnormal oscillations and may be applicable to other common disorders in which there are no structural abnormalities in the brain such as essential tremor.