Saccadic Burst 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.

Cerebellar Degeneration Causing Saccadic Dysmetria and Ocular Flutter: A Seronegative Paraneoplastic Syndrome (P4-5.015)

<h3>Objective:</h3> To report a challenging case of a woman who developed eye movement abnormalities, progressive truncal, and gait ataxia due to a paraneoplastic syndrome. <h3>Background:</h3> Progressive cerebellar degeneration is a well-known paraneoplastic syndrome. However, it can be challenging to define phenotypically and diagnose in the absence of relevant antibodies. Response to treatment is often poor. <h3>Design/Methods:</h3> Case Report. <h3>Results:</h3> A 68-year-old woman presented with several months of moderately progressive truncal, gait ataxia, followed by development of saccadic hypermetria and ocular flutter. Her metastatic small cell lung cancer was in remission, and she no longer showed bilateral cerebellar metastases on brain MRI, following treatment with chemotherapy, durvalumab, and whole brain radiation. CSF analysis revealed lymphocytic pleocytosis (8/μL), normal protein, normal glucose, and 4 oligoclonal bands. Paraneoplastic antibodies from serum and CSF were negative. She was diagnosed with a probable paraneoplastic syndrome, based on a PNS-Care score of 7. She was treated with high dose intravenous methylprednisolone and plasmapheresis, with resolution of eye movement abnormalities, and improvement of ataxia. <h3>Conclusions:</h3> Subacute development of saccadic dysmetria and ocular flutter in this case helped define a new onset cerebellar syndrome in a patient with possible residual cerebellar dysfunction from prior cerebellar metastatic disease. Saccadic hypermetria is typically caused by dysfunction of the fastigial oculomotor region (FOR). In our case, ocular flutter might have been caused by indirect instability of the brainstem network due to impairment of the FOR projections to the omnipause neurons (OPN) in the pontine saccadic burst generator area. Even in the absence of relevant antibodies and in the setting of confounders such as prior cerebellar metastases, use of checkpoint inhibitors, clinical presentation and CSF findings should raise concern for a paraneoplastic disorder. Cerebellar paraneoplastic syndromes may respond to Immunotherapy with methylprednisolone and plasmapheresis. <b>Disclosure:</b> Dr. Zampino has nothing to disclose. Dr. Figgie has nothing to disclose. Dr. Shaikh has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Acorda. Dr. Serra has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Biogen Idec. Dr. Serra has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Bristol Myers Squibb.

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 Flutter in Parainfectious Meningoencephalitis: A Case Report

Ocular flutter is a rare, horizontal eye movement disorder characterized by intermittent bursts of conjugate horizontal saccades without intersaccadic intervals. It can occur in various clinical conditions such as metabolic dysfunction, infection and paraneoplastic syndrome. Herein, a 50-year-old male showed ocular flutter in parainfectious meningoencephalitis and immunoglobulin therapy led to an improvement of symptoms. This case can improve the understanding of the pathological mechanisms of ocular flutter.

Impairment but not abolishment of express saccades after unilateral or bilateral inactivation of the frontal eye fields.

Express saccades are a manifestation of a visual grasp reflex triggered when visual information arrives in the intermediate layers of the superior colliculus (SCi), which in turn orchestrates the lower level brainstem saccade generator to evoke a saccade with a very short latency (~100 ms or less). A prominent theory regarding express saccades generation is that they are facilitated by preparatory signals, presumably from cortical areas, which prime the SCi before the arrival of visual information. Here, we test this theory by reversibly inactivating a key cortical input to the SCi, the frontal eye fields (FEF), while monkeys perform an oculomotor task that promotes express saccades. Across three tasks with a different combination of potential target locations and unilateral or bilateral FEF inactivation, we found a spared ability for monkeys to generate express saccades, despite decreases in express saccade frequency during FEF inactivation. This result is consistent with the FEF having a facilitatory but not critical role in express saccade generation, likely because other cortical areas compensate for the loss of preparatory input to the SCi. However, we also found decreases in the accuracy and peak velocity of express saccades generated during FEF inactivation, which argues for an influence of the FEF on the saccadic burst generator even during express saccades. Overall, our results shed further light on the role of the FEF in the shortest-latency visually-guided eye movements.NEW & NOTEWORTHY Express saccades are the shortest-latency saccade. The frontal eye fields (FEF) are thought to promote express saccades by presetting the superior colliculus. Here, by reversibly inactivating the FEF either unilaterally or bilaterally via cortical cooling, we support this by showing that the FEF plays a facilitative but not critical role in express saccade generation. We also found that FEF inactivation lowered express saccade peak velocity, emphasizing a contribution of the FEF to express saccade kinematics.

Integrating Brain and Biomechanical Models-A New Paradigm for Understanding Neuro-muscular Control.

To date, realistic models of how the central nervous system governs behavior have been restricted in scope to the brain, brainstem or spinal column, as if these existed as disembodied organs. Further, the model is often exercised in relation to an in vivo physiological experiment with input comprising an impulse, a periodic signal or constant activation, and output as a pattern of neural activity in one or more neural populations. Any link to behavior is inferred only indirectly via these activity patterns. We argue that to discover the principles of operation of neural systems, it is necessary to express their behavior in terms of physical movements of a realistic motor system, and to supply inputs that mimic sensory experience. To do this with confidence, we must connect our brain models to neuro-muscular models and provide relevant visual and proprioceptive feedback signals, thereby closing the loop of the simulation. This paper describes an effort to develop just such an integrated brain and biomechanical system using a number of pre-existing models. It describes a model of the saccadic oculomotor system incorporating a neuromuscular model of the eye and its six extraocular muscles. The position of the eye determines how illumination of a retinotopic input population projects information about the location of a saccade target into the system. A pre-existing saccadic burst generator model was incorporated into the system, which generated motoneuron activity patterns suitable for driving the biomechanical eye. The model was demonstrated to make accurate saccades to a target luminance under a set of environmental constraints. Challenges encountered in the development of this model showed the importance of this integrated modeling approach. Thus, we exposed shortcomings in individual model components which were only apparent when these were supplied with the more plausible inputs available in a closed loop design. Consequently we were able to suggest missing functionality which the system would require to reproduce more realistic behavior. The construction of such closed-loop animal models constitutes a new paradigm of computational neurobehavior and promises a more thoroughgoing approach to our understanding of the brain's function as a controller for movement and behavior.

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.

眼球運動異常をきたした脳脊髄液減少症の2症例

Cerebrospinal fluid leakage is associated with several symptoms, such as headache, nausea, photophobia, diplopia and lassitude. In our practice, dizziness is a frequent presenting symptom in patients with this disorder. However, the mechanism and features of dizziness are unclear. In this report, we examined two patients with cerebrospinal fluid leakage with dizziness, exhibiting in particular flutter-like oscillations. Ocular flutter is characterized by intermittent bursts of horizontal saccades lacking an intersaccadic interval. Although the precise mechanisms are unknown, ocular flutter is often observed in cerebellar or brainstem lesions. In patients such as ours, ocular flutter may indicates that a central nervous system disorder may be present in cerebrospinal fluid leakage with dizziness.

Cerebellar output encodes a corrective saccadic command (Commentary on Sun et al.).

Cerebellar output encodes a corrective saccadic command (Commentary on Sun et al.).

Hybrid model of the context dependent vestibulo-ocular reflex: implications for vergence-version interactions.

The vestibulo-ocular reflex (VOR) is an involuntary eye movement evoked by head movements. It is also influenced by viewing distance. This paper presents a hybrid nonlinear bilateral model for the horizontal angular vestibulo-ocular reflex (AVOR) in the dark. The model is based on known interconnections between saccadic burst circuits in the brainstem and ocular premotor areas in the vestibular nuclei during fast and slow phase intervals of nystagmus. We implemented a viable switching strategy for the timing of nystagmus events to allow emulation of real nystagmus data. The performance of the hybrid model is evaluated with simulations, and results are consistent with experimental observations. The hybrid model replicates realistic AVOR nystagmus patterns during sinusoidal or step head rotations in the dark and during interactions with vergence, e.g., fixation distance. By simply assigning proper nonlinear neural computations at the premotor level, the model replicates all reported experimental observations. This work sheds light on potential underlying neural mechanisms driving the context dependent AVOR and explains contradictory results in the literature. Moreover, context-dependent behaviors in more complex motor systems could also rely on local nonlinear neural computations.

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

Anti-GAD antibody ocular flutter: expanding the spectrum of autoimmune ocular motor disorders

Antibodies directed against glutamic acid decarboxylase (GAD) have been described in patients with progressive cerebellar ataxia [1] and in a few patients affected by primarily oculomotor disorders [2]. The abnormal eye movements described with anti-GAD antibodies, so far, range from nystagmus (up/down-beat, periodic alternating nystagmus) [2, 3] to opsoclonus [4], but ocular flutter has never been reported. A 69-year-old woman was admitted to our hospital for a 10-month progressive oscillopsia, blurred vision and gait imbalance with significant impairment of daily activities (such as reading a book, watching television and leaving home alone). Neurological examination showed ocular flutter, characterized by intermittent bursts of horizontal conjugate saccades without an intersaccadic interval. The eye oscillations were independent of eye position and occurred during fixation (voluntary and guided changes in gaze position), regardless of gaze direction, with eyes open or closed. The patient had full range of eye motion and did not report diplopia. Unsteadiness with severe retropropulsion was also evident. The remaining neurologic examination was normal. Analysis of ocular movements using video-oculography revealed bursts of rapid horizontal, symmetric movements without intersaccadic interval (Fig. 1a). Results of electrophysiological examinations, such as somatosensory and visual evoked potentials, nerve conduction study and electroencephalography, were normal. Routine blood cell counts and biochemistry were normal. Serological tests, cultures, and polymerase chain reactions performed on blood and cerebrospinal fluid (CSF) samples were negative for viral, bacterial, and fungal infections. Brain magnetic resonance imaging showed no abnormality. Results of screening examinations for neoplasms, including abdominal ultrasonography, computed tomography of the abdomen and chest, as well as whole-body positron emission tomography, were all unremarkable. CSF examination revealed normal protein concentration and no cells, isoelectric focusing showed two oligoclonal bands and the immunoglobulin G index was within the normal range. The patient tested negative for anti-gliadin, paraneoplastic antibodies (anti-Ri, anti-Hu, anti-Yo, antiMa2, anti-CV2 and anti-amphiphysin), anti-LGI1, antiCaspr2, antiganglioside Q1b and anti-NMDA receptor in the serum and CSF. Antibodies against GAD65 were measured by radioimmunoassay. GAD65 antibody titre was increased in serum (2,378 IU/mL, normal value \1 IU/mL) and in CSF (55.7 IU/mL, normal value \1 IU/mL), with an intrathecal synthesis index of 10.64 (normal range 0.7–1.3). An intravenous immunoglobulin (IVIg) treatment (400 mg/kg/day for 5 days) in six cycles once a month was started. The symptoms gradually resolved and continued to improve after the last administration of IVIg and at the same time serum GAD65 antibody titre decreased significantly (Fig. 1c). To avoid clinical relapses, azathioprine 200 mg orally daily was added to the last cycle of IVIg (Fig. 1c). R. Dubbioso F. Manganelli R. Iodice M. Esposito L. Santoro (&) Department of Neuroscience, Reproductive Sciences and Odontostomatology, University of Naples ‘‘Federico II’’, Via Sergio Pansini, 5, 80131 Naples, Italy e-mail: lusantor@unina.it

Physiology and pathology of saccades and gaze holding

Foveation is the fundamental requirement for clear vision. Saccades rapidly shift the gaze to the interesting target while gaze holding ensures foveation of the desired object. We will review the pertinent physiology of saccades and gaze holding and their pathophysiology leading to saccadic oscillations, slow saccades, saccadic dysmetria, and nystagmus. Motor commands for saccades are generated at multiple levels of the neuraxis. The frontal and parietal eye field send saccadic commands to the superior colliculus. Latter then projects to the brain-stem saccadic burst generator. The brain-stem burst generators guarantee optimum signal to ensure rapid saccadic velocity, while the neural integrator, by mathematically integrating the saccadic pulse, facilitates stable gaze holding. Reciprocal innervations that ensure rapid saccadic velocity are prone to inherent instability leading to saccadic oscillations. In contrast, suboptimal function of the burst generators causes slow saccades. Impaired error correction, either at the cerebellum or the inferior olive, leads to impaired saccade adaptation and ultimately saccadic dysmetria and oculopalatal tremor. Impairment in the function of neural integrator causes nystagmus. Neurophysiology of saccades, gaze holding, and their deficits are well recognized. These principles can be implemented to define novel therapeutic and rehabilitation approaches.

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

Saccadic oscillations: membrane, model and medicine

Saccadic oscillations are continuous back-to-back saccades that cause excessive image motion across fovea and threaten clear vision. Acquired processes, related to immune or metabolic mechanisms, are common culprits. Saccadic oscillations are also seen in degenerative cerebellar disease or as a part of a familial syndrome of saccadic oscillations and limb tremor. Some normal individuals have innate ability to voluntarily trigger saccadic oscillations (i.e., voluntary nystagmus). Contemporary theory for the pathogenesis for saccadic oscillations has emphasized a hyperexcitable or disinhibited state of the brainstem saccadic burst neuron membrane. This review discusses etiologies and treatment of saccadic oscillations in light of a novel cell membrane-based theory.

Neural mechanisms for predictive head movement strategies during sequential gaze shifts

Humans adopt very different head movement strategies for different gaze behaviors, for example, when playing sports versus watching sports on television. Such strategy switching appears to depend on both context and expectation of future gaze positions. Here, we explored the neural mechanisms for such behaviors by training three monkeys to make head-unrestrained gaze shifts toward eccentric radial targets. A randomized color cue provided predictive information about whether that target would be followed by either a return gaze shift to center or another, more eccentric gaze shift, but otherwise animals were allowed to develop their own eye-head coordination strategy. In the first two animals we then stimulated the frontal eye fields (FEF) in conjunction with the color cue, and in the third animal we recorded from neurons in the superior colliculus (SC). Our results show that 1) monkeys can optimize eye-head coordination strategies from trial to trial, based on learned associations between color cues and future gaze sequences, 2) these cue-dependent coordination strategies were preserved in gaze saccades evoked during electrical stimulation of the FEF, and 3) two types of SC responses (the saccade burst and a more prolonged response related to head movement) modulated with these cue-dependent strategies, although only one (the saccade burst) varied in a predictive fashion. These data show that from one moment to the next, the brain can use contextual sensory cues to set up internal "coordination states" that convert fixed cortical gaze commands into the brain stem signals required for predictive head motion.

Components of the neural signal underlying congenital nystagmus

Congenital nystagmus is an involuntary bilateral horizontal oscillation of the eyes that develops soon after birth. In this study, the time constants of each of the components of the neural signal underlying congenital nystagmus were obtained by time series analysis and interpreted by comparison with those of the normal oculomotor system. In the neighbourhood of the fixation position, the system generating the neural signal is approximately linear with 3 degrees of freedom. The shortest time constant was in the range of 7-9ms and corresponds to a normal saccadic burst signal. The other stable time constant was in the range of 22-70ms and corresponds to the slide signal. The final time constant characterises the unidentified neural mechanism underlying the unstable drift component of the oscillation cycle and ranges between 31 and 32ms across waveforms. The characterisation of this unstable time constant poses a challenge for the modelling of both the normal and abnormal oculomotor control system. We tentatively identify the unstable component with the eye position signal supplied to the superior colliculus in the normal eye movement system and explore some of the implications of this hypothesis.