Excitatory Burst Neurons Research Articles

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.

Saccades in Parkinson's disease: Hypometric, slow, and maladaptive.

Visuomotor impairments, such as hypometria of visually guided saccades, are common in Parkinson's disease (PD). Explaining the mechanistic underpinning of such abnormal voluntary (eye) movements can provide insights into the pathophysiology of limb movement disorders in PD. We measured visually guided saccades in 20 PD patients using quantitative high-resolution oculography. The experiments source to determine whether common motor deficits in PD, such as those affecting visually-guided saccades reflect excessive inhibition of the superior colliculus or rather involvement of brainstem saccade generators. We found slowing, interruptions, and curvatures in the saccade trajectory. The curvature not only reflected the mismatch in the velocity of relatively slower vertical (compared to horizontal) saccades, but could be due to aberrant activation of the superior colliculus. The irregularities in the saccade trajectory and slowing were prominent in the vertical direction. We suggest that abnormal saccades in PD not only reflect abnormal tectal function, but also suggest abnormal oscillatory behavior in the reciprocally innervating circuit of excitatory and inhibitory burst neurons. Impaired function of excitatory and inhibitory burst neurons causing maladaptive feedback and premature activation of the superior colliculus can cause irregularity in saccade trajectory.

Paraneoplastic seesaw nystagmus and opsoclonus provides evidence for hyperexcitable reciprocally innervating mesencephalic network

Seesaw nystagmus is characterized by the rhythmic combination of vertical and torsional dysconjugate oscillations where one eye moves up and inward while the other moves down and outward. Common association of seesaw nystagmus with accessory optic track lesions lead to traditional hypothesis that it is due to the mismatch in the vision and vestibular systems. Here we propose a novel mechanism for seesaw nystagmus. We hypothesize that reverberations due to abnormal increases in the excitability of the reciprocally innervating circuit of excitatory burst neuron in the midbrain interstitial nucleus of Cajal causes the seesaw nystagmus. Analogous oscillations of the brainstem burst generators may be responsible for generation of saccadic oscillations or opsoclonus. The key difference is that the interstitial nucleus of Cajal lacks inhibitory burst neurons, hence the lack of post-inhibitory rebound, and relatively lower frequency of the oscillatory cycles causing pendular seesaw nystagmus. In contrast the brainstem burst generator, with reciprocally innervating excitatory and inhibitory burst neurons, and further inhibitory influence of the omnipause neurons results in the post-inhibitory rebound at the burst neurons, hence high oscillation frequency. This novel concept is supported by a unique observation in a patient with antineuronal nuclear autoantibody type 2 due to breast cancer who had combined seesaw nystagmus and superimposed saccadic oscillations. The patient neither had cerebellar deficits typically thought to cause paraneoplastic opsoclonus nor visual deficits that are known cause of seesaw nystagmus. We propose that hyperexcitability of the burst neurons in the interstitial nucleus of Cajal due to paraneoplastic antibody caused pendular seesaw nystagmus. On the other hand, increased excitability of brainstem burst generators and reduced efficacy of the omnipause neurons caused saccadic oscillations.

Saccades in progressive supranuclear palsy - maladapted, irregular, curved, and slow.

Slowed and curved rapid eye movements, saccades, are the well-known features of progressive supranuclear palsy (PSP). We hypothesized that the saccades in PSP are not only slow and curved, but they are also irregular and have timing deficits. We tested this hypothesis in 12 patients with PSP by measuring vertical and horizontal visually guided saccades using a limbus tracker. Both, horizontal and vertical saccades were slow and had irregular trajectory and velocity profiles, but deficits were much more robust in vertical saccades. The irregularity in the saccade velocity was due to premature interruptions that either completely stopped the eyes, or moved the eyes at much slower velocity along or in the opposite direction of the ongoing saccade. The direction of the eyes' trajectory was often changed after the interruption. We simulated a conductance based single-compartment model of the burst neurons embedded in local feedback circuit for saccade generation. This model mimicked anatomical and physiological realism, while allowing the liberty to selectively change the activation of individual burst neurons or the pause neurons. The PSP saccades were comparable to the simulations during reduced activity of the inhibitory and excitatory burst neurons. PSP saccades are due to the paucity in burst generation at the excitatory and imprecise timing signal from the inhibitory burst neurons. Premature discharge of the inhibitory burst neuron further leads to breaks in the saccade trajectory, and maladaptive superior colliculus activity leading to aberrant saccades changing the intended trajectory of the ongoing saccade.

A GABAergic Dysfunction in the Olivary-Cerebellar-Brainstem Network May Cause Eye Oscillations and Body Tremor. II. Model Simulations of Saccadic Eye Oscillations.

Eye and body oscillations are shared features of several neurological diseases, yet their pathophysiology remains unclear. Recently, we published a report on two tennis players with a novel presentation of eye and body oscillations following self-administration of performance-enhancing substances. Opsoclonus/flutter and limb tremor were diagnosed in both patients. Common causes of opsoclonus/flutter were excluded. High-resolution eye movement recordings from one patient showed novel spindle-shaped, asymmetric saccadic oscillations (at ~3.6 Hz) and ocular tremor (~40–60 Hz). Based on these findings, we proposed that the oscillations are the result of increased GABAA receptor sensitivity in a circuit involving the cerebellum (vermis and fastigial nuclei), the inferior olives, and the brainstem saccade premotor neurons (excitatory and inhibitory burst neurons, and omnipause neurons). We present a mathematical model of the saccadic system, showing that the proposed dysfunction in the network can reproduce the types of saccadic oscillations seen in these patients.

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

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

Opsoclonus in a patient with increased titers of anti-GAD antibody provides proof for the conductance-based model of saccadic oscillations

Paucity in gamma-amino butyric acid (GABA) due to blockage in the action of glutamic acid decarboxylase (GAD), as seen in the syndrome of anti-GAD antibody, causes adult onset cerebellar ataxia, muscle rigidity, and episodic spasms. Downbeat nystagmus, saccadic dysmetria, impaired ocular pursuit, and impaired cancelation of vestibular ocular reflex are typical ocular motor deficits in patients with syndrome of anti-GAD antibody. We describe opsoclonus, in addition to downbeat nystagmus, in a patient with increased titers of anti-GAD antibody. Paucity in GABA leading to disinhibition to Purkinje target neurons at deep cerebellar and vestibular nuclei might have caused downbeat nystagmus in our patient. Anti-GAD antibody can also increase levels of glutamate the precursor of GABA and the substrate for the action of GAD. We propose that opsoclonus might be due to increased levels of glutamate and subsequent hyperexcitability of excitatory and inhibitory burst neurons leading to reverberation in their reciprocally innervating circuit.

Saccadic Palsy following Cardiac Surgery: Possible Role of Perineuronal Nets.

ObjectivePerineuronal nets (PN) form a specialized extracellular matrix around certain highly active neurons within the central nervous system and may help to stabilize synaptic contacts, promote local ion homeostasis, or play a protective role. Within the ocular motor system, excitatory burst neurons and omnipause neurons are highly active cells that generate rapid eye movements – saccades; both groups of neurons contain the calcium-binding protein parvalbumin and are ensheathed by PN. Experimental lesions of excitatory burst neurons and omnipause neurons cause slowing or complete loss of saccades. Selective palsy of saccades in humans is reported following cardiac surgery, but such cases have shown normal brainstem neuroimaging, with only one clinicopathological study that demonstrated paramedian pontine infarction. Our objective was to test the hypothesis that lesions of PN surrounding these brainstem saccade-related neurons may cause saccadic palsy.MethodsTogether with four controls we studied the brain of a patient who had developed a permanent selective saccadic palsy following cardiac surgery and died several years later. Sections of formalin-fixed paraffin-embedded brainstem blocks were applied to double-immunoperoxidase staining of parvalbumin and three different components of PN. Triple immunofluorescence labeling for all PN components served as internal controls. Combined immunostaining of parvalbumin and synaptophysin revealed the presence of synapses.ResultsExcitatory burst neurons and omnipause neurons were preserved and still received synaptic input, but their surrounding PN showed severe loss or fragmentation.InterpretationOur findings support current models and experimental studies of the brainstem saccade-generating neurons and indicate that damage to PN may permanently impair the function of these neurons that the PN ensheathe. How a postulated hypoxic mechanism could selectively damage the PN remains unclear. We propose that the well-studied saccadic eye movement system provides an accessible model to evaluate the role of PN in health and disease.

Saccadic palsy following cardiac surgery: a review and new hypothesis.

The ocular motor system provides several advantages for studying the brain, including well-defined populations of neurons that contribute to specific eye movements. Generation of rapid eye movements (saccades) depends on excitatory burst neurons (EBN) and omnipause neurons (OPN) within the brainstem, both types of cells are highly active. Experimental lesions of EBN and OPN cause slowing or complete loss of saccades. We report a patient who developed a permanent, selective saccadic palsy following cardiac surgery. When she died several years later, surprisingly, autopsy showed preservation of EBN and OPN. We therefore considered other mechanisms that could explain her saccadic palsy. Recent work has shown that both EBN and OPN are ensheathed by perineuronal nets (PN), which are specialized extracellular matrix structures that may help stabilize synaptic contacts, promote local ion homeostasis, or play a protective role in certain highly active neurons. Here, we review the possibility that damage to PN, rather than to the neurons they support, could lead to neuronal dysfunction-such as saccadic palsy. We also suggest how future studies could test this hypothesis, which may provide insights into the vulnerability of other active neurons in the nervous system that depend on PN.

A neuron-based time-optimal controller of horizontal saccadic eye movements.

A neural network model of biophysical neurons in the midbrain for controlling oculomotor muscles during horizontal human saccades is presented. Neural circuitry that includes omnipause neuron, premotor excitatory and inhibitory burst neurons, long lead burst neuron, tonic neuron, interneuron, abducens nucleus and oculomotor nucleus is developed to investigate saccade dynamics. The final motoneuronal signals drive a time-optimal controller that stimulates a linear homeomorphic model of the oculomotor plant. To our knowledge, this is the first report on modeling the neural circuits at both premotor and motor stages of neural activity in saccadic systems.

A physiological neural controller of a muscle fiber oculomotor plant in horizontal monkey saccades.

A neural network model of biophysical neurons in the midbrain is presented to drive a muscle fiber oculomotor plant during horizontal monkey saccades. Neural circuitry, including omnipause neuron, premotor excitatory and inhibitory burst neurons, long lead burst neuron, tonic neuron, interneuron, abducens nucleus, and oculomotor nucleus, is developed to examine saccade dynamics. The time-optimal control strategy by realization of agonist and antagonist controller models is investigated. In consequence, each agonist muscle fiber is stimulated by an agonist neuron, while an antagonist muscle fiber is unstimulated by a pause and step from the antagonist neuron. It is concluded that the neural network is constrained by a minimum duration of the agonist pulse and that the most dominant factor in determining the saccade magnitude is the number of active neurons for the small saccades. For the large saccades, however, the duration of agonist burst firing significantly affects the control of saccades. The proposed saccadic circuitry establishes a complete model of saccade generation since it not only includes the neural circuits at both the premotor and motor stages of the saccade generator, but also uses a time-optimal controller to yield the desired saccade magnitude.

Huntington's disease (HD): degeneration of select nuclei, widespread occurrence of neuronal nuclear and axonal inclusions in the brainstem.

Huntington's disease (HD) is a progressive polyglutamine disease that leads to a severe striatal and layer-specific neuronal loss in the cerebral neo-and allocortex. As some of the clinical symptoms (eg, oculomotor dysfunctions) suggested a degeneration of select brainstem nuclei, we performed a systematic investigation of the brainstem of eight clinically diagnosed and genetically confirmed HD patients. This post-mortem investigation revealed a consistent neuronal loss in the substantia nigra, pontine nuclei, reticulotegmental nucleus of the pons, superior and inferior olives, in the area of the excitatory burst neurons for horizontal saccades, raphe interpositus nucleus and vestibular nuclei. Immunoreactive intranuclear neuronal inclusions were present in all degenerated and apparently spared brainstem nuclei and immunoreactive axonal inclusions were observed in all brainstem fiber tracts of the HD patients. Degeneration of brainstem nuclei can account for a number of less well-understood clinical HD symptoms (ie, cerebellar, oculomotor and vestibular symptoms), while the formation of axonal aggregates may represent a crucial event in the cascades of pathological events leading to neurodegeneration in HD.

Convergent synaptic inputs from the caudal fastigial nucleus and the superior colliculus onto pontine and pontomedullary reticulospinal neurons

The caudal fastigial nucleus (FN) is known to be related to the control of eye movements and projects mainly to the contralateral reticular nuclei where excitatory and inhibitory burst neurons for saccades exist [the caudal portion of the nucleus reticularis pontis caudalis (NRPc), and the rostral portion of the nucleus reticularis gigantocellularis (NRG) respectively]. However, the exact reticular neurons targeted by caudal fastigioreticular cells remain unknown. We tried to determine the target reticular neurons of the caudal FN and superior colliculus (SC) by recording intracellular potentials from neurons in the NRPc and NRG of anesthetized cats. Neurons in the rostral NRG received bilateral, monosynaptic excitation from the caudal FNs, with contralateral predominance. They also received strong monosynaptic excitation from the rostral and caudal contralateral SC, and disynaptic excitation from the rostral ipsilateral SC. These reticular neurons with caudal fastigial monosynaptic excitation were not activated antidromically from the contralateral abducens nucleus, but most of them were reticulospinal neurons (RSNs) that were activated antidromically from the cervical cord. RSNs in the caudal NRPc received very weak monosynaptic excitation from only the contralateral caudal FN, and received either monosynaptic excitation only from the contralateral caudal SC, or monosynaptic and disynaptic excitation from the contralateral caudal and ipsilateral rostral SC, respectively. These results suggest that the caudal FN helps to control also head movements via RSNs targeted by the SC, and these RSNs with SC topographic input play different functional roles in head movements.

Neural mechanisms of saccadic eye movements: common ground with the vestibular system

The superior colliculus (SC) plays an important role in controlling eye and head movements. The neural organization of the pathways from the SC to motoneurons in the horizontal oculomotor system has been well analyzed, but the neural mechanisms in the vertical saccade have not yet been analyzed in detail. This article reviews the current state of knowledge of the neural mechanisms of the horizontal and vertical saccadic eye movement system, and shows that they have common features: both systems contain excitatory and inhibitory burst neurons which receive inputs from the SC and directly project to motoneurons. Our recent study showed the presence of commissural inhibition between the upper and lower fields of motor map of the bilateral SCs. This reciprocal inhibition between the medial upward saccade area in one SC and the lateral downward saccade area in the other SC is very similar to that in the vestibular system. This similarity of the patterns of reciprocal inhibition in the SC system and the semicircular canal system implies that the SC output system may use the coordinate system based on the semicircular canals.

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.

Impairment of Vertical Saccades From an Acute Pontine Lesion in Multiple Sclerosis

A 62-year-old woman with relapsing-remitting multiple sclerosis suddenly complained of diplopia associated with bilateral adduction impairment, nystagmus of the abducting eye bilaterally, and sparing of abduction, convergence, and vertical eye movements, consistent with bilateral internuclear ophthalmoplegia. Within 1 week, she had developed a complete horizontal gaze paralysis even with the oculocephalic maneuver. Vertical saccades were slow and convergence was preserved. There was a right lower motor neuron seventh cranial nerve palsy. Brain MRI showed a new enhancing lesion involving the pontine tegmentum. Clinical and MRI follow-up showed recovery after 6 months. The slowing of vertical saccades may have been due to spread of the demyelinating lesion to the adjacent paramedian pontine reticular formation, which contains omnipause neurons lying in the raphe interpositus nucleus thought to inhibit excitatory burst neurons for horizontal and vertical saccades. Our patient verifies the fact that vertical saccadic abnormalities may occur from a lesion apparently confined to the pons.

In the flicker of an eye

In the flicker of an eye

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.

Membrane channel properties of premotor excitatory burst neurons may underlie saccade slowing after lesions of omnipause neurons

Chemical lesions of the brain stem region containing glycinergic omnipause neurons (OPNs) cause saccade slowing with no change in latency. To explore the mechanisms responsible for this deficit, simulation studies were performed with a conductance-based model of premotor excitatory burst neurons (EBNs) that incorporated multiple membrane channels, including the T-type calcium channel. The peak speed of a normal saccade was determined by the T- and NMDA currents in EBNs after the OPNs shut off. After OPN lesions, the model made slow saccades, because the EBN activity was lower than normal due to a reduced T-current (caused by the loss of hyperpolarization), and a reduced NMDA current (caused by a reduced glycine concentration around the receptors). Thus, we propose that two biophysical mechanisms are responsible for saccade slowing after OPN lesions: reduced T-current and reduced NMDA current, both of which are caused by the loss of glycine from OPNs.

Temporal characteristics of neurons in the central mesencephalic reticular formation of head unrestrained monkeys

The accompanying paper demonstrated two distinct types of central mesencephalic reticular formation (cMRF) neuron that discharged before or after the gaze movement: pre-saccadic or post-saccadic. The movement fields of pre-saccadic neurons were most closely associated with gaze displacement. The movement fields of post-saccadic neurons were most closely associated with head displacement. Here we examine the relationships of the discharge patterns of these cMRF neurons with the temporal aspects of gaze or head movement. For pre-saccadic cMRF neurons with monotonically open movement fields, we demonstrate that burst duration correlated closely with gaze duration. In addition, the peak discharge of the majority of pre-saccadic neurons was closely correlated with peak gaze velocity. In contrast, discharge parameters of post-saccadic neurons were best correlated with the time of peak head velocity. However, the duration and peak discharge of post-saccadic discharge was only weakly related to the duration and peak velocity of head movement. As a result, for the majority of post-saccadic neurons the discharge waveform poorly correlated with the dynamics of head movement. We suggest that the discharge characteristics of pre-saccadic cMRF neurons with monotonically open movement fields are similar to that of direction long-lead burst neurons found previously in the paramedian portion of the pontine reticular formation (PPRF; Hepp and Henn 1983). In light of their anatomic connections with the PPRF, these pre-saccadic neurons could form a parallel pathway that participates in the transformation from the spatial coding of gaze in the superior colliculus (SC) to the temporal coding displayed by excitatory burst neurons of the PPRF. In contrast, closed and non-monotonically open movement field pre-saccadic neurons could play a critical role in feedback to the SC. The current data do not support a role for post-saccadic cMRF neurons in the direct control of head movements, but suggest that they may serve a feedback or reafference function, providing a signal of current head amplitude to upstream regions involved in head control.