Electrophysiology of Extraocular Cranial Nerves: Oculomotor, Trochlear, and Abducens Nerve.

The utility of extraocular cranial nerve electrophysiologic recordings lies primarily in the operating room during skull base surgeries. Surgical manipulation during skull base surgeries poses a risk of injury to multiple cranial nerves, including those innervating extraocular muscles. Because tumors distort normal anatomic relationships, it becomes particularly challenging to identify cranial nerve structures. Studies have reported the benefits of using intraoperative spontaneous electromyographic recordings and compound muscle action potentials evoked by electrical stimulation in preventing postoperative neurologic deficits. Apart from surgical applications, electromyography of extraocular muscles has also been used to guide botulinum toxin injections in patients with strabismus and as an adjuvant diagnostic test in myasthenia gravis. In this article, we briefly review the rationale, current available techniques to monitor extraocular cranial nerves, technical difficulties, clinical and surgical applications, as well as future directions for research.

A noninvasive electromagnetic perturbation approach to probe extraocular proprioception.

BACKGROUND: Extraocular proprioception has been shown to participate in spatial perception and binocular alignment. Yet the physiological approaches used to study this sensory signal are limited because proprioceptive signaling takes place at the same time as visuomotor signaling. It is critical to dissociate this sensory signal from other visuomotor events that accompany eye movements. METHODS: We present a novel noninvasive and quantifiable method for probing extraocular proprioception independent of other visuomotor processing by attaching a rare-earth magnet to a real-time model eye and placing an electromagnet <20 mm from the eye. An electromagnet can increase or decrease angular displacements and velocities of the model eye. RESULTS: Electromagnetic activation rapidly affected (<2 ms) the rotation kinematics of the eye, which were correlated linearly with both the current supply and the distance of the electromagnet relative to the eye. CONCLUSIONS: This method circumvented the constraints of conventional physiological manipulation of extraocular proprioception, such as manually or mechanically tugging on the eye ball. It can be applied to produce the discrepancy between the intended and the executed eye movements, so that proprioceptive reafference signals are dissociated from corollary motor discharges and other visuomotor events.

Cranial nerve palsies in childhood.

We review ocular motor cranial nerve palsies in childhood and highlight many of the features that differentiate these from their occurrence in adulthood. The clinical characteristics of cranial nerve palsies in childhood are affected by the child's impressive ability to repair and regenerate after injury. Thus, aberrant regeneration is very common after congenital III palsy; Duane syndrome, the result of early repair after congenital VI palsy, is invariably associated with retraction of the globe in adduction related to the innervation of the lateral rectus by the III nerve causing co-contraction in adduction. Clinical features that may be of concern in adulthood may not be relevant in childhood; whereas the presence of mydriasis in III palsy suggests a compressive aetiology in adults, this is not the case in children. However, the frequency of associated CNS abnormalities in III palsy and the risk of tumour in VI palsy can be indications for early neuroimaging depending on presenting features elicited through a careful history and clinical examination. The latter should include the neighbouring cranial nerves. We discuss the impact of our evolving knowledge of congenital cranial dysinnervation syndromes on this field.

Input-output organization of inhibitory neurons in the interstitial nucleus of Cajal projecting to the contralateral trochlear and oculomotor nucleus.

Neurons in the interstitial nucleus of Cajal (INC) that are known to be involved in eye and head movements are excitatory. We investigated the input-output organization of inhibitory INC neurons involved in controlling vertical saccades. Intracellular recordings were made in INC neurons activated antidromically by stimulation of the contralateral trochlear or oculomotor nucleus, and their synaptic input properties from the superior colliculi (SCs) and the contralateral INC were analyzed in anesthetized cats. Many INC neurons projected to the contralateral trochlear nucleus, Forel's field H, INC, and oculomotor nucleus, and mainly received monosynaptic excitation followed by disynaptic inhibition from the ipsi- and contralateral SCs. After sectioning the commissural connections between the SCs, these neurons received monosynaptic excitation from the ipsilateral medial SC and disynaptic inhibition via the INC from the contralateral lateral SC. Another group of INC neurons were antidromically activated from the contralateral oculomotor nucleus, INC and Forel's field H, but not from the trochlear nucleus, and received monosynaptic excitation from the ipsilateral lateral SC and disynaptic inhibition from the contralateral medial SC. The former group was considered to inhibit contralateral trochlear and inferior rectus motoneurons in upward saccades, whereas the latter was considered to inhibit contralateral superior rectus and inferior oblique motoneurons in downward saccades. The mutual inhibition existed between these two groups of INC neurons for upward saccades on one side and downward saccades on the other. This pattern of input-output organization of inhibitory INC neurons suggests that the basic neural circuits for horizontal and vertical saccades are similar.

Role of the trochlear nerve in eye abduction and frontal vision of the red-eared slider turtle (Trachemys scripta elegans).

Horizontal head rotation evokes significant responses from trochlear motoneurons of turtle that suggests they have a functional role in abduction of the eyes like that in frontal-eyed mammals. The finding is unexpected given that the turtle is generally considered lateral-eyed and assumed to have eye movements instead like that of lateral-eyed mammals, in which innervation of the superior oblique muscle by the trochlear nerve (nIV) produces intorsion, elevation, and adduction (not abduction). Using an isolated turtle head preparation with the brain removed, glass suction electrodes were used to stimulate nIV with trains of current pulses. Eyes were monitored via an infrared camera with the head placed in a gimble to quantify eye rotations and their directions. Stimulations of nIV evoked intorsion, elevation, and abduction. Dissection of the superior oblique muscle identified lines of action and a location of insertion on the eye, which supported kinematics evoked by nIV stimulation. Eye positions in alert behaving turtles with their head extended were compared with that when their heads were retracted in the carapace. When the head was retracted, there was a reduction in interpupillary distance and an increase in binocular overlap. Occlusion of peripheral fields by the carapace forces the turtle to a more frontal-eyed state, perhaps the reason for the action of abduction by the superior oblique muscle. These findings support why trochlear motoneurons in turtle respond in the same way as abducens motoneurons to horizontal rotations, an unusual characteristic of vestibulo-ocular physiology in comparison with other mammalian lateral-eyed species.

The treatment of medically intractable trigeminal autonomic cephalalgia with supraorbital/supratrochlear stimulation: a retrospective case series.

INTRODUCTION: This is a retrospective case series of five patients with intractable trigeminal autonomic cephalalgia (TAC) who were implanted with a supraorbital/supratrochlear neuromodulation system. OBJECTIVES: The aim of this Institutional Review Board-approved study was to investigate the percentage of pain relief, treatment response, pain level, work status, medication intake, implantation technique, lead placement, programming information, and device use. RESULTS: Trial stimulation led to implantation of all five patients. All patients reported improvement in their functional status in regard to activities of daily living. The device was revised in two patients due to skin erosion. It was later reimplanted in both patients due to worsening of symptoms, again with good pain relief. The device was explanted in two other patients because of the need to perform a magnetic resonance imaging or implant an automatic implantable cardioverter defibrillator. The follow-up of the patients ranged between 18 months and 36 months, with a mean of 25.2 months. There was no change in work status. Following the implant, the Visual Analog Scale score was reduced to a mean of 1.6 from an initial mean score of 8.9. Three patients were completely weaned off opioid medications, while two patients continued to take opioid at a lower dosage. All patients experienced a decrease of the adjuvant neuropathic drugs. CONCLUSION: Supraorbital/supratrochlear nerve stimulation appears to be a promising modality for the treatment of patients with intractable TAC.

Vertical alignment in monkeys with unilateral IV section: effects of prolonged monocular patching and trigeminal deafferentation.

We investigated monocular viewing and trigeminal (V) deafferentation on the vertical deviation (VD) in monkeys following intracranial IV section. Two monkeys wore a patch for four to six weeks, one over the paretic eye and the other over the normal eye following IV section. Two other monkeys had combined IV and V section with the paretic eye patched postlesion. In monkeys with IV section alone, the VD lessened within the first week postlesion but then increased gradually with the same eye still patched. Thus binocular viewing was unnecessary for the later VD increase. With combined IV and V section, the VD also transiently lessened postlesion. We have proposed that the decrease in VD after IV section is adaptive, driven by an error signal using ocular proprioception and efference copy. Since V section did not eliminate the early decrease in VD, we suggest some orbital afference is transmitted centrally via other cranial nerves. However, the later increase in VD suggests either that the proprioceptive effect cannot be sustained or that mechanical changes supervene to increase the VD.

Stromal cell-derived factor-1 and hepatocyte growth factor guide axon projections to the extraocular muscles.

Vertebrate eye movements depend on the co-ordinated function of six extraocular muscles that are innervated by the oculomotor, trochlear, and abducens nerves. Here, we show that the diffusible factors, stromal cell-derived factor-1 (SDF-1) and hepatocyte growth factor (HGF), guide the development of these axon projections. SDF-1 is expressed in the mesenchyme around the oculomotor nerve exit point, and oculomotor axons fail to exit the neuroepithelium in mice mutant for the SDF-1 receptor CXCR4. Both SDF-1 and HGF are expressed in or around the ventral and dorsal oblique muscles, which are distal targets for the oculomotor and trochlear nerves, respectively, as well as in the muscles which are later targets for oculomotor axon branches. We find that in vitro SDF-1 and HGF promote the growth of oculomotor and trochlear axons, whereas SDF-1 also chemoattracts oculomotor axons. Oculomotor neurons show increased branching in the presence of SDF-1 and HGF singly or together. HGF promotes the growth of trochlear axons more than that of oculomotor axons. Taken together, these data point to a role for both SDF-1 and HGF in extraocular nerve projections and indicate that SDF-1 functions specifically in the development of the oculomotor nerve, including oculomotor axon branch formation to secondary muscle targets. HGF shows some specificity in preferentially enhancing development of the trochlear nerve.

Effects of intracranial trochlear neurectomy on the structure of the primate superior oblique muscle.

PURPOSE. Although cyclovertical strabismus in humans is frequently attributed to superior oblique (SO) palsy, anatomic effects of SO denervation have not been studied. Magnetic resonance imaging (MRI) and orbital histology was used to study the effects of acute trochlear (CN4) denervation on the monkey SO. METHODS. Five juvenile macaque monkeys were perfused with formalin for 5 weeks: 15 months after unilateral or bilateral 10-mm intracranial trochlear neurectomy. Denervated and fellow orbits were imaged by MRI, embedded whole in paraffin, serially sectioned at 10-mum thickness, and stained with Masson trichrome. Whole muscle and individual fiber cross sections were quantified in SO muscles throughout the orbit and traced larger fibers in one specimen where they were present. RESULTS. MRI demonstrated marked reduction in midorbital cross section in denervated SO muscles, with anterior shift of SO mass preserving overall volume. Muscle fibers exhibited variable atrophy along their lengths. Denervated orbital layer (OL) fiber cross sections were slightly but significantly reduced from control at most anteroposterior locations, but this reduction was much more profound in global layer (GL) fibers. Intraorbital and intramuscular CN4 were uniformly fibrotic. In one animal, there were scattered clusters of markedly hypertrophic GL fibers that exhibited only sparse myomyous junctions only anteriorly. CONCLUSIONS. CN4 denervation produces predominantly SO GL atrophy with relative OL sparing. Overall midorbital SO atrophy was evident by MRI as early as 5 weeks after denervation, as denervated SO volume shifted anteriorly. Occasional GL fiber hypertrophy suggests that at least some SO fibers extend essentially the full muscle length after trochlear neurectomy.

The effect of acute superior oblique palsy on torsional optokinetic nystagmus in monkeys.

PURPOSE: To investigate the effects of acquired superior oblique palsy (SOP) and corrective strabismus surgery on torsional optokinetic nystagmus (tOKN) in monkeys. METHODS: The trochlear nerve was severed intracranially in two rhesus monkeys (M1 and M2). For each monkey, more than 4 months after the SOP, the ipsilateral inferior oblique muscle was denervated and extirpated. For M2, 4 months later, the contralateral inferior rectus muscle was recessed by 2 mm. tOKN was elicited during monocular viewing of a rotating stimulus that was rear projected onto a screen 43.5 cm in front of the animal. Angular rotation of the stimulus about the center was 40 deg/s clockwise or counterclockwise. RESULTS: The main findings after trochlear nerve sectioning were (1) the amplitude and peak velocity of torsional quick and slow phases of the paretic eye was less than that in the normal eye for both intorsion and extorsion, and (2) the vertical motion of the paretic eye increased during both torsional slow and quick phases. After corrective inferior oblique surgery, both of these effects were even greater. CONCLUSIONS: Acquired SOP and corrective inferior oblique-weakening surgery create characteristic patterns of change in tOKN that reflect alterations in the dynamic properties of the extraocular muscles involved in eye torsion. tOKN also provides information complementary to that provided by the traditional Bielschowsky head-tilt test and potentially can help distinguish among different causes of vertical ocular misalignment.

Dendrodendritic and dendrosomatic contacts between oculomotor and trochlear motoneurons of the frog, Rana esculenta.

Gaze fixation requires very fast movements of the eye during body displacement. The morphological and physiological background of the very fine and continuous tuning of gaze fixation is not yet fully understood. In a previous study we have shown that the dendrites of oculomotor neurons form bundles which invade the trochlear nucleus, and vice versa, trochlear dendritic bundles invade the oculomotor nucleus. Earlier physiological observations demonstrating electrotonic coupling between dendrites of spinal motoneurons in the frog suggest a similar mechanism between the oculomotor and trochlear motoneurons. We studied a possible morphological basis of gaze fixation. The experiments were carried out on common water frogs, Rana esculenta. The trochlear and oculomotor nerves were cut, and their proximal stumps were labeled simultaneously with different retrograde fluorescent tracers. Using confocal laser scanning microscope we detected a large number of close contacts in both nuclei, the majority of them were dendrodendritic apposition. The distance between the adjacent profiles suggested close membrane appositions without intercalating glial or neuronal elements. At the ultrastructural level, the dendrodendritic and dendrosomatic contacts did not show any morphological specialization; the long membrane appositions may provide ephaptic interactions between the neighboring profiles. This electrotonic coupling between the oculomotor and trochlear nerve motoneurons may promote the co-activation of the muscles responsible for vertical eye movements.

Morphology, intrinsic membrane properties, and rotation-evoked responses of trochlear motoneurons in the turtle.

Intrinsic properties and rotation-evoked responses of trochlear motoneurons were investigated in the turtle using an in vitro preparation consisting of the brain stem with attached temporal bones that retain functional semicircular canals. Motoneurons were divided into two classes based on intrinsic properties. The first class exhibited higher impedance (123.0 +/- 11.0 MOmega), wider spikes (0.99 +/- 0.05 ms), a single spike afterhyperpolarization (AHP), little or no spike frequency adaptation (SFA), and anomalous rectification, characterized by an initial "sag" in membrane potential in response to hyperpolarizing current injection. The second class exhibited lower impedance (21.8 +/- 2.5 MOmega), narrower spikes (0.74 +/- 0.03 ms), a double AHP, substantial SFA, and little or no rectification. Vestibular responses were evoked by horizontal sinusoidal rotation (1/12-1/3 Hz; peak velocity: 30-100 degrees /s). Spiking in higher-impedance cells was recruited earlier in the response and exhibited a more limited dynamic range relative to that of lower impedance cells. Spiking evoked by injecting depolarizing current during rotation was blocked during contraversive motion and was consistent with a shunting inhibition. No morphological features were identified in neurobiotin-filled cells that correlated with the two physiological classes. Recovered motoneurons were multipolar but exhibited a less-complex dendritic morphology than ocular motoneurons of similarly sized mammals. The two physiologically defined cell classes have homologues in other vertebrates, suggesting that intrinsic membrane properties play an important role in oculomotor processing.

The effects of unilateral eighth nerve block on fictive VOR in the turtle.

Multiunit activity during horizontal sinusoidal motion was recorded from pairs of oculomotor, trochlear, or abducens nerves of an in vitro turtle brainstem preparation that received inputs from intact semicircular canals. Responses of left oculomotor, right trochlear and right abducens nerves were approximately aligned with leftward head velocity, and that of the respective contralateral nerves were in-phase with rightward velocity. We examined the effect of sectioning or injecting lidocaine (1-2 microL of 0.5%) into the right vestibular nerve. Nerve block caused a striking phase shift in the evoked response of right oculomotor and left trochlear nerves, in which (rightward) control responses were replaced by a smaller-amplitude response to leftward table motion. Such "phase-reversed" responses were poorly defined in abducens nerve recordings. Frequency analysis demonstrated that this activity was advanced in phase relative to post-block responses of the respective contralateral nerves, which were in turn phase-advanced relative to pre-block controls. Phase differences were largest (approximately 10 degrees) at low frequencies (approximately 0.1 Hz) and statistically absent at 1 Hz. The phase-reversed responses were further investigated by eliminating individual canal input from the left labyrinth following right nVIII block, which indicated that the activation of the vertical canal afferents is the source of this activity.

Do motoneurons encode the noncommutativity of ocular rotations?

As we look around, the orientation of our eyes depends on the order of the rotations that are carried out, a mathematical feature of rotatory motions known as noncommutativity. Theorists and experimentalists continue to debate how biological systems deal with this property when generating kinematically appropriate movements. Some believe that this is always done by neural commands to a simplified eye plant. Others have postulated that noncommutativity is implemented solely by the mechanical properties of the eyeball. Here we directly examined what the brain tells the muscles, by recording motoneuron activities as monkeys made eye movements. We found that vertical recti and superior/inferior oblique motoneurons, which drive sensory-generated torsional eye movements, do not modulate their firing rates according to the noncommutative-driven torsion during pursuit. We conclude that part of the solution for kinematically appropriate eye movements is found in the mechanical properties of the eyeball, although neural computations remain necessary and become increasingly important during head movements.

Proposed treatment strategy for cavernous sinus meningiomas: a prospective study.

OBJECTIVE: To establish a safe and effective treatment strategy for cavernous sinus (CS) meningiomas, we prospectively analyzed the outcome of a treatment protocol combining surgery and radiosurgery during the past 7 years. METHODS: Tumors confined to the CS and distant from the optic apparatus and the brainstem were treated with radiosurgery alone. Tumors attached to or compressing the optic apparatus and brainstem and that were larger than 3 cm in mean diameter, extended into the multiple cranial fossae, and were suspected of being malignant were treated with combined nonradical microsurgery and radiosurgery. RESULTS: In accordance with this treatment protocol, 40 patients aged 26 to 72 years (median, 51 yr) with primary (n = 27) or recurrent (n = 13) CS meningiomas (volume range, 0.9-39.3 cm(3); median volume, 5.4 cm(3)) were treated with combined surgery and radiosurgery (n = 23) or radiosurgery alone (n = 17). During radiosurgery, 12 to 18 Gy (median, 16 Gy) was delivered to the tumor margin. The follow-up period ranged from 14 to 79 months (median, 47 mo). The actuarial tumor control rate was 94.1% at 5 years. The improvement of cranial nerve function was significantly frequent in patients with primary CS meningiomas (P < 0.05). Permanent cranial nerve dysfunction was significantly frequent in patients with tumors compressing the brainstem or smaller than 10 cm(3) (P < 0.05). All 36 patients with a pretreatment Karnofsky Performance Scale score of 90 or more maintained the same range after treatment. CONCLUSION: Proper combination of microsurgery and radiosurgery for CS meningiomas provides excellent growth control with favorable functional state. Outcomes were better when this protocol was adopted at the initial diagnosis for patients with smaller tumors that did not compress the brainstem.

Origins of surface potentials evoked by electrical stimulation of oculomotor nerves: are they related to electrooculographic or electromyographic events?

OBJECT: Evoked potentials elicited by electrical stimulation of the oculomotor nerve and recorded from surface electrodes placed on the skin around the eyeball reportedly originate in the eye and are represented on electrooculograms. Because evoked potentials recorded from surface electrodes are extremely similar to those of extraocular muscles, which are represented on electromyograms, the authors investigated the true origin of these potentials. METHODS: Evoked potentials elicited by electrical stimulation of the canine oculomotor nerve were recorded from surface electrodes placed on the skin around the eyeball. A thread sutured to the center of the cornea was pulled and the potentials that were evoked during the resultant eye movement were recorded. These potentials were confirmed to originate in the eye and to be represented on electrooculograms because their waveforms were unaffected by the administration of muscle relaxant. To eliminate the influence of this source, the retina, a main origin of standing potentials of the eyeball, was removed. This resulted in the disappearance of electrooculography (EOG) waves elicited by eye movement. Surface potentials elicited by oculomotor nerve stimulation were the same before and after removal of the retina. Again the oculomotor nerve was electrically stimulated and electromyography (EMG) response of the extraocular muscles was recorded at the same time that potentials were recorded from the surface electrodes. In their peak latencies, amplitudes, and waveforms, the evoked potentials obtained from surface electrodes were almost identical to EMG responses of extraocular muscles. CONCLUSIONS: Evoked potentials elicited by electrical stimulation of the oculomotor nerves and obtained from surface electrodes originated from EMG responses of extraocular muscles. These evoked potentials do not derive from the eye.