Midbrain Activation Age Limit
Shawna Erholm
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The homeobox gene Otx2 is expressed in the anterior neural tube with a sharp limit at the midbrain/hindbrain junction (the isthmic organizer). Otx2 inactivation experiments have shown that this gene is essential for the development of its expression domain. Here we investigate whether the caudal limit of Otx2 expression is instrumental in positioning the isthmic organizer and in specifying midbrain versus hindbrain fate, by ectopically expressing Otx2 in the presumptive anterior hindbrain using a knock-in strategy into the En1 locus. Transgenic offspring display a cerebellar ataxia. Morphological and histological studies of adult transgenic brains reveal that most of the anterior cerebellar vermis is missing, whereas the inferior colliculus is complementarily enlarged. During early neural pattern formation expression of the midbrain markers Wnt1 and Ephrin-A5, the isthmic organizer markers Pax2 and Fgf-8 and the hindbrain marker Gbx2 are shifted caudally in the presumptive hindbrain territory. These findings show that the caudal limit of Otx2 expression is sufficient for positioning the isthmic organizer and encoding caudal midbrain fate within the mid/hindbrain domain.
The human midbrain and pons contain nuclei of major neurotransmitter systems that send long-range projections to regulate brain activity in cortical and subcortical structures. Despite being small structures, these nuclei are critically implicated in a very wide range of cognitive and bodily functions, and their dysfunction plays an important role in a number of neurological and neuropsychiatric conditions. Hence, there is a considerable interest to develop functional MRI approaches that allow to image their activity in health and disease.
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Internuclear ophthalmoplegia or ophthalmoparesis (INO) is an ocular movement disorder that presents as an inability to perform conjugate lateral gaze and ophthalmoplegia due to damage to the interneuron between two nuclei of cranial nerves (CN) VI and CN III (internuclear).[1] This interneuron is called the medial longitudinal fasciculus (MLF). The MLF can be damaged by any lesion (e.g., demyelinating, ischemic, neoplastic, inflammatory) in the pons or midbrain. The MLF is supplied by branches of the basilar artery and ischemia in the vertebrobasilar system can produce an ischemic INO.[2]
The MLF is a heavily myelinated nerve tract connecting the oculomotor nucleus (CN III) of the ipsilateral side with the paramedian pontine reticular formation (PPRF) and CN VI in the contralateral pons. Thus, demyelinating lesions in the midbrain or pons often produce a unilateral or bilateral INO, usually in young patients. The MLF is located at the dorsomedial brainstem tegmentum (midbrain and pons) ventral to the aqueduct or the fourth ventricle. MLF lies very near to the midline. As both MLFs are close to each other and near to midline, bilateral INO is not rare.
Foveation and binocular single vision of the mobile and immobile objects require coordination between the cranial nerves (II, III, IV, and VI), their interneurons, and various supranuclear influences. CN VI is the final common pathway for lateral horizontal gaze. The PPRF or paraabducens nucleus is the key structure in conjugate horizontal gaze and horizontal saccades. Damage to the PPRF results in impaired horizontal saccade in the same direction. Typically, the PPRF receives information from the higher cortical centers such as the frontal eye fields, occipital and parietal lobes, and the superior colliculus. The frontal eye field controls contralateral saccades and the parietal lobe controls ipsilateral pursuits.[3]
PPRF sends a signal to the CN VI. Some axons from the CN VI innervate the ipsilateral lateral rectus resulting in the abduction of the ipsilateral eye. The signal for contraction of the contralateral medial rectus (for adduction of the contralateral eye) is sent from the CN VI to the contralateral medial rectus subnucleus of CN III via the internuclear pathway called MLF. The activation of the contralateral medial rectus and ipsilateral lateral rectus muscle produces horizontal conjugate eye movement. The side of the INO is named by the side of the adduction deficit, which is ipsilateral to the MLF lesion. The MLF is also involved in multiple other functions including oculovestibular reflex, vertical pursuit, optokinetic (OKN) nystagmus, and coordinates the conjugate ocular movements in response to movement of the head and neck.[4]
Symptoms of INO may vary in severity. Symptoms range from, horizontal diplopia, difficulty in tracking high-speed objects, or dizziness on lateral gaze. Horizontal diplopia is caused by the limitation of adduction in the ipsilateral eye. The diplopia becomes more prominent on looking at objects on the opposite side of the lesion and diplopia is usually not seen in the primary gaze. The patient may also complain of headaches or other deficits due to the involvement of the brainstem. Vertical oblique diplopia related to associated skew deviation may also be another symptom. Interruption of binocular vision resulting from defective conjugate horizontal movements of eyes may cause reading fatigue, visual confusion, loss of stereopsis, oscillopsia, and diplopia. The difficulty in looking at the sides may lead to difficulties during driving or walking and may increase the risk of road traffic accidents or falls. The patients may complain of headaches and vertigo.
A good ocular examination is often all that is required to diagnose INO. The INO is characterized clinically by an ipsilesional adduction deficit (partial or complete) with a contralateral, dissociated, horizontal abducting saccade/nystagmus on attempted gaze to the contralesional side. There is a slow adducting saccadic velocity in the affected side. A skew deviation with the ipsilateral hypertropic eye may be noted. Vertical gaze nystagmus may be noted on upgaze. The INO can be unilateral or bilateral and may present with or without (neurologically isolated) other brainstem findings.
The partial adduction defect may be made clinically more apparent by performing horizontal saccades. There is adduction lag or reduced adducting saccadic velocity on the ipsilateral eye. The OKN drum also can reveal such a subtle reduction in adducting saccadic velocity. The defective input to the medial rectus subnucleus of CN III from the CN VI via MLF causes this ipsilesional adduction deficit or lag.
These may be present in INO and are not necessary for the diagnosis of INO. These are usually seen with bilateral INO and may represent INO plus syndromes. Such abnormal vertical ocular movements include:[4]
Usually, convergence is not affected even in the eye with adduction deficit in horizontal gaze. This is called ''dissociation of convergence''. This is due to the sparing of the convergence pathway including the fibers from the medial rectus subnucleus of the CN III in INO. However, the absence of convergence does not rule out the diagnosis of INO. Previously, the anterior INO of Cogan was thought to arise due to lesion at the level of the CN III nucleus and it was characterized by the absence of convergence.[9] Posterior INO of Cogan was thought to involve the MLF below the CN III nucleus and the convergence was preserved. However, recent studies have found this rule to be debatable.[10]
This syndrome[14] is characterized by no horizontal movement in the ipsilateral eye. The contralateral eye's abduction is preserved, while adduction is nule and there is a abduction nystagmus.[15] However, the convergence, elevation, and depression on both eyes are usually intact. In primary gaze, the contralateral eye is exotropic (paralytic pontine exotropia).[4] When the CN VI nucleus is spared, on volitional horizontal gaze, a gaze palsy is present. However, the vestibulo-ocular reflex[16] and ocular response to caloric stimulus in the ear is normal.
This syndrome[17] is characterized by having one-and-a-half syndrome and a facial fascicular nerve (CN VII) palsy. The fascicle of CN VII wraps around the nucleus of CN VI in the dorsal pons. The ipsilateral eye does not have any horizontal gaze movement and there is ipsilateral lower motor neuron CN VII palsy. The contralateral eye does not have adduction as a part of horizontal gaze palsy, but this eye abducts with abduction nystagmus. The proximity of the PPRF, facial nerve nucleus, and MLF located in the dorsal pons makes this syndrome much more likely. The lesion is most often vascular or demyelinating in the dorsal tegmentum of the caudal pons[18].
Other names for this entity include reverse INO and pseudo abducens palsy. This syndrome is a rare ophthalmoplegia, either bilateral or unilateral that exhibits contralateral adducting eye (rather than abducting eye) nystagmus with abduction restriction on physical exam. It is the reverse of the typical INO, and although the lesion localization is not consistent, it likely is due to CN VI pre-nuclear input asymmetry.[23]
A lesion in the MLF interrupts the neural communication to the CN III subnuclei that allows for conjugate horizontal gaze arising from the final common pathway for horizontal gaze (CN VI nuclei). An INO is a common presentation of multiple sclerosis (MS) in younger patients. Demyelination of the MLF in MS can involve any segment and is frequently bilateral. [24] Internuclear ophthalmoplegia can serve as an important sign for diagnosing MS as it can occur as its first symptom. [25] The relationship between INO and MS has also been extended showing that INO can be used as a biomarker of axonal and myelin integrity in MS. [26]
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