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Keywords:

  • brainstem;
  • neuroanatomy;
  • Nissl-pigment staining;
  • oculomotor system;
  • polyglutamine diseases

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. The human oculomotor system generates seven types of eye movements
  5. Six of the seven types of eye movements generated by the human oculomotor system may be impaired in HD
  6. The premotor oculomotor brainstem network is essential for the generation of all types of eye movements necessary for frontal vision and binocularity
  7. The role of the premotor oculomotor brainstem network in the pathogenesis of oculomotor dysfunctions in HD
  8. Application of an unconventional morphological approach is promising for the identification of the pathogenic role of the premotor oculomotor brainstem network in HD
  9. Conclusions
  10. Acknowledgements
  11. References

Recent progress in oculomotor research has enabled new insights into the functional neuroanatomy of the human premotor oculomotor brainstem network. In the present review, we provide an overview of its functional neuroanatomy and summarize the broad range of oculomotor dysfunctions that may occur in Huntington's disease (HD) patients. Although some of these oculomotor symptoms point to an involvement of the premotor oculomotor brainstem network in HD, no systematic analysis of this functional system has yet been performed in brains of HD patients. Therefore, its exact contribution to oculomotor symptoms in HD remains unclear. A possible strategy to clarify this issue is the use of unconventional 100-µm-thick serial tissue sections stained for Nissl substance and lipofuscin pigment (Nissl-pigment stain according to Braak). This technique makes it possible to identify the known nuclei of the premotor oculomotor brainstem network and to study their possible involvement in the neurodegenerative process. Studies applying this morphological approach and using the current knowledge regarding the functional neuroanatomy of this human premotor oculomotor brainstem network will help to elucidate the anatomical basis of the large spectrum of oculomotor dysfunctions that are observed in HD patients. This knowledge may aid clinicians in the diagnosis and monitoring of the disease.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. The human oculomotor system generates seven types of eye movements
  5. Six of the seven types of eye movements generated by the human oculomotor system may be impaired in HD
  6. The premotor oculomotor brainstem network is essential for the generation of all types of eye movements necessary for frontal vision and binocularity
  7. The role of the premotor oculomotor brainstem network in the pathogenesis of oculomotor dysfunctions in HD
  8. Application of an unconventional morphological approach is promising for the identification of the pathogenic role of the premotor oculomotor brainstem network in HD
  9. Conclusions
  10. Acknowledgements
  11. References

Huntington's disease (HD) belongs to the polyglutamine or CAG (cytosine, adenine, guanine)-repeat diseases [1–7]. It is a rare, autosomal dominantly inherited, progressive and currently untreatable neuropsychiatric disorder with an estimated prevalence in Europe and the USA of 4–8:100 000 [8,9]. The HD gene was identified in 1993 on chromosome 4p16.3 and has an expanded and meiotically unstable CAG trinucleotide repeat [10]. The HD gene encodes the disease protein huntingtin, whose mutant form harbours an elongated polyglutamine stretch [1,3–6,11–15]. The function of huntingtin and the mechanism of pathogenesis caused by the polyglutamine expansion in the HD gene currently are only poorly understood [14]. The HD gene in unaffected individuals comprises 6–35 CAG triplets. CAG-repeats that exceed 28 show meiotic instability and CAG-repeat sequences longer than 35 are considered expanded. If the CAG expansion has 41 or more repeats, HD is fully penetrant, while with 36–40 repeats incomplete penetrance occurs [1,3,4,6,7,12–14].

The neuropathological features of HD comprise macroscopical (that is, atrophy of the frontal and temporal cerebral lobes, loss of deep cerebral white matter, widened third ventricles, atrophy of the striatum) (Figures 1 and 2) [1,2,4,14,16–19] and microscopical changes (that is, striatal degeneration and layer-specific neuronal loss in the cerebral neo- and allocortex [1,2,4,14,15,17,19–23]). As striatal degeneration and interruption of basal ganglia loops represent the neuropathological hallmarks of HD [4,14,17,19,22,23], a neuropathological grading system describing the striatal disease progression has been developed by Vonsattel et al. and is widely used as a research tool [1,4,14,19]. Along with the cerebral cortex and striatum, however, several other subcortical grey components may also undergo neurodegeneration during HD: the thalamus, pallidum and hypothalamus [1,4,15–18,23–28].

image

Figure 1. Cerebral atrophy in Huntington's disease (HD). (A) Dorso-lateral aspect of the left cerebral hemisphere of a typical control individual without a medical history of neurological or psychiatric diseases. (B) Dorso-lateral aspect of the left cerebral hemisphere of a clinically diagnosed and genetically confirmed male HD patient (onset of disease symptoms: 55 years; age at death: 91 years; CAG-repeats in the mutated HD allele: 41). Note the marked atrophy of the frontal lobe (1), pericentral region (2), occipital lobe (3) and temporal lobe (4).

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image

Figure 2. Atrophy of the striatum and white matter loss in Huntington's disease (HD). (A) Frontal section through the right basal forebrain of a representative control individual. (B) Frontal section through the right basal forebrain of a clinically diagnosed and genetically confirmed HD patient (onset of disease symptoms: 35 years; age at death: 61 years; CAG-repeats in the mutated HD allele: 45). Note the loss of deep white matter (1), the narrowed corpus callosum (CC) (2) and widened third ventricle (3). The atrophy of the caudate nucleus (C) (4) and putamen (PU) (5) corresponds to grade 2 according to Vonsattel et al.[4,14,19]. AC, anterior commissure; PA, pallidum; PU, putamen.

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Onset of HD symptoms commonly occurs around the age of 40 years [29,30] and is characterized by motor symptoms, such as ‘clumsiness’, ‘tremor’, ‘balance trouble’ or ‘jerkiness’[12]. Choreatic movements, which represent the primary involuntary movement abnormalities in HD, are often among the earliest HD symptoms, progress early, then plateau and wane in the later disease stages [5–7,11,12,27]. Abnormalities of voluntary movements (that is, bradykinesia, dystonia, rigidity, impaired fine motor movements, dysarthria, dysphagia) progress until the time of death and are intimately associated with the functional disability or immobility of HD patients [5–7,11,12,27]. In addition, myoclonic jerks evolving into generalized tonic clonic seizures have been decribed as a rare clinical feature of HD patients [31].

Cognition difficulties may also appear early and progress in tandem with the voluntary movement impairments [1,2,5–7,11,12,27]. Along with additional executive dysfunctions, personality changes, psychiatric disturbances (that is, depression, schizophrenia-like psychotic symptoms) [1–3,5–7,12,27], weight loss [1,2,16,23,27,28,32] and metabolic changes [32], different kinds of oculomotor dysfunctions (that is, impairments of saccades, smooth pursuits, vergence, vestibulo-ocular reflex, optokinetic nystagmus and fixation) [1,33–36] are part of the clinical picture of HD. The occurrence of a subset of these oculomotor dysfunction points to an involvement of the premotor oculomotor brainstem network [2,5,6,27] and underscores the necessity of detailed brainstem studies in HD [37].

In the present review, we: (i) summarize the current knowledge regarding the functional neuroanatomy of the human premotor oculomotor brainstem network; (ii) outline the types of oculomotor dysfunctions that may occur in HD; (iii) provide an overview of the current ideas concerning the pathogenesis of oculomotor dysfunctions in HD; and (iv) recommend systematic pathoanatomical investigations of the premotor oculomotor brainstem network to clarify its role in the pathogenesis of oculomotor HD symptoms.

The human oculomotor system generates seven types of eye movements

  1. Top of page
  2. Abstract
  3. Introduction
  4. The human oculomotor system generates seven types of eye movements
  5. Six of the seven types of eye movements generated by the human oculomotor system may be impaired in HD
  6. The premotor oculomotor brainstem network is essential for the generation of all types of eye movements necessary for frontal vision and binocularity
  7. The role of the premotor oculomotor brainstem network in the pathogenesis of oculomotor dysfunctions in HD
  8. Application of an unconventional morphological approach is promising for the identification of the pathogenic role of the premotor oculomotor brainstem network in HD
  9. Conclusions
  10. Acknowledgements
  11. References

Stabilization of the images of objects of the visual world onto the central foveal region of the retina is a prerequisite for a clear and stable view of our environment. This is achieved by seven different types of eye movements (Table 1) [36]. These eye movements are generated relatively independently by distinct and widely separated oculomotor circuits, which involve a variety of premotor oculomotor brainstem nuclei and only converge at the level of the oculomotor cranial nerve nuclei (that is, oculomotor, trochlear and abducens nuclei) [38–40]. The principle aim of these different types of eye movements is either to stabilize gaze to hold images steadily on the central foveal region or to shift gaze and bring images of objects of the visual world to the retina's fovea independent of head movements (Table 1) [36]. These types of eye movements can be subdivided on the basis of how they aid vision and their physiological properties: saccades, smooth pursuits, vergence, vestibulo-ocular reflex, optokinetic nystagmus, fixation and gaze holding (Table 1) [36,38,40,41].

Table 1.  The eye movements generated by the human oculomotor system and their dysfunctions in Huntington's disease (HD)
Type of eye movementNormal function – dysfunctions in HDReferences
SaccadesFast conjugate eye movements that bring new images of objects of interest onto the central foveal region of the retina; saccades can be voluntary or present as fast phases of vestibulo-ocular reflex and optokinetic nystagmus[36,38,40]
Saccades in HDInitiation deficits, slowing and restricted range of vertical and horizontal saccades; loss of vertical and horizontal saccades[33–37,43–56]
Smooth pursuitsConjugate eye movements that track and hold the image of a small moving visual target on the fovea[36,38,40]
Smooth pursuits in HDVelocity reduction and interruption by inappropriate saccades or square wave jerks[33–36,42,45,49,52]
VergenceDisconjunctive eye movements towards (that is, convergence) or away from each other (that is, divergence) that direct the fovea of both eyes at a single visual object simultaneously and guarantee nearing of visual objects as well as stereoscopic vision[36,38,40]
Vergence in HDInability to converge[33–36,57]
Vestibulo-ocular reflexConjugate eye movements with a slow tracking phase and a rapid resetting phase that hold images of the seen world steady on the fovea during brief head rotations or translations[36,38,40]
Vestibulo-ocular reflex in HDReduced gain of the slow component[33–35,57]
Optokinetic nystagmusCombined conjugate slow tracking pursuit movements and quick repositioning saccades that track and keep the images of large moving visual targets on the fovea[36,38,40]
Optokinetic nystagmus in HDReduced gain of the slow or rapid component; loss of optokinetic nystagmus[33,42,43,45, 49, 54,56–58]
FixationKeeps the image of stationary objects of the visual world on the fovea by minimizing ocular drifts and suppresses saccades that turn the fovea away from the object of interest[36]
Fixation in HDSteady fixation impaired by unwanted saccades[33–36,43,47,48,52,53]
Gaze holdingStabilizes images of objects of the visual world subsequent to gaze shifting and permits stable eye position between eye movements[36,38,40]
Gaze holding in HDVertical and horizontal gaze holding consistently intact (even in the late clinical HD stages)[34–36]

Six of the seven types of eye movements generated by the human oculomotor system may be impaired in HD

  1. Top of page
  2. Abstract
  3. Introduction
  4. The human oculomotor system generates seven types of eye movements
  5. Six of the seven types of eye movements generated by the human oculomotor system may be impaired in HD
  6. The premotor oculomotor brainstem network is essential for the generation of all types of eye movements necessary for frontal vision and binocularity
  7. The role of the premotor oculomotor brainstem network in the pathogenesis of oculomotor dysfunctions in HD
  8. Application of an unconventional morphological approach is promising for the identification of the pathogenic role of the premotor oculomotor brainstem network in HD
  9. Conclusions
  10. Acknowledgements
  11. References

Oculomotor dysfunctions are common clinical features of HD, which can help to establish the clinical diagnosis [42]. Patients in advanced HD stages show a broad range of eye movement abnormalities, including impairments of saccades, smooth pursuits, vergence, optokinetic nystagmus, vestibulo-ocular reaction and fixation (Table 1) [33–37,42,43]. The most prominent symptoms in clinical HD patients are problems with initiating voluntary saccades, slowing of saccades and impaired steady fixation coupled with excessive distractibility (Table 1) [34–36,43,44].

Initiation deficits of vertical and horizontal saccades are very frequent in HD and may already be present in preclinical HD gene carriers and in the early clinical phase of HD [34–37,43–51]. Owing to these initiation deficits, saccades often can only be started with an associated head thrust or blink [33–36,49]. In addition, the vertical and horizontal saccades of HD patients may also be slowed [33–37,42–45,48,49,51–55], hypo- or hypermetric [33–35,37,51–53], restricted in range [34,35,45,48,49] or completely lost [45,55] (Table 1). In the majority of HD patients, slowed and range-limited saccades more frequently occur in the vertical, rather than in the horizontal plane [33,37,45,54]. As with deficits of saccadic initiation, slowed saccades may already be present in presymptomatic HD gene carriers and may emerge early during the course of HD [33,56].

Impaired steady fixation is a frequent, early and characteristic dysfunction of HD (Table 1) [33–36,43,47, 48,52,53]. As affected patients are unable to suppress unwanted saccades during fixation [34–36,48,52,53], they cannot maintain steady fixation (Table 1).

Some HD patients may also show an inability to converge (Table 1) [33–36], a reduced gain of the slow component of the vestibulo-ocular reaction (Table 1) [33–35,57], as well as impairments of the optokinetic nystagmus (Table 1) [33,42–44,49,54,56–58].

Impairments of vertical and horizontal smooth pursuits emerge comparatively late during the course of HD (Table 1). The deficits pertain predominantly to velocity reduction [33–35,42,49], as well as an interruption by inappropriate saccades [34,35,52] or square wave jerks [33,36,45,52].

Vertical and horizontal gaze holding, even in the late clinical stages, are consistently intact in HD patients (Table 1) [34–36].

As oculomotor dysfunctions not only facilitate the clinical diagnosis of HD [42], but also may occur already early during the course of HD, clinicians raised the question whether these dysfunctions could be used as reliable parameters for monitoring the disease progression of HD and for the assessment of therapeutic trials aimed at delaying the onset or progression of HD [36,44,47,55]. Accordingly, specific HD studies aimed at testing the suitability of saccadic latency and velocity for such clinical questions have been performed [36,44,47,55]. These saccadic impairments do not occur consistently in HD patients [33,34,36,42,46,47,54] and may show a ceiling effect [55]. In addition, none of these clinical studies have provided clear evidence on how progression of these saccadic dysfunctions is related to changes in other aspects of motor performance or to cognitive decline over the entire disease course [34]. Therefore, it remains an open question whether oculomotor dysfunctions can serve as reliable parameters for monitoring the clinical progression of HD and/or the assessment of therapeutical interventions.

The premotor oculomotor brainstem network is essential for the generation of all types of eye movements necessary for frontal vision and binocularity

  1. Top of page
  2. Abstract
  3. Introduction
  4. The human oculomotor system generates seven types of eye movements
  5. Six of the seven types of eye movements generated by the human oculomotor system may be impaired in HD
  6. The premotor oculomotor brainstem network is essential for the generation of all types of eye movements necessary for frontal vision and binocularity
  7. The role of the premotor oculomotor brainstem network in the pathogenesis of oculomotor dysfunctions in HD
  8. Application of an unconventional morphological approach is promising for the identification of the pathogenic role of the premotor oculomotor brainstem network in HD
  9. Conclusions
  10. Acknowledgements
  11. References

Before dealing with the role of the premotor oculomotor brainstem network in the pathogenesis of oculomotor dysfunctions in HD, it is important to recapitulate the functional neuronatomy of this human neural network, which has been reviewed recently by us and other authors [38–41,59,60].

The human premotor oculomotor network involves neural circuits subserving the generation of saccades, smooth pursuits, vergence, the vestibulo-ocular reflex, optokinetic nystagmus, fixation, as well as gaze holding [36,59]. It generates and modifies different physiological features of slow and rapid eye movements (e.g. initiation, velocity, accuracy), which become necessary with the emergence of frontal vision and binocularity [36,40]. Located in the brainstem tegmentum, its interconnected nuclei steer the three oculomotor brainstem nuclei (that is, oculomotor, trochlear and abducens nuclei) by means of direct or indirect projections [36,40,41]. The human premotor oculomotor nuclei, with their highly characteristic anatomical alignment and architectonic features, are made up of: the rostral interstitial nucleus of the medial longitudinal fascicle (riMLF), the interstitial nucleus of Cajal (IC), the superior colliculus (SC), the reticulotegmental nucleus of the pons (RTTG; nucleus Bechterew), the superior (SUV) and lateral vestibular (LV) nuclei, the area of the excitatory burst neurones for horizontal saccades (EBN) and the raphe interpositus (RIP), medial vestibular (MV), prepositus hypoglossal (PPH) and dorsal paragigantocellular reticular (DPGI) nuclei (Figures 3 and 4; Table 2) [41].

image

Figure 3. The human premotor oculomotor brainstem nuclei that may play a significant role in the pathogenesis of oculomotor dysfunctions in Huntington's disease. (A) The schematized frontal section through the rostral midbrain shows the medial longitudinal fascicle (MLF) and the rostral interstitial nucleus of the medial longitudinal fascicle (riMLF). The presence of the subparafascicular nucleus (SPF) in the mid-portion of the central complex of the thalamus can serve as an anatomical hallmark for the reliable identification of the riMLF in frontal sections. (B) Schematized horizontal section through the caudal midbrain with the superior colliculus (SC). (C) The schematized horizontal section through the mid-pons shows the reticulotegmental nucleus of the pons (RTTG; nucleus Bechterew) and the MLF. (D) Schematized horizontal section through the caudal portion of the pons with the superior vestibular nucleus (SUV) and the caudal pole of the RTTG, as well as the area of the excitatory burst neurones for horizontal saccades (EBN) located within the reaches of the caudal nucleus of the pontine reticular formation (PNC). (E) Schematized horizontal section through the caudal pons with the SUV, the lateral (LV) and medial vestibular nuclei (MV), the abducens nucleus (VI) and nerve (VI), the raphe interpositus nucleus (RIP) and the MLF. AQ, aqueduct; CG, central grey; CM, centromedian nucleus of the thalamic central complex; CP, cerebral peduncle; DRC, dorsal raphe nucleus, caudal part; EW, Edinger–Westphal nucleus; GI, gigantocellular reticular nucleus; GR, great raphe nucleus; ICP, inferior cerebellar peduncle; JRB, juxtarestiform body; LR, linear raphe nucleus; MCP, medial cerebellar peduncle; MD, mediodorsal nucleus of the thalamus; MEV, mesencephalic trigeminal nucleus; MEV, mesencephalic trigeminal tract; ML, medial lemniscus; MOV, motor trigeminal nucleus; MV, medial vestibular nucleus; PAG, periaqueductal grey; PBB, pontobulbar body; PF, parafascicular nucleus of the thalamic central complex; PL, paralemniscal nucleus; PN, pontine nuclei; PNO, pontine reticular formation, oral nucleus; PV, principal trigeminal nucleus; PVT, paraventricular nuclei of the thalamus; RD, red nucleus; SCP, superior cerebellar peduncle; SN, substantia nigra; SO, superior olive; VPMpc, ventral posterior medial nucleus of the thalamus, parvocellular part; III, oculomotor nucleus; III, oculomotor nerve; V, trigeminal nerve; VII, facial nucleus; gVII, inner genu of the facial nerve; VII, facial nerve; 3, third ventricle; 4, fourth ventricle.

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image

Figure 4. The human midbrain and pontine premotor oculomotor nuclei in Nissl-pigment stained thick tissue sections. (A) Frontal section through the rostral midbrain of a representative control with the rostral interstitial nucleus of the medial longitudinal fascicle (riMLF). The asterisk marks the thalamo-subthalamic paramedian artery. This artery together with the subparafascicular nucleus (SPF) in the mid-portion of the thalamic central complex are anatomical hallmarks for the reliable identification of the human riMLF in frontal sections. For topographical orientation, see Figure 3A. (B) The area of the excitatory burst neurones for horizontal saccades (EBN) of the caudal nucleus of the pontine reticular formation (PNC) in a horizontal section through the caudal pons of a typical control individual. Anatomical hallmarks for the reliable identification of the human EBN in frontal sections are the: inner genu of the facial nerve (gVII) and the pontine component of the medial longitudinal fascicle (MLF). For topographical orientation, see Figure 3D. (C) The raphe interpositus nucleus (RIP) in a horizontal section through the caudal pons of a typical control case. The framed area at the right shows the typical omnipause neurones oriented with their long axes perpendicular to the midline (arrows) at higher magnification. The rootlets of the abducens nerve (VI) passing through the pontine tegmentum can be used as an anatomical landmark for the reliable identification of the human RIP in horizontal brainstem sections. For topographical orientation, see Figure 3E. (D) The lateral (LV) and medial vestibular nuclei (MV) at the pontomedullary junction of a typical control case without any neuropsychiatric diseases. For topographical orientation, see Figure 3E. AD: aldehydefuchsin-Darrow red staining, 100-µm PEG sections. CG, central grey; JRB, Juxtarestiform body; ICP, Inferior cerebellar peduncle; RD, Red nucleus.

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Table 2.  The human premotor oculomotor brainstem nuclei possibly involved in Huntington's disease (HD)
Premotor brainstem nucleusFunctional consequences of lesionsReferencesPrevious pathoanatomica l findings in HDReferences
Rostral interstitial nucleus of the medial longitudinal fascicleSlowing of vertical and torsional saccades; loss or restricted range of vertical and torsional saccades[36,38–40, 59–62,70]No clear evidence for degeneration or intactness[84]
Colliculus superiorIncreased saccade latencies, saccadic intrusions[36,38,39,59]Not investigated 
Reticulotegmental nucleus of the ponsSaccadic smooth pursuits, dysmetrical saccades[38,40,59,65]Not investigated 
Superior vestibular nucleusReduced gain or loss of vestibulo-ocular reflex and optokinetic nystagmus[36,38,66,86]Not investigated 
Lateral vestibular nucleusReduced gain or loss of optokinetic nystagmus[36,86]Degeneration Suggested[16,18]
Area of the excitatory burst neurones for horizontal saccadesSlowing of horizontal and torsional saccades; loss or restricted range of horizontal and torsional saccades[36,38,40,59, 60,62,67]Unclear – inappropriately delineated[83]
Raphe interpositus nucleusSlowed vertical and horizontal saccades[36,38–40,59, 62,69]Unclear – inappropriately delineated[83]
Medial vestibular nucleusReduced gain or loss of vestibulo-ocular reflex, horizontal gaze-evoked nystagmus[36,38,60,86]Not investigated 

The midbrain riMLF contains the premotor burst neurones necessary for the generation of vertical and torsional saccades (Figures 3A and 4A; Table 2) [36,38,39,41,60–62], while the neurones of the adjacent IC participate in vertical and torsional gaze holding [36,38,39,41,59,60,62,63]. The midbrain SC is crucial for the generation of the orienting response to visual or auditory stimuli and is involved in the initiation of saccades. The SC also contributes to vergence and is important for the suppression of unwanted saccades when steady fixation of a target is necessary (Figure 3B; Table 2) [36,38–41,62,64]. The RTTG is integrated into the oculomotor circuit, which guarantees the accuracy of horizontal saccades. It also participates in the generation of horizontal smooth pursuits and harbours vergence-related nerve cells (Figure 3C,D; Table 2) [36,38,41,59,62,65]. The pontine SUV plays a major role in the generation of the vestibulo-ocular reflex and together with the LV contributes to the performance of the optokinetic nystagmus (Figures 3D,E and 4D; Table 2) [36,38,41,66]. The pontine EBN plays a decisive role in the generation of horizontal saccades, as its neurones provide the premotor signals for these rapid horizontal eye movements (Figures 3D and 4B; Table 2) [38–41,59,60,67]. The pontine RIP harbours the saccadic omnipause neurones, which act as a trigger for the initiation of saccades in all directions (Figures 3E and 4C; Table 2) [36,38–41,59,68,69]. The MV, likewise, is integrated into the neural circuit subserving the vestibulo-ocular reflex (Figures 3E and 4D; Table 2). Together with the PPH the MV also participates in horizontal gaze holding [36,38–41,60,62]. In contrast to the inhibitory burst neurones for vertical saccades, the exact anatomical localization of the inhibitory burst neurones for horizontal saccades is well known. They reside in the pontine DPGI [36,38–41,59,60,67]. The main functional consequences of damage to the riMLF, SC, RTTG, SUV, LV, EBN, RIP and MV are summarized in Table 2.

Some of the premotor oculomotor brainstem nuclei involved in the generation of saccades have only recently been identified and neuroanatomically described in studies of the brains of nonhuman primates and humans (that is, riMLF, EBN and RIP) [38,39,59,61,67–69]. These studies represent milestones in our understanding of the functional neuroanatomy of the human premotor oculomotor brainstem network and enabled detailed clinico-pathological correlations in patients suffering from neurodegenerative diseases and showing saccadic dysfunctions [36,38,41,61,70–73].

Along with the post mortem anatomical and pathoanatomical approaches, neuroradiological in vivo studies can also contribute to the research of the human premotor oculomotor brainstem system, thanks to the development and application of advanced techniques (that is, structural and functional magnetic resonance imaging). However, in contrast to the pathoanatomical approach, even the most advanced in vivo neuroradiological techniques merely allow the unequivocal identification of selected human premotor oculomotor brainstem nuclei (that is, SC) and the approximate location of others (that is, riMLF, IC, paramedian pontine reticular formation and PPH) [41,63,74–78]. Unfortunately, these advanced techniques still do not allow an exact location of discrete brainstem lesions [79,80], nor an unequivocal attribution of functional activation to specific human brainstem nuclei [74,79,81]. Thus, the contribution of the in vivo neuroradiological approach to the research of the human premotor oculomotor network is still limited. Post mortem investigation of the brainstems of clinically and neuropathologically well-characterized individuals will therefore continue to reveal the most reliable structure–function relationships and clinico-pathological correlations in the field of human oculomotor research [41,63].

The role of the premotor oculomotor brainstem network in the pathogenesis of oculomotor dysfunctions in HD

  1. Top of page
  2. Abstract
  3. Introduction
  4. The human oculomotor system generates seven types of eye movements
  5. Six of the seven types of eye movements generated by the human oculomotor system may be impaired in HD
  6. The premotor oculomotor brainstem network is essential for the generation of all types of eye movements necessary for frontal vision and binocularity
  7. The role of the premotor oculomotor brainstem network in the pathogenesis of oculomotor dysfunctions in HD
  8. Application of an unconventional morphological approach is promising for the identification of the pathogenic role of the premotor oculomotor brainstem network in HD
  9. Conclusions
  10. Acknowledgements
  11. References

At present, little is known about the morphological correlates of oculomotor dysfunctions in HD, whereby the contribution of the premotor oculomotor brainstem network has not yet been systematically studied. Explanations of oculomotor dysfunctions in HD have most frequently focused on the most prominent oculomotor abnormalities (that is, delay and slowing of saccades, fixation instability) [34–37,46,47,50–54] and have been based mostly on the well-known interruption of the basal ganglia loops [33,34,36,46,47,50,53]. Other explanations have involved a hypothetical contribution of brainstem lesions to the pathogenesis of some oculomotor HD dysfunctions (that is, damage to neural circuits, including the SC to initiating deficits of saccades [34–36,46,50]); degeneration of the saccadic burst neurones in the EBN and/or in the riMLF, or affection of the pontine omnipause neurones to saccadic slowing [34–36,51,53,54]; degeneration of the omnipause neurones of the RIP or the SC to dysmetrical saccades [37,53]; affection of neural circuits, including the SC to fixation instability [34,35,37,46,47,53]. All these explanations failed to consider research from the pregenetic area, which postulated that the vestibular brainstem nuclei may undergo neurodegeneration during HD (Table 2) [16,18]. In addition, based on the results of stereological studies, we suggested a contribution of the thalamic centromedian-parafascicular complex and mediodorsal nucleus to saccadic dysfunctions in HD [25,26]. It is well known that these thalamic nuclei are integrated into neural circuits subserving saccades [25,26,36,82]. However, in contrast to the nuclei of the premotor oculomotor brainstem network, their exact physiological role in the generation of saccades is still a matter of debate [36].

Considering the close parallels between the pathological features of the oculomotor HD dysfunctions (Table 1) and the main effects of damage to a subset of the nuclei of the premotor oculomotor brainstem network (that is, riMLF, SC, RTTG, SUV, LV, EBN, RIP and MV), it appears likely that this subset of brainstem nuclei also undergoes neurodegeneration during HD (Table 2).

In previous HD studies, the aforementioned brainstem nuclei (that is, SC, RTTG) either have not been considered (Table 2), could not be exactly delineated due to inaccurate previous neuroanatomical data (that is, EBN, RIP) (Table 2) [83] or were only investigated in thin tissue sections (that is, riMLF) (Table 2) [84]. Therefore, the role of the premotor oculomotor network in the pathogenesis of oculomotor dysfunctions in HD is still unclear, rendering our knowledge regarding the spectrum of morphological alterations underlying the various oculomotor impairments of HD patients fragmentary (Table 2) [33]. Future pathoanatomical studies of the premotor oculomotor network and clinico-pathological correlations in HD applying the current knowledge about the functional neuroanatomy of this network not only may provide new insights into its role in the pathogenesis of oculomotor HD dysfunctions in HD, but also may be helpful in better understanding the central nervous spread of the pathological process underlying HD.

Application of an unconventional morphological approach is promising for the identification of the pathogenic role of the premotor oculomotor brainstem network in HD

  1. Top of page
  2. Abstract
  3. Introduction
  4. The human oculomotor system generates seven types of eye movements
  5. Six of the seven types of eye movements generated by the human oculomotor system may be impaired in HD
  6. The premotor oculomotor brainstem network is essential for the generation of all types of eye movements necessary for frontal vision and binocularity
  7. The role of the premotor oculomotor brainstem network in the pathogenesis of oculomotor dysfunctions in HD
  8. Application of an unconventional morphological approach is promising for the identification of the pathogenic role of the premotor oculomotor brainstem network in HD
  9. Conclusions
  10. Acknowledgements
  11. References

Pathoanatomical investigation of unconventional 100-µm-thick serial tissue sections stained for Nissl substance (Darrow red) and lipofuscin pigment (aldehydefuchsin), which is complementary to the routine neuropathological procedure, have revealed improved insights into the morphological basis of a large spectrum of oculomotor dysfunctions in different neurodegenerative diseases [41,65,71–73,85–87], but has never been applied in HD brainstem research. Unconventional 100-µm-thick serial tissue sections display significantly more nerve cells in a given grey brain component than the thin single-tissue sections routinely applied by neuropathologists. This not only facilitates the unequivocal identification of discrete central grey components, such as the premotor oculomotor brainstem nuclei, but also aids the detection of pathological changes in them [41,71–73,85–88]. Accordingly, this unconventional post mortem approach represents a promising tool for future studies of the premotor oculomotor brainstem network in HD.

To illustrate the strength of this technique [88], the localization and architectonic appearance of the human premotor oculomotor brainstem nuclei in unconventional 100-µm-thick Nissl-pigment stained tissue sections have been decribed in detail in a recent review [41] (Figure 4).

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. The human oculomotor system generates seven types of eye movements
  5. Six of the seven types of eye movements generated by the human oculomotor system may be impaired in HD
  6. The premotor oculomotor brainstem network is essential for the generation of all types of eye movements necessary for frontal vision and binocularity
  7. The role of the premotor oculomotor brainstem network in the pathogenesis of oculomotor dysfunctions in HD
  8. Application of an unconventional morphological approach is promising for the identification of the pathogenic role of the premotor oculomotor brainstem network in HD
  9. Conclusions
  10. Acknowledgements
  11. References

The clinical picture of HD is associated with a variety of oculomotor impairments. Although the pathological features of some of these impairments point to a pathogenic role of the premotor oculomotor brainstem network in the developmemt of these impairments, this network has never been studied systematically in HD. Therefore, pathoanatomical investigations of this functional network are warranted to define the role of its nuclei in the pathogenesis of oculomotor HD dysfunctions. Unconventional 100-µm-thick Nissl-pigment stained serial tissue sections allow the unequivocal anatomical identification of the human premotor oculomotor brainstem nuclei and are also well suited in defining the pathoanatomy of the premotor oculomotor brainstem network in HD. Studies based on this morphological approach and also incorporating current knowledge about the functional neuroanatomy of this network will help to establish meaningful clinico-pathological correlations in HD, as well as identify the currently unknown role of the premotor oculomotor brainstem network in the pathogenesis of oculomotor dysfunctions in HD.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. The human oculomotor system generates seven types of eye movements
  5. Six of the seven types of eye movements generated by the human oculomotor system may be impaired in HD
  6. The premotor oculomotor brainstem network is essential for the generation of all types of eye movements necessary for frontal vision and binocularity
  7. The role of the premotor oculomotor brainstem network in the pathogenesis of oculomotor dysfunctions in HD
  8. Application of an unconventional morphological approach is promising for the identification of the pathogenic role of the premotor oculomotor brainstem network in HD
  9. Conclusions
  10. Acknowledgements
  11. References