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Mesencephalic Locomotor Region/ Mesencephalic Reticular Formation
The pedunculopontine nucleus (PPN) and the cu- neiform nucleus (CNF) make up the mesencephalic locomotor region (MLR),6 also known as the mesen- cephalic reticular formation (MRF). The MLR/MRF is involved in eye movement-related activity.7-9 In ad- dition, it promotes locomotion through the reticulo- spinal pathways10 and influences postural tone and locomotor rhythmicity.11-13 In animal studies, stimu- lation of the CNF has been found to be associated with locomotor initiation, while stimulation of the PPN was associated with locomotor suppression.14 The PPN contains cholinergic, glutaminergic and GABAergic neurons; the cholinergic neurons are those closely associated with locomotion.15 PPN cholinergic neurons are also associated with rapid eye movements in sleep.15 The PPN directly inner- vates the motor neurons involved in eye movements and receives direct projections from the frontal and supplementary eye fields in the cortex.16-20 Neuronal recordings of the PPN in primates have shown differ- ent firing patterns during fixations and saccades.21,22
The PPN receives input from the cerebral cortex and has reciprocal connections with components of the basal ganglia, namely, the substantia nigra [both the substantia nigra pars reticulata (SNr) and the sub- stantia nigra pars compacta (SNc)], globus pallidus and subthalamic nucleus (STN).23-28
Superior colliculus
The superior colliculus (SC) receives inputs from the retina and visual cortex (VC).29-32 Neurons in the SC have projections to saccade generators in the brainstem.33 The SC has been reported to be associ- ated with fixation- and saccade-related activity.34-36 There is no evidence for locomotor function related to the SC; however, the SC does receive afferents from various subcortical structures common to the loco- motor network, such as the SNr, pretectum, and oth- er nuclei in the pons and medulla. SC efferents proj- ect to the thalamus, MLR/MRF, paramedian pontine reticular formation (PPRF), cerebellar locomotor re- gion and cerebellar vermis.37 The PPRF is important for coordinating horizontal saccadic eye move- ments, but its role in locomotion has not yet been ex plored. The PPRF receives input from the frontal eye fields (FEF) through the contralateral SC38 and con- tains burst neurons that generate horizontal sac- cades.39-41
Pontomesencephalic reticular formation
Reticulospinal neurons in the pontomesencephal- ic reticular formation are involved in controlling and maintaining head movements and in generating the quick phase of vestibular and optokinetic head nystagmus toward the same side.42 Omnidirectional pause neurons (OPNs) are inhibitory interneurons in the pontomesencephalic reticular formation that are thought to stabilize fixations and saccades in the horizontal, vertical and oblique directions. OPNs are tonically active during fixations and are silent (i.e., “paused”) during saccades.43 Dysfunction in OPNs is thought to result in fixational instability, with reports of macrosaccadic oscillations, saccadic dysmetria, ocular flutter, and opsoclonus.44,45 The pontomesen- cephalic reticular formation is also involved in trans- mitting locomotor signals to central pattern gener- ators in the spinal cord46 and in controlling balance, locomotion and posture.47,48
Cerebellar vermis
The cerebellum is involved in both locomotion49-54 and saccades.55-65 The fastigial nucleus (FN) of the cerebellum receives input from the vermis, which in turn receives input from the SC through the nucleus reticularis tegmenti pontis.55,66,67 Brainstem saccade generators are driven by the FN and the vermis.41 Studies of transcranial magnetic stimulation direct- ed toward the cerebellar vermis have demonstrated that this area coordinates saccades ipsilateral to the side of stimulation.68 Neuronal discharge in the FN, also known as the cerebellar locomotor region, is linked to coding of proximal movement during lo- comotion.55,69 The FN is thought to act as a pace- maker during locomotion70 and projects to the pon- tomedullary reticular formation in the brainstem.
Thalamus
The thalamus serves as the major relay between cortical and subcortical saccadic generators.71-73 The internal medullary lamina, a myelinated area that divides the thalamus into the anterior, medial and lateral masses, contains nuclei that relay information among multiple areas that control saccades, namely,
the frontal and parietal eye fields, SC, PPRF, stria- tum, cerebellum and the lateral geniculate nuclei.71
The lateral geniculate nuclei and pulvinar are two thalamic nuclei in the ventrolateral area that specif- ically process visual input. The lateral geniculate nu- cleus projects information from the retina to the VC. Connections between the SC and the lateral genicu- late nucleus contribute to saccades that are involved in foveating objects of interest with a high degree of resolution (e.g., facial recognition).74 The pulvinar has connections between the SC and visual cortices and is involved in visuospatial attention to areas in the visual field.75 The pulvinar is an important relay for generating saccades toward visual targets or re- flexive saccades toward or away from stimuli, and this nucleus influences visually guided behavior, in- cluding locomotion. It has been speculated that visu- al and motor information may be integrated in the pulvinar, allowing a distinction between changes in the visual environment caused by external sources versus self-generated visual motion (caused by eye movements or locomotion).74
The ventrolateral nucleus (VL) receives all major saccade-generating afferents in the brainstem and cerebellum and projects to the frontal eye field and the supplementary eye field.76 Similar to the pulvinar, the VL is closely involved in visually guided sac- cades.77 The VL is also a major afferent to the pri- mary motor cortex, and it is not surprising that this region is important for locomotion.78,79
The thalamic reticular nucleus is a thin capsule of inhibitory GABAergic neurons that surrounds the dorsolateral thalamus and functions to modu- late thalamocortical and corticothalamic signals for a multitude of functions.80 In terms of saccadic and locomotor networks, this region functions as an in- hibitory modulator. The thalamic reticular nucleus sends reciprocal inhibitory signals to the lateral ge- niculate nucleus in response to saccade-related vi- sual perturbations to maintain a stable image.81 Re- cordings have revealed phasic bursts of activity in reticular neurons within the receptive field of distal limbs during walking tasks that are thought to fine tune ongoing locomotor activity.82
Basal ganglia
The basal ganglia refers mainly to the caudate and the putamen, which consist of the striatum, globus pallidus, substantia nigra and STN. The nigrostria tal pathway modulates the striatum, affecting all motor output, and is not specific to saccadic or loco- motor control, though its influence over these func- tions is considerable.83-87 The STN receives inputs from the cortex via the striatum and the globus pal- lidus externa (GPe) through the indirect pathway and direct connections from the cortex through the hyperdirect pathway.88 The STN receives inputs from the brainstem, thalamus and cortex. Efferents from the STN travel mainly to the GPi and SNr.89-91 There is evidence that patients with Parkinson disease (PD) who receive deep brain stimulation (DBS) of the STN experience a significant improvement in both saccadic performance92,93 and locomotion93-95 compared to patients that receive other DBS targets, such as the globus pallidus interna (GPi). GPi DBS has been shown to improve locomotion,96 but there is less evidence supporting an improvement in sac- cadic performance,97 though one study found im- provement in antisaccades.98
Aus: The Relationship between Saccades and Locomotion, Anshul Srivastava,1 Omar F. Ahmad,1 Christopher Pham Pacia,2 Mark Hallett,1 Codrin Lungu3, J Mov Disord 2018;11(3):93-106
