Fig. 1. Major SPEM-related structures and their connections. The cortical structures (FEF, SEF, MT, MST) project via pontine structures (NRTP, PN) to the cerebellum [vermis, VPFL (FL)]. From here, activity travels via deep cerebellar nuclei (FOR) and the vestibular nuclei (MVN, Y group) to the oculomotor neurons in the brainstem. The anatomical pathway from the FOR to the motoneurons is not well established (dashed line). There is some evidence that the frontal cortex projects mainly via NRTP to the vermis and the posterior cortex mainly via PN to the FL

Anatomy and Physiology

Smooth Pursuit Eye Movements

SPEM are the result of a complex visuo-oculomotor transformation process, which involves many structures at the cortical as well as the cerebellar and brainstem level [31, 32] (fig. 1). Frontal as well parietotemporal areas are involved in smooth pursuit generation. The main areas posterior to the central sulcus are the occipital cortex, the MT, the MST and the parietal cortex. With lesions in the occipital cortex SPEM are abolished in the contralateral hemifield, when step-ramp stimuli are used [33]. However, with sinusoidal stimuli SPEM remain intact due to the use of predictive SPEM properties and the sparing of the macular projection.

Area 17 (occipital cortex) projects ipsilaterally to the MT (also called V5). Neurons here have large receptive fields and encode the speed and the direction of moving visual stimuli [34]. In the monkey, small lesions in the extrafoveal part of the MT cause a deficit in SPEM initiation [35]. Based on functional MRI, the MT in humans is located posterior to the superior temporal sulcus at the parieto-temporo-occipital junction (Brodmann areas 19, 37 and 39) [36].

The MST is adjacent to the MT, from where it receives an input. Also neurons in the MST have large receptive fields and are well suited for the analysis of optic flow [37]. In contrast to the MT, MST neurons can still be active without retinal motion being present [38]. Experimental lesions of the MST produce a SPEM deficit to the ipsilateral side in both visual hemifields [39]. The MST appears to be largely involved in SPEM maintenance, whereas the MT is more involved in SPEM initiation [32]. In man, the homologues of the MT and MST are also adjacent to each other at the occipitotemporoparietal junction.

Over the last years, it became increasingly clear that also the frontal eye fields (FEFs) and the supplementary eye field (SEF) in the frontal cortex are involved in SPEM generation. Both structures, FEF and SEF, have been known for their involvement in saccade generation. The SPEM-area of the FEF is anatomically distinct of the saccade area [40]. Lesions in monkeys [41] and humans [42] cause a severe ipsidirectional deficit particularly in predictive aspects of SPEM. Interestingly, optokinetic responses can be preserved [43]. Also the SEF appears to be involved in predictive aspects of SPEM [44]. It has been suggested that SEF is particularly involved in the planning of SPEM [32].

Evidence starts to emerge that also the basal ganglia [45] and the thalamus are involved in SPEM control. Anatomically, it has been shown that both the saccade and the SPEM-related division of the FEF project to separate areas in the caudate nucleus [46]. Also, the saccade and the SPEM-related division of FEF receive different thalamic inputs [47]. Recent single unit studies indicate that the thalamus regulates and monitors SPEM by providing a corollary discharge to the cortex [48].

There is some evidence that FEF projects mainly to the nucleus reticularis tegmenti pontis (NRTP) [49] and MT/MST more strongly to the dorsolateral pontine nuclei (DLPN) [50] (fig. 1). The DLPN projects only to the cerebellum. Here afferents terminate in lobulus VI and VII of the vermis (oculomotor vermis; OV) [51] and the paraflocculus [49]. Neuronal activity in DLPN would preferentially allow a role in maintaining steady-state SPEM [49]. Discrete chemical lesions in DLPN in monkeys produce mainly an ipsilateral SPEM deficit [52]. NRTP projects to the OV [51] and to a lesser degree to the paraflocculus [53]. Neurons here encode primarily eye acceleration, which would indicate a larger role of NRTP in smooth pursuit initiation [49].

In the cerebellar cortex, the floccular region (FL) and OV are most intensively investigated in relation to SPEM. In monkeys, lesions in both the FL [54] and OV [55] lead to SPEM deficits. OV lesions in monkeys lead to a smooth pursuit gain reduction particularly during the first 100 ms (in the open-loop period). Deficits are also seen in humans after OV lesions [56]. The OV projects to the caudal part of the fastigial nucleus (fastigial oculomotor region; FOR) (fig. 1), where lesions also cause a SPEM deficit (to the contralateral side) [57].

The FL projects directly to the vestibular nuclei, from where SPEM signals can reach the oculomotor nuclei. It is not quite clear yet, how the SPEM signals from FOR reach the oculomotor nuclei.

There is some evidence for two parallel pathways from the cortex for SPEM. The parietotemporal structures (MT, MST) project preferentially to the pontine nuclei, which in turn send afferents to the FL. In contrast, the FEF mainly sends signals via NRTP to the OV and FOR (fig. 1). The functional differences for these two routes at all levels still have to be determined.

Optokinetic Nystagmus

As outlined above, here only the ‘indirect’ or ‘velocity storage’ component of OKN will be considered. Although the ‘velocity storage’ component can be transmitted solely via brainstem pathways, it is important to remember, that these pathways are under cortical control. Bilateral occipital lesions lead to a loss of optokinetic responses in both humans [58] and monkeys [59].

Fibers from the retina terminate in the brainstem in the nuclei of the accessory optic tract (AOT) and the nucleus of the optic tract (NOT), only the latter being part of the pretectal nuclear complex [60]. Both AOT [61] and NOT [50] receive cortical inputs. Being located in the mesencephalon, they project to more caudal brainstem areas like the pontine nuclei, NRTP, the inferior olive, nucleus prepositus hypoglossi and the vestibular nuclei. Neurons in AOT and NOT have large receptive fields and respond best to large textured stimuli moving in specific directions [62].

It is well known that vestibular nuclei neurons not only respond to vestibular stimulation in the dark but also to large moving visual stimuli that cause OKN [15, 14]. During OKAN, vestibular nuclei activity and slow-phase eye velocity change in parallel.

The cerebellum does not appear to play a major role in mediating the ‘indirect’ component of OKN [63]. Cerebellectomy in cat does not greatly affect optokinetic responses. The nodulus and uvula appear to have an inhibitory effect. In the monkey, ablation maximizes the ‘indirect’ component [64]. This lack of inhibition is considered as the cause for periodic alternating nystagmus.

Ocular Following Response

Single unit recordings and chemical lesion studies indicate that the OFR is mediated by a pathway including the MST, DLPN and the ventral paraflocculus (VPFL), i.e. pathways involved in SPEM. Detailed analysis of the neural activity suggests that the MST locally encodes the dynamic properties of the visual stimulus, whereas the VPFL provides the motor command for OFR [65].