interacting closely with the SC and parts of the cerebellum. This review focuses on the role of the subcortical structures involved in the generation of saccades, placing special emphasis on the cerebellum and the major precerebellar nuclei. Readers interested in the cognitive control of saccades and the spatial processing preparing target-directed saccades, largely cortical functions, are referred to several excellent reviews available on the topic [13, 21].

The Brainstem Saccadic Generator

Oculomotor MNs discharge a burst of action potentials for saccades in their respective ‘on-direction’ and suppress their discharge during saccades in the ‘off-direction’. Burst amplitude is correlated with eye velocity and the number of spikes in the burst scales with saccade amplitude. These transient changes in the discharge of MNs pass over into a tonic level of activity, whose amplitude depends on eye position. Both the size of the transient change during the movement as well at the level of the subsequent tonic activity are determined by input from premotor neurons located in mesencephalic, pontine and medullary regions of the brainstem reticular formation [22]. The burst component of the MN discharge is generated by short-lead burst neurons (fig. 2). Burst neurons for horizontal saccades are located in the paramedian pontine reticular formation (PPRF) next to the abducens nucleus [23], while those for vertical saccades lie in the rostral interstitial nucleus in the midbrain reticular formation (MRF) near the oculomotor nucleus [24, 25]. As the functional architecture of the circuit subserving vertical saccades in the MRF follows the same principles as the one for horizontal saccades in the PPRF, we will restrict our description to the latter (for review on the vertical system, see [26]).

The PPRF projects ipsilaterally to the abducens nucleus [27–30], to the prepositus hypoglossi nucleus (NPH) [27, 28, 30, 31], to the median vestibular nucleus (MVN) [32] and to the posterior vermis [33]. The PPRF receives input from the SC, the posterior vermis via the fastigial nuclei and the FEF. In the PPRF, two types of burst neurons can be distinguished with respect to their action: the excitatory burst neurons (EBNs, or short-lead burst neurons) and the inhibitory burst neurons (IBNs) [34–36] (fig. 2).

The Excitatory and Inhibitory Burst Neurons

The EBNs of the PPRF are responsible for the activation of the agonist MNs of the abducens nucleus which activate the ipsilateral lateral rectus muscle, and via internuclear neurons in the abducens nucleus neurons (INs) they are also responsible for the activation of the agonist MNs in the oculomotor nucleus controlling the contralateral medial rectus muscle [37, 38]. The EBNs are

SC-BN

LLBNs

SC-FN

Fig. 2. Brainstem circuitry involved in the execution of leftward saccades, involving a contraction of the left lateral rectus and the right medial rectus, while the left medial rectus and the right lateral rectus are relaxed (antagonist muscles). VI Abducens nucleus; III oculomotor nucleus; La latch neurons; Tr trigger neurons. Excitatory connections are indicated by filled lines. The inhibitory connections are indicated by dashed lines.

completely silent during intersaccadic periods. On the other hand, these neurons exhibit sharp and vigorous bursts of action potentials during the saccade that starts around 5–15 ms before the ipsilateral saccade [23, 39]. The number of action potentials fired during the saccade increases with saccade amplitude as well as with instantaneous eye velocity [39].

The second type of burst neuron is represented by the IBNs. These neurons inhibit the MN and IN of the contralateral abducens nucleus [35, 40]. The IBNs are involved in the process of relaxation of the antagonist muscles. As the EBNs, the IBNs are silent during the intersaccadic periods and their saccade-related

burst precedes the saccade onset by around 5–15 ms [41]. The duration of the burst is proportional to the duration of the horizontal component of the movement [26].

The Omnipause Neurons

The PPRF contains another distinct population of neurons, critical for the timing of saccades, the OPNs. OPNs discharge tonically during fixation at rates of more than 100 spikes per second and pause for saccades in all directions [42]. The pause starts a few milliseconds before the onset of the burst of EBNs/IBNs and ends at saccade offset. As EBNs and IBNs are subject to potent inhibition from the OPNs, the OPNs contribute to stabilizing fixation. The pause in OPN firing during the saccade, needed in order to allow the saccade to develop, is most probably due to changes in several types of signals, impinging on OPNs. First, it could be due to the cessation of the sustained activity of fixation neurons (SC-FNs) located in the rostral pole of the SC, exciting OPNs monosynaptically [43]. Second, the inhibition of the OPNs during the saccade could also be a consequence of the excitation of the long-lead burst neurons (LLBNs) in the rostral PPRF, influenced by the saccade-related burst neurons located in the SC, outside the fixation zone (SC-BN). These LLBNs, then, excite the EBNs, which inhibit the OPNs via inhibitory latch neurons. A third way to inhibit the OPNs is the excitation of inhibitory neurons located directly between SC-BN and the OPNs [44]. Fourth, inhibition of the OPNs during saccades could originate from indirect inhibitory projections from the caudal fastigial nucleus (cFN), output nucleus of the oculomotor cerebellum [45].

The Tonic Neurons

The EBNs discussed before provide a signal related to eye velocity needed in order to move the eyes against velocity-dependent viscous forces to the target. However, in order to stabilize the eyes in the new position acquired by the saccade, a signal related to eye position, counteracting position-dependent elastic forces, trying to move the eyes back towards straight-ahead, is needed. This signal is provided by tonic neurons (TNs). Horizontal TNs are located in the PPRF, intermingled with horizontal EBNs, and like EBNs they make excitatory connections with MNs. Vertical TNs are found in the MRF next to vertical EBNs. The discharge of TNs is linearly related to eye position. Robinson [54] suggested that the eye position-related signal of TNs could be the result of a mathematical integration of the eye velocity-related signal provided by EBNs. A copy of the eye velocity signal would be sent to a ‘neural integrator’ (NI) in order to generate a tonic command coding for the eye position. This command would allow the MNs to offer the constant position-dependent firing rate needed in order to stabilize the eyes at an eccentric position. Lesion experiments

Fig. 3. The Robinson internal feedback model for saccades. Ed Eye-desired displacement; E* actual eye displacement.

suggest that two structures, the MVN, located caudally to the PPRF, and the NPH, reciprocally connected to the PPRF, MVN, vestibular cerebellum (flocculus) and oculomotor cerebellar vermis (lobuli VI and VII ) are involved in the integration of the velocity command as they lead to an inability to maintain the eyes in an eccentric position: after any centrifugal saccades the eyes turn systematically back to a stable position at straight-ahead [46–48]. It has been proposed that the integration by the NI could be based on local recurrent excitation, i.e. neurons will excite their neighbors, which in turn will feed them back with excitation [49, 50]. The NPH, located caudal of the abducens nucleus, which also contains a high number of TNs coding the position of the eye, is probably part of this excitatory feedback network [51–53]. The activity of TNs increases with the ipsilateral deviation of the gaze. The types of neurons found in the PPRF have distinct roles in an influential model of the control of saccadic eye movements, put forward by Robinson [54], whose key features pervade any later models up to the present day. Probably the major feature is the idea of internal feedback as a way to deal with the unacceptably long latencies of visual feedback signals (fig. 3).

An ongoing targeting saccade should be stopped once the object image has reached the fovea. However, the long latency of visual signals, having an order of magnitude of 50 ms and more, precludes the possibility to use information from the fovea to stop the saccade at the right point in time. The Robinson model (fig. 3) assumes short-latency internal or ‘local’ feedback as an alternative to visual feedback. According to the local feedback concept, the eyes are driven by a signal that is the difference between desired eye position and an estimate of current eye position, the latter provided by the eye position-related TNs. This ‘motor error’ activates the saccadic burst neurons, the EBNs, that generate a pulse of activity proportional to the size of the motor error. The EBN pulse and the TN position step signals are integrated by the ocular MNs and