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1 CHAPTER 17

2 Interactions of eye and

3 eyelid movements

4 Neeraj J. Gandhi and Husam A. Katnani

5 Abstract

6 Eyelid movements introduce a profound and transient modification in the positions of the eyes. 7 This chapter describes the types of eye position perturbations and highlights the neural signature 8 within the oculomotor neuraxis that may mediate them. Such results also imply that neural 9 commands considered to encode a coordinated movement of the eyes and the head may, in fact, also 10 integrate movements of the eyelid musculature as well as other skeletomotor effectors. This review 11 also considers the use of blinks as a tool to evaluate the time-course of motor preparation of saccades 12 and to probe whether a premotor signal is present during cognitive processes requiring executive 13 control.

14 Neural commands for the generation of eye movements are routinely relayed to non-extraocular 15 effectors. For example, electromyography (EMG) activity in neck muscles precedes the generation of 16 a saccadic eye movement (see also Corneil, Chapter 16, this volume), even when a head movement 17 is not required or generated. Likewise, activity observed in numerous cortical and subcortical regions 18 encodes integrated movements of the eyes and hand (e.g. Buneo and Andersen, 2006 ; Lünenburger 19 et al., 2001 ). Similarly, eyelid musculature is innervated in association with eye movements (Evinger 20 et al., 1994 ; Fuchs et al., 1992 ; Gandhi, 2007 ; Williamson et al., 2005 ). The objective of this chapter is 21 to review the integration of eyelid and eye movements. The first section of this chapter will briefly 22 characterize eyelid movements. The second will discuss the neural pathways that produce eyelid 23 movements and emphasizes the loci of overlapping control for blinks and eye movements, particu- 24 larly saccades. The third section will review the effects of blinks on characteristics of eye movements, 25 and the neural signatures that correlate with the observed behaviour will be highlighted. The final 26 section will consider the use of blinks as a tool to evaluate the time-course of motor preparation and 27 to probe whether a motor signal is present during cognitive processes requiring executive control. 28 Another important topic on disorders associated with eyelid musculature is not considered here but 29 is covered in a recent review by Helmchen and Rambold ( 2007 ).

30 Characteristics of eyelid movements

31 Two types of lid movements are prevalent. The first is a lid saccade, for which the movement of the 32 upper eyelid is yoked primarily to the vertical component of the eye movement. During upward

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1 vertical movements (Fig. 17.1A ) the levator palpebrae (LP) muscle contracts and raises the upper 2 eyelid to prevent obstruction of vision. The speed of the lid movement matches that of the eye move- 3 ment, generating lid saccades with rapid eye movements or more gradual changes during smooth 4 pursuit (Becker and Fuchs, 1988 ). Downward eye movements (Fig. 17.1B ) are accompanied by 5 a depression of the eyelid, which is mediated by a reduction in LP muscle activity. During down- 6 ward saccades, in particular, LP EMG ceases and the lid ‘falls’. Such downward lid movements are 7 considered passive since they are controlled entirely by the viscoelastic properties of the ligaments 8 and connective tissue surrounding the lid (Becker and Fuchs, 1988 ; Evinger et al., 1984 ; Guitton 9 et al., 1991 ). 10 The second type of lid movement occurs when the eyelid musculature produces a blink. It can be 11 a reflexive movement, triggered by mechanical stimulation of the cornea or the periorbital skin 12 including the eyelashes. It can also be evoked by electrical stimulation of the supraorbital branch of 13 the trigeminal nerve and by exposure to strong visual and acoustic stimuli. It can be produced as a 14 conditioned response as well. Nevertheless, a blink is most prevalent as a spontaneous movement, 15 likely serving to wet and protect the cornea. In addition, it can be voluntary and accompany facial 16 movements such as winking or grimacing. It can also occur as a gaze-evoked blink that accompanies 17 a head-restrained and head-unrestrained gaze shift (Evinger et al., 1994 ; Gandhi, 2007 ) (Fig. 17.1C ). 18 This chapter will only consider gaze-evoked blinks and reflexive blinks triggered through trigeminal 19 activation. 20 Blinks are initiated as a rapid depression of the upper eyelid. This response is due to a cessation of 21 activity in the LP muscle plus a burst of activity in the orbicularis oculi (OO) muscle. In contrast to 22 lid saccades, however, the eyelid gradually returns to an elevated position as a result of a decrease in 23 OO discharge and an increase in LP activity (Björk and Kugelberg, 1953 ; Evinger et al., 1984 ). The 24 amplitude of a lid movement during a blink can span a large range, depending on the strength of the 25 mechanical or electrical stimulation. Regardless of the triggering mechanism, all blinks exhibit simi- 26 lar characteristics (Evinger et al., 1991 ; Gruart et al., 1995 ). The peak speeds of both downward and 27 ensuing upward phases of the blink are linearly related to blink amplitude. However, the duration of 28 the downward component is relatively constant, approximately 30 ms for reflexive blinks and 29 approximately 75 ms for spontaneous blinks; while the return or upward component is slower and

20 A B C 0 0 10 –15 –10 Vertical Vertical –30 0 Horizontal eye amp (deg) eye amp (deg) eye amp (deg) –20 TY071309 TY071309 WL101707 10 0 0

5 –5 –10 Vertical Vertical Vertical 0

blink amp (a.u.) –10 –20 blink amp (a.u.) 0 100 200 blink amp (a.u.) 0 100 200 0 100 200 Time (ms) Time (ms) Time (ms) Fig. 17.1 Coordination of eye and eyelid movements. Temporal traces of eye and corresponding eyelid movements during upward (A) and downward (B) head-restrained saccades. Each trace corresponds to one trial, and movements are aligned on saccade onset. The magnetic search coil technique was used to record the position signals. For the eyelid, a small coil was taped to the upper lid (Gandhi and Bonadonna, 2005 ). Note that these lid saccades are fast movements executed in the same direction as the vertical saccades they accompany. The lid saccade data were collected on the same day from one animal. Thus, although the blink signals are shown in arbitrary units, their calibration is identical for the two panels. C) Temporal traces of horizontal, head-restrained saccades (top) accompanied by gaze-evoked blinks (bottom). Data obtained from another animal. The initial, downward phase of the blink is rapid, while the returning upward phase has a slower time course.

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1 lasts 100–200 ms, with a modest increase in duration with blink amplitude. Thus, the main sequence 2 trends for blinks are different from those observed for saccades, for which duration increases linearly 3 with amplitude and peak velocity obeys a saturating function (Bahill et al., 1975 ).

4 Integration of neural pathways for eye and eyelid movements

5 The tight coordination of saccade–blink interaction can be attributed to the neural circuits which 6 integrate the generation of saccades with the musculature of the eyelid. The OO muscle resembles a 7 skeletal muscle and is controlled by motoneurons in the facial nucleus (Fig. 17.2 ). Most of the neural 8 projections are from the dorsolateral and intermediate divisions of the ipsilateral nucleus (Porter 9 et al., 1989 ). The firing rates of the motoneurons are correlated with lid velocity (Trigo et al., 1999a ). 10 With respect to oculomotor structures, evidence for contralateral tectofacial and tectoreticulofacial 11 projections exists in the rat and cat (Dauvergne et al., 2004 ; May et al., 1990 ; Morcuende et al., 2002 ; 12 Vidal et al., 1988 ), although it can be argued that these collicular signals may encode movement 13 commands for the vibrissae and pinnae (Cowie and Robinson, 1994 ; Hemelt and Keller, 2008 ; 14 Miyashita and Mori, 1995 ; Vidal et al., 1988 ). The superior colliculus also relays information to the 15 facial nucleus via the regions of sensory trigeminal nucleus complex that receives dense afferents 16 from the eyelids (Dauvergne et al., 2004 ; May and Porter, 1998 ). Even neural signals in cortical struc- 17 tures like the frontal eye fields are polysynaptically relayed to OO muscles (Gong et al., 2005 ). Thus, 18 neural commands from numerous oculomotor structures have multiple avenues to innervate the 19 OO muscle for coordinating blinks with saccadic eye movements. In addition, anatomical studies 20 have also identified trigeminotectal pathways (Huerta et al., 1981 , 1983 ; Ndiaye et al., 2002 ) through 21 which blinks can contribute to the activity in superior colliculus and other oculomotor regions. This 22 sensory information does not appear to encode lid position but is most likely limited to information 23 arising from cutaneous receptors (Trigo et al., 1999b ). 24 The LP is considered an extraocular muscle because it shares its embryogenesis with the supe- 25 rior rectus and is innervated by a branch of the superior division of the oculomotor nerve (Fig. 17.2 ). 26 The cell bodies of these motoneurons reside bilaterally within the central caudal division of the

CCN MRF

Levator palpebrae (LP) STC SC (5n) Orbicularis oculi (OO)

Fac Nuc (7n)

Fig. 17.2 A simplified representation of the neural circuit involved in the control of coordinated eye and eyelid movements. Sensory afferents are relayed by the trigeminal nerve to various subnuclei in the sensory trigeminal complex (STC). Direct inhibition of the levator palpebrae (LP) motoneurons in the central caudal nucleus (CCN) results in rapid depression of the LP muscle. Direct projections from the STC to the facial nucleus (Fac Nuc) terminate on motoneurons that innervate the orbicularis oculi (OO) muscle. These two pathways produce the blink reflex associated with the trigeminal reflex. Interactions of neural elements involved in controlling eyelid musculature and eye movements are known to occur at the level of the superior colliculus (SC) and the mesencephalic reticular formation (MRF). See text for details.

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1 oculomotor nucleus complex (Porter et al., 1989 ). Like extraocular motoneurons, the LP moto- 2 neurons are recruited at a threshold lid position and exhibit a tonic firing rate that increases linearly 3 with upward positions. Burst-tonic profiles are observed for upward lid saccades, and a pause in 4 activity precedes fast downward deflections (Fuchs et al., 1992 ). It has been proposed that premotor 5 inputs for upward lid movements originate from the ipsilateral M-group neurons (Horn et al., 2000 ), 6 which reside in the rostral mesencephalon and in the vicinity of the rostral interstitial nucleus of the 7 medial longitudinal fasciculus (riMLF). Neurons in the M-group, in turn, receive inputs from oculo- 8 motor structures like the riMLF and the superior colliculus (Horn and Büttner-Ennever, 2008 ). 9 Passive downward deflection of the lid during a downward saccade requires inhibition of activity in 10 LP motoneurons. This could be implemented as direct inhibition by GABA-ergic neurons that 11 encode downward saccades (Horn and Büttner-Ennever, 2008 ). Such cells are found in the intersti- 12 tial nucleus of Cajal (INC) (Horn et al., 2003 ). They could also inhibit the M-group neurons, thereby 13 reducing or removing their excitatory drive to the LP motoneurons. Additional inhibition of LP 14 motoneurons is postulated to stem from projections from the sensory trigeminal complex either 15 directly or via an interneuron (May et al., 2002 ; van Ham and Yeo, 1996 ). 16 The omnipause neurons (OPNs) in the paramedian pontine reticular formation are normally 17 associated with saccadic eye movements (see also Cullen and Van Horn, Chapter 9, this volume). 18 They serve to ‘gate’ saccades (Keller, 1974 ) by inhibiting the burst generator neurons. In addition, 19 they also become quiescent during blinks (Fuchs et al., 1991 ; Mays and Morrisse, 1994 ), although the 20 cessation of activity appears linked to the transient eye movement associated with the blink that the 21 blink itself (Schultz et al., 2010 ). While this result downplays the potential association between OPNs 22 and blinks, they cannot explain why stimulation of the OPNs prevents reflexive blinks (Mays and 23 Morrisse, 1995 ). More recently, Horn and Büttner-Ennerver (2008 ) reported that a subgroup of 24 OPNs inhibit LP motoneurons in the central caudal nucleus. This observation is counterintuitive 25 because inhibition of OPNs would disinhibit the LP motoneurons, which would prevent the rapid 26 depression of the upper lid. We speculate that the source of suppression on the OPNs also imposes a 27 potent inhibition of the LP motoneurons such that the resulting disinhibition from OPNs is negligi- 28 ble. The source of this inhibition is not known and needs to be addressed by future investigations.

29 Effects of blinks on eye movements

30 Blinks evoked during fixation 31 The eyes rotate within the orbits during blinks. Blink-induced eye movements during fixation are 32 caused by co-contraction of the extraocular muscles, except the superior oblique. For blinks gener- 33 ated when fixation is maintained in the straight-ahead location (Bergamin et al., 2002 ; Bour et al., 34 2000 ; Evinger et al., 1984 ; Helmchen and Rambold, 2007 ; Riggs et al., 1987 ; Rottach et al., 1998 ), the 35 eyes move downward and nasally with an extorsional component during the downward phase. They 36 then return in a loop-like fashion towards the original position before the end of the upward phase 37 of the blink. It has been suggested that these eye movements are too slow to be considered saccades 38 (Collewijn et al., 1985 ). Furthermore, the movement of the eye during a blink is dependent on initial 39 eye position. For blinks produced or evoked with the eyes in more eccentric positions, the horizontal 40 component increases for the abducting eye, while the vertical component increases with increas- 41 ingly upward gaze. In contrast, the two components decrease with adduction and downward gaze, 42 respectively. These results conform to the notion that the blink induced eye movement brings the 43 eyes toward a primary position during the downward phase, and the eyes return towards the initial 44 position as the eyes reopen. 45 Mechanical interactions of the eyelid and the globe do not fully account for the observed eye move- 46 ment patterns. Neural activity recordings from oculomotor and abducens motoneurons reflect 47 changes associated with the movement (Delgado-Garcia et al., 1990 ; Evinger and Manning, 1993 ; 48 Trigo et al., 1999a ). The blink-related signal most likely originates from the ophthalmic region of the 49 trigeminal nucleus which projects to the supraoculomotor area that has connections with oculomotor

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1 motoneurons (Evinger et al., 1987 ). Trigeminal inputs have also been identified in the abducens 2 motoneurons (Baker et al., 1980 ; Cegavske et al., 1979 ).

3 Saccade–blink interactions 4 A reflexive blink, timed to occur during a saccade, grossly perturbs the spatiotemporal properties of 5 the eye movement. Such eye movements have been useful in probing neural mechanisms that trigger 6 and control the accuracy of saccades. For a normal saccade, the spatial trajectory is a relatively straight 7 line between the initial and final positions, and the temporal velocity waveform exhibits a bell-shaped 8 profile. For a saccade accompanied by a blink, in contrast, the trajectory is highly curved, typically 9 upwards (Goossens and Van Opstal, 2000a ); the peak velocity is substantially reduced; and the dura- 10 tion of the movement increases. The endpoint accuracy is preserved even in the absence of visual 11 feedback (Gandhi and Bonadonna, 2005 ; Goossens and Van Opstal, 2000a ; Rambold et al., 2002 ; 12 Rottach et al., 1998 ). These eye movement patterns observed during blink-perturbed saccades cannot 13 be accounted for by a linear superposition of a normal saccade and a blink-associated eye movement 14 observed during fixation (Goossens and Van Opstal, 2000a ). Blinks also influence the latency of 15 saccades. In particular, a blink triggered around a typical saccade reaction time reduces the latency 16 (Evinger et al., 1994 ; Gandhi and Bonadonna, 2005 ; Goossens and Van Opstal, 2000a ; Rambold 17 et al., 2002 ). A comprehensive examination of latency effects is considered later in this chapter, in the 18 section on motor preparation. 19 The effect of reflexive blinks on saccades is represented in the neural activity patterns of saccade 20 related neurons in various oculomotor structures. The initial effect of the air puff, which evokes the 21 reflexive blink, is an immediate attenuation of activity in superior colliculus neurons (Goossens and 22 Van Opstal, 2000b ). The weakened discharge is prolonged in duration such that the total number of 23 action potentials fired by the neuron remains comparable in the control and blink perturbations 24 conditions. The fast response time of approximately 10 ms suggests that the trigeminotectal pathway 25 most likely produces the suppressive effect, either directly or through interneurons. Nigrotectal 26 input, which imposes global inhibition on the superior colliculus, may also participate in blink 27 induced modulation (Basso et al., 1996 ; Evinger et al., 1993 ). 28 To the best of our knowledge, no published accounts exist of neural recordings performed during 29 saccades accompanied by gaze-evoked blinks. One reason for the absence of data is that the probabil- 30 ity of generating a blink is negligible during small saccades, although the likelihood does increase 31 with saccade amplitude (Williamson et al., 2005 ). Furthermore, the tendency of blink generation is 32 also modulated by extraretinal factors, such as the cognitive set of performing an oculomotor task, 33 because blinks are routinely generated during the ‘return saccades’ in the intertrial interval 34 (Williamson et al., 2005 ).

35 Effects of blinks on head-unrestrained gaze shifts 36 Like head-restrained saccades, head-unrestrained gaze shifts generate a rapid change in the line of 37 sight, except that the action is produced as a coordinated movement of the eyes and the head. The 38 velocity profile of the saccadic eye component of large amplitude head-unrestrained gaze shifts is 39 generally not the bell-shaped curve typically seen with head-restrained saccades. The waveform will 40 often exhibit two pronounced peaks with a significant attenuation in-between. The observation has 41 led to the hypothesis that the head command attenuates the gain of the eye pathway: the saccade 42 proceeds more slowly and takes longer to complete (Freedman, 2001 ; Freedman and Sparks, 2000 ). 43 As described above, blinks grossly attenuate the spatiotemporal profile of saccades. Furthermore, 44 the probability of gaze-evoked blinks, assessed by the EMG of OO muscle, increases with both 45 gaze and head amplitude (Evinger et al., 1994 ). This enhanced EMG is observed even during large 46 head movements generated with the eyes closed. Hence, Evinger et al. (1994 ) concluded that one 47 component of the command for large amplitude gaze shifts is used to generate a gaze-evoked blink. 48 Therefore, the attenuation in the eye velocity could also be accounted for by gaze-evoked blinks

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1 (see Gandhi ( 2007 ) for a preliminary study). Gaze, head, eye, and eyelid signals were measured as 2 monkeys oriented to visual targets. For matched eye, head, and target positions, the gaze shifts were 3 separated into movements with and without gaze-evoked blinks. Figure 17.3A shows temporal plots 4 of head and eye-in-head velocities, and blink amplitude of individual trials aligned on gaze onset. 5 The initial head and fixation target was 30 ° to the right, thus the eyes were centred in the orbits.

A 0

Head vel –200

200 Eye vel

–200 Velocity (deg/s)

–400 Amp (a.u.) Blink

–200 0 200 400 600

B 600

400

200 Firing rate (Hz)

0 –50 0 50 100 150 Time (ms) Fig. 17.3 Effects of gaze-evoked blinks on coordinated eye-head movements. A) Temporal traces of head velocity (top), eye-in-head velocity (middle) and eyelid amplitude (bottom) for large amplitude gaze shifts matched for initial eye and head position. Each trace represents one movement, and all traces are aligned on gaze onset. Black traces represent trials with gaze-evoked blinks, denoted by the deflection in the blink signal. Grey traces are trials without an accompanying blink. The vertical arrows denote the average times of peak head velocity in the two conditions. For gaze-evoked blink trials the head velocity reaches its peak later, and its average magnitude is greater also. B) Mean discharge profile of an excitatory burst neuron recorded during gaze shifts with (black trace) and without (grey trace) gaze-evoked blinks. Time zero corresponds to gaze onset. The neural activity does not correspond to the data shown in panel (A). The purpose of the panel is only to demonstrate blink related modulation in the neural activity. Also note that the time scale is different from panel (A). Adapted from Gandhi ( 2007 ).

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1 Gaze shifts were directed to a target presented 36° to the left. For these movements, the average head 2 amplitude was 55 ° . Blinks overlapped with gaze shifts on trials in which the eye velocity profiles 3 showed distinct multiple peaks (two peaks in black traces). The eye velocity profiles on trials without 4 blinks did not exhibit pronounced multiple peaks (grey traces). Neural activity of excitatory burst 5 neurons in the oculomotor pons also reflect the multiple peaks observed in the eye and gaze velocity 6 profiles of gaze shifts accompanied by gaze-evoked blinks, and the multiple peaks are absent in non- 7 blink trials (Fig. 17.3B ). Our unpublished data also indicate that the temporal pattern of multiple 8 peaks in eye velocity depends on the relative timing of the blink and gaze shift, which can vary 9 between animals. These results collectively provide another, perhaps additional, explanation for the 10 multiple peaks observed in the eye velocity waveform. We do not view these observations as either 11 test or rejection of the eye-head coupling hypothesis (Freedman, 2001 ; Freedman and Sparks, 2000 ). 12 We instead prefer the interpretation that the brain issues a command for an integrated movement of 13 the eyes, eyelids, and the head, and the altered eye velocity profiles during such movements could be 14 due to both eye-head coupling and eye-eyelid interactions. 15 Head-unrestrained gaze shifts associated with blinks show other interesting characteristics also. 16 When a reflexive blink is triggered just prior to the onset of a gaze shift, the latency of both gaze and 17 head components are reduced (Evinger et al., 1994 ). The blink induced perturbation in the eye veloc- 18 ity increases the duration of the gaze shift. We have observed that both the magnitude and time of 19 peak head velocity also increase (see black and grey arrows in Fig. 17.2A ) (Gandhi, 2007 ), such that 20 the peak aligns with the end of the gaze shift (Chen, 2006 ).

21 Effects of blinks on slow eye movements 22 The effects observed for saccade-blink interactions also extend to slow eye movements. For example, 23 blinks attenuate the speed of ongoing smooth pursuit regardless of direction of pursuit (Rambold 24 et al., 2005 ), and evoking a reflexive blink just before the typical onset of smooth pursuit reduces the 25 latency by approximately 10 ms (Rambold et al., 2004 ). For vergence eye movements accompanied 26 by a blink, the initial response is a transient convergence followed by a divergence independent of 27 the direction of the eye movement. This pattern is followed by an attenuation in the velocity and 28 increase in duration (Rambold et al., 2002 ), comparable to the effects seen for head-restrained and 29 head-unrestrained gaze shifts and smooth pursuit.

30 Behavioural evaluation of motor preparation

31 A typical saccadic eye movement is initiated approximately 200 ms after a stimulus is presented in 32 the visual periphery. Approximately 60–80 ms are required for afferent processes, such as the relay of 33 sensory signals from the retina to various cortical and subcortical regions. Another 20 ms are 34 accounted for by efferent pathways to send motor commands from the superior colliculus, for 35 example, to the extraocular muscles. Thus the transduction time for a neural signal to travel from 36 the retina to the extraocular muscles is substantially shorter than the typical reaction time of a 37 saccade (Carpenter, 1981 ). A subset of saccade related burst neurons in the frontal eye fields (Hanes 38 and Schall, 1996 ; see also Johnston and Everling, Chapter 15, this volume) and superior colliculus 39 (Paré and Hanes, 2003 ; see also White and Munoz, Chapter 11, this volume) exhibit a low frequency 40 discharge that increases its firing rate gradually during the intervening approximately 100 ms 41 sensory-to-motor transformation period. When the firing rate reaches a threshold activation level, 42 which can vary from neuron to neuron, the cell emits a high frequency burst, which leads to the 43 inhibition of OPNs and initiation of the planned saccade. Furthermore, the firing rate level of the 44 low-frequency response is negatively correlated with the saccade reaction time (Dorris et al., 1997 ). 45 It has been hypothesized that the low frequency discharge represents a motor preparation signal that 46 encodes both timing and metrics of the desired saccade (Glimcher and Sparks, 1992 ). 47 Gandhi and Bonadonna (2005 ) asked whether it was possible to obtain a behavioural readout of the 48 planned movement. They reasoned that if prematurely inhibiting the OPNs before they ordinarily

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ACB 500

400

300

200

100

Saccade latency (ms) 0 TY021204 TY021304 TY031904 Fixation point Target –400 –200 0 200 400 –600 –400 –200 0 200 400 –800 –600 –400 –200 0 200 400 Time of blink re saccade cue (ms) Fig. 17.4 Saccade onset is plotted as a function of the time of the trigeminal blink reflex during performance in the step (A), gap (B), and delayed (C) saccade tasks. Both parameters are measured with respect to the cue to initiate the saccade, which is defined as the later of fixation point offset or target onset. Note the lawful relationship between blink time and saccade latency across the three tasks. Blinks evoked well before (< − 200 ms) the cue epoch typically did not influence saccade time; the values are similar for non-puff trials. This is followed by a period for which blinks increase saccade latencies. Then, there is an abrupt decrease in latencies, to values lower than control. We refer to these as blink-triggered saccades because the blink and saccade onset temporally overlap (enclosed within the dashed ellipses). In the delayed saccade task, the shaded area denotes the overlap period for which both fixation point and the eccentric saccade target remain illuminated. Both rightward (circles) and leftward (squares) target presentation trials are shown. Horizontal dashed lines are drawn to mark a latency of zero (equal to cue to initiate saccade). The bottom portion of each panel shows the time course of the behavioural task. Adapted from Gandhi and Bonadonna ( 2005 ).

1 become quiescent is equivalent to reducing or eliminating the activation threshold, then an eye move- 2 ment should be triggered at a reduced latency if the low frequency activity in neurons of the oculomo- 3 tor neuraxis indeed encodes a motor component. Testing this hypothesis requires transient inhibition 4 of the OPNs, which was accomplished by invoking the trigeminal blink reflex. Monkeys were required 5 to make visually-guided saccades from a central fixation point to another stimulus that was illumi- 6 nated briefly at one of two locations. On randomly selected trials and at unpredictable times during 7 these trials, a puff of air was delivered to evoke a blink. The latency, accuracy and kinematics of the 8 saccade were measured. This approach allowed experimental control of evoking the blink at various 9 times relative to stimulus onset, thereby permitting the characterization of the time-course of blink 10 effects on saccade latency. 11 Figure 17.4 plots saccade latency as a function of blink time for three different oculomotor tasks 12 performed on separate days. In the step paradigm (Fig. 17.4A ), the offset of fixation point coincided 13 with the presentation of the peripheral stimulus, and this event served as the cue to initiate the 14 saccade (time=0). For blinks evoked more than 150 ms before the target presentation, saccade latency 15 remained constant (∼225 ms in panel A), and this value was comparable to the latency observed in 16 non-blink trials. For blinks evoked between 150 before to 100 ms after target onset, saccade latency 17 increased linearly (Gandhi and Bonadonna, 2005 ; Rambold et al., 2002 ). The most logical explana- 18 tion for the increase is that the eyes are closed or closing when the target is illuminated. The visual 19 target is sufficiently processed only after the eyes reopen. Thus the later the blink occurs within this 20 period, the later the eyes re-open, and the longer the saccade latency. If the blink is evoked some time 21 after the peripheral target is turned on, then there exists the possibility that the sensory neural chan- 22 nels in the brain may have processed the stimulus before the eyes closed. In such cases, the blink 23 triggers the eye movement at a reduced latency. Indeed blinks triggered more than 60 ms after stimu- 24 lus onset are often accompanied by a saccade towards the stimulus (Gandhi and Bonadonna, 2005 ;

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1 Rambold et al., 2004 ). Additionally delaying the blink also prolongs the onset of the saccade, and 2 saccade latency increases linearly with blink time until the typical reaction time of saccades is reached 3 (points enclosed within dashed ellipse). An air puff, timed to evoke a blink even later, typically results 4 in an average latency saccade that precedes the blink. 5 Figure 17.4A also highlights a window of time around stimulus onset during which blinks can 6 either reduce or prolong saccade latency. It has been suggested that the rate of increase in activity in 7 saccade related burst neurons in the oculomotor system is a stochastic property (Carpenter and 8 Williams, 1995 ; Hanes and Schall, 1996 ). If the low frequency discharge at blink onset is high enough 9 to exceed the blink-reduced threshold, then a combined saccade-blink movement will occur. On the 10 other hand, if the instantaneous firing rate is too low at the time of blink onset, the visual target 11 would need to be reprocessed after the eyes reopen, which will result in an increase in saccade reac- 12 tion time. 13 In the gap task (Fig. 17.4B ), a fixed 200-ms interval elapses between the offset of the fixation point 14 and the onset of the peripheral stimulus. This permits fixation to become disengaged prior to saccade 15 preparation. The overall effects of blinks on saccade latency were comparable to those observed with 16 the step task. Interestingly, blinks generated towards the end of the gap period often triggered 17 saccades to one of the two possible target locations. Thus, saccade latency can lead stimulus onset, 18 and the endpoint of the eye movement can land at the future target location on approximately 50% 19 of the trials. This result is consistent with the observation that disengaged fixation introduced by the 20 gap period allows preparatory activity encoding the two possible goals to begin accumulating in 21 superior colliculus neurons (Dorris et al., 1997 ). When the blink occurs towards the end of the gap 22 period, the saccade that gets generated is the one encoded by the winner of the competing low 23 frequency activity at the separate sites in two colliculi. 24 In the delayed saccade task (Fig. 17.4C ), the fixation point remains illuminated for few hundred 25 milliseconds after the saccade target is presented. In this paradigm, the animal must implement top- 26 down control to inhibit the tendency to reflexively orient to the stimulus. The animal is rewarded for 27 looking at the peripheral stimulus only after the fixation point is extinguished. Neural recordings 28 from various oculomotor regions show sustained low-frequency discharge during the ‘overlap 29 period’ during which both the fixation point and saccade target are illuminated (e.g. Wurtz et al., 30 2001 ). The effect of a blink evoked after the animal receives the cue to initiate (fixation offset) the 31 saccade is very similar to that observed for the step and gap tasks. Of chief interest in this task, 32 however, is the overlap period (shaded region in Fig. 17.4C ). In general, blinks evoked during much 33 of the overlap period are not effective in triggering saccades (Gandhi and Bonadonna, 2005 ). 34 Multiple, non-exclusive interpretations can be extracted from the data and additional experiments 35 are required to test them. On one hand, it is possible that the premotor signal isn’t formulated unless 36 the animal is operating in a reflexive mode or until the animal receives permission to trigger the 37 saccade. On the other hand, the blink-induced attenuation in the low frequency activity in saccade 38 related neurons (Goossens and Van Opstal, 2000b ) might not exceed the activation threshold during 39 the overlap period, even though the OPNs presumably cease to fire during the eye closure. Note that 40 the blink-induced suppression in activity must be greater during the overlap period of the delayed 41 saccade task compared to that seen during visually-guided step saccades because, in the latter condi- 42 tion, the blink does trigger a saccade. Another potential explanation is that OPNs are not the only 43 source of inhibition that must be overcome to trigger a saccade, and that these inputs are not 44 suppressed during blinks produced across periods requiring top-down control (such as during the 45 overlap period). Both the basal ganglia (substantia nigra pars reticulata and caudate nucleus) and the 46 so-called fixation neurons in the rostral superior colliculus are viable candidates since each is postu- 47 lated to prevent saccade generation (Hikosaka and Wurtz, 1983 ; Munoz and Wurtz, 1993a , 1993b ; 48 Watanabe and Munoz, 2010 ). However, the activity patterns of these structures during blinks, both 49 with and without saccades, remain to be investigated. 50 The results of blink-triggered saccades conform to the hypothesis that the low-frequency discharge 51 observed during sensorimotor integration encodes motor preparation, although it does not discount 52 the possibility that other cognitive processes, such as target selection (e.g. Basso and Wurtz, 1997 )

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1 and reward expectation (e.g. Ikeda and Hikosaka, 2003 ), may be represented also. If so, what aspect(s) 2 of motor preparation are signalled by the low frequency activity? For the blink-triggered saccades in 3 all three oculomotor tasks, the endpoint accuracy of the saccade was preserved even though the eye 4 movements were highly curved, attenuated in peak velocity, lengthened in duration, and directed to 5 a remembered location. Thus, the metrics of the saccade are not reflected in the firing rate; the 6 saccade vector is encoded by the locus of population activity in the superior colliculus and cortical 7 eye fields. The temporally evolving low frequency discharge likely indicates the speed of the desired 8 movement. For saccades triggered soon after stimulus onset, when the low frequency activity is mini- 9 mal, the initial speed of the eye movement is very slow. As the time of the evoked blink is delayed, the 10 low frequency activity has the opportunity to accumulate, and the initial speed of the accompanying 11 saccade is higher (Gandhi and Bonadonna, 2005 ). The notion that the location of active population 12 encodes the saccade metrics while the firing rate determines the speed of the movement has been 13 termed dual-coding hypothesis, at least for the superior colliculus (Sparks and Mays, 1990 ).

14 Executive control 15 Existing data indicates that air-puff perturbation is most effective at producing a blink-triggered saccade 16 once the animal has permission to produce the eye movement, in other words, when the animal is 17 performing reflexive oculomotor tasks (Gandhi and Bonadonna, 2005 ). It is possible to implement 18 conditions that employ executive or top-down control even within the context of such reflexive tasks. 19 We consider the use of blinks to gain insights into executive control for two such tasks.

20 Movement cancellation 21 Voluntary control of action has been studied through behavioural, theoretical, and neurophysiologi- 22 cal frameworks associated with the cancellation of an intended movement, also called the counter- 23 manding task (e.g. Hanes and Schall, 1995 , 1996 ; Lappin and Eriksen, 1966 ; Logan and Cowan, 1984 ; 24 Mirabella et al., 2006 ; Paré and Hanes, 2003 ). The standard procedure employed in the laboratory is 25 to perform visually-guided saccades, as in the step task discussed above. On a subset of trials, a second 26 cue is illuminated, instructing the subject to cancel the intended movement. The time elapsed 27 between the onset of the saccade target and the presentation of the stop cue generally dictates the 28 likelihood of successfully cancelling the movement. Analyses of the behavioural data have been used 29 to estimate the minimum time required to cancel a planned movement, also known as the stop signal 30 reaction time (SSRT). Note that the SSRT is unobservable because if the movement is successfully 31 withheld, there is no way to know exactly when the movement was cancelled. Thus, the SSRT has 32 been estimated using statistical techniques. Walton and Gandhi (2006 ) attempted to provide a behav- 33 ioural readout of the SSRT estimate and thereby test its validity. They argued that evoking a blink 34 ceases activity in the OPNs (Fuchs et al., 1991 ; Mays and Morrisse, 1994 ; Schultz et al., 2010 ), which 35 in turn would ‘unmask’ the existing motor preparation signal as long as it is not successfully inhibited 36 after presentation of the stop cue. As observed for visually guided saccades, blinks evoked approxi- 37 mately 50 ms after presentation of the saccade target generally resulted in a prematurely triggered eye 38 movement. On countermanding trials, blink-triggered saccades were rarely observed approximately 39 70 ms after the stop cue. This value closely matches the estimated value of SSRT and therefore grants 40 validity to the statistical approach as well as neurophysiological studies that rely on this assumption.

41 Antisaccades 42 In general, the default action plan is to orient to a stimulus presented in the periphery. For a stimulus- 43 response mapping that requires the generation of an eye movement to the mirror location of the 44 stimulus (antisaccade), a reflexive motor plan to the stimulus must be inhibited and the antisaccade 45 movement plan must be formulated (Munoz and Everling, 2004 ). Katnani and Gandhi ( 2008 ) explored 46 whether the trigeminal blink reflex can be used as a behavioural readout of the motor planning that

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1 takes place during an antisaccade task. They employed a modified version of the visual search task used 2 by Schall and colleagues (Juan et al., 2004 ; Sato and Schall, 2003 ). Each trial began with several hundred 3 milliseconds of fixation on a central visual target. The stimulus was then extinguished and fixation was 4 maintained at the central location for another 200 ms. Following this gap period, a visual search array 5 consisting of four stimuli spaced apart by 90° was presented. Randomly, on each trial, one of the four 6 stimuli could be either red or green in colour indicating the singleton stimulus in the array, while the 7 other three targets were purple. The monkeys were trained to make a saccade to the singleton if it was 8 green and to the opposite distractor, 180 o from the singleton, if red. Working on the premise that 9 1) blinks can provide a readout of the motor plan (Gandhi and Bonadonna, 2005 ) and 2) an underlying 10 motor preparation signal is present during this task, the transition in the motor command from the 11 singleton to the opposite distractor should be revealed by a blink reflex at some short time after the 12 search array is presented. For the prosaccade condition, in contrast, all blink-triggered saccades should 13 be directed to the singleton across the entire range of blink times. 14 Figure 17.5 , panels A and B, show saccade latency as a function of blink time for prosaccade and 15 antisaccade trials. Note that the distribution of data observed with the visual search task is very simi- 16 lar to that observed for the single target condition (Fig. 17.4 ), suggesting that the blink-induced 17 effects are also present during performance in the visual search paradigm. For prosaccade trials the 18 majority of the blink-triggered saccades, the subset shown within the dashed ellipse, are to the single- 19 ton. This is better visualized when the direction of the saccade is plotted as a function of saccade 20 latency for only the blink-triggered movements (Fig. 17.5C ). A moving average through the points 21 (black curve) shows that most of the movements are directed toward the singleton. There are a small 22 percentage of trials directed to the opposite distractor, but this fraction is not significantly different 23 from the likelihood of errors the animal made during non-puff trials. For antisaccade trials the 24 correct response should be directed 180° away from the singleton; however, most of the reduced 25 latency movements are directed to the oddball stimulus. A plot of saccade direction against its latency 26 for blink-triggered saccades (Fig. 17.5D ) reveals that nearly all movements with latency less than 27 120 ms are directed to the singleton. As saccade latency increases, the blink-triggered movement 28 is more likely to be directed to the correct location, indicating that the initial motor plan to the 29 singleton was inhibited and the corrected mirror movement was programmed. 30 The premotor theory of attention (Rizzolatti et al., 1987 ) posits that the neural elements that allo- 31 cate spatial attention to the singleton also encode a motor command. A competing hypothesis states 32 that spatial allocation and motor preparation can be dissociated, and both electrophysiological and 33 anatomical studies of frontal eye field neurons have been used to support this view (Juan et al., 2004 ; 34 Pouget et al., 2009 ; Sato and Schall, 2003 ). While the blink triggered saccade results (Katnani and 35 Gandhi, 2008 ) conform to the principles of the premotor theory of attention, at least within the 36 context of the reflexive saccade task, they do not distinguish whether the neural signals in individual 37 responsive neurons encode spatial attention, motor preparation or both. Interestingly, however, 38 recordings in the frontal eye fields and the superior colliculus during comparable visual search para- 39 digms have revealed neural correlates for target discrimination (allocation of attention) around 40 100–150 ms after stimulus onset (McPeek and Keller, 2002 ; Murthy et al., 2001 ; Sato and Schall, 41 2003 ). Note that in Fig. 17.5A and B , blink-triggered saccades occurred within a similar time window 42 after stimulus onset, suggesting that motor preparation can exist at the same time scale as allocation 43 of attention.

44 Conclusions and future directions

45 The purpose of this chapter was to convey two important features of the interactions between eye 46 movements and blinks. First, the eyelid musculature serves a purpose far greater than physically 47 protecting the eye. Coordinated contraction of the LP and OO muscles induces a transient change in 48 eye position. If the eyes are fixating at the onset of a blink, the perturbation is observed as a small, 49 slow and ‘loopy’ eye movement. If the blink overlaps temporally with a saccade, its trajectory is 50 altered, and its speed is often grossly reduced. Nevertheless, a reacceleration allows the saccade to

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334 · Neeraj J. Gandhi and Husam A. Katnani

AB 600 Success (singleton) Success (opposite distractor) Failure (opposite distractor) Failure (singleton) 500 Failure (orthogonal distractor) Failure (orthogonal distractor) 400

300

200

100 Saccade latency (ms) 0 –600 –400 –200 0 200 400 600 –600 –400 –200 0 200 400 600 Blink re saccade cue (ms) Blink re saccade cue (ms)

180 CD Opposite distractor

90 distractor Orthogonal Saccade direction (deg) 0 100 200 300 400 100 200 300 400 Singleton Saccade latency (ms) Saccade latency (ms) Fig. 17.5 Behavioural test of motor preparation during a behavioural task requiring executive control. (A, B) Saccade latency is plotted as a function of blink time for an animal performing the visual search array within the context of a gap task. Blink-triggered saccades are the subsets enclosed within the dashed ellipses. A) Performance in the prosaccade condition, in which the required saccade was to the ‘green’ singleton embedded within three purple distractors. Solid grey circles indicate saccades correctly directed to the oddball stimulus. Open black circles denote saccades incorrectly directed to the distractor located 180° away. Grey crosses mark movements directed to an orthogonal distractor. B) Performance in the antisaccade condition, in which a ‘red’ singleton indicated that the correct response was a saccade to the opposite distractor. Solid grey circles represent a correct response to the opposite location. Open black circles mark error trials with eye movements directed to the singleton. Grey crosses also denote error trials but the saccade ended near an orthogonal distractor. C) and D) Saccade direction is plotted as a function of its reaction time for only blink-triggered saccades for prosaccade and antisaccade trials, respectively. Saccades toward the singleton are represented near a direction of 0° , while saccades directed to the opposite distractor cluster near 180° . The continuous, black trace represents a computed moving average of data specified in 30-ms time epochs through the distribution. Note the transition from near 0 ° to close to 180 ° in the antisaccade condition. Data obtained from a conference proceeding (Katnani and Gandhi, 2008 ).

1 land near the desired location. This interaction cannot solely be accounted for by biomechanical 2 factors. Modulation of the high-frequency bursts of neurons in the superior colliculus (Goossens and 3 Van Opstal, 2000b ) and paramedian pontine reticular formation (Gandhi, unpublished observa- 4 tions) correlates with the attenuation in eye velocity associated with such blink-perturbed saccades. 5 The presence of a neurophysiological contribution raises many questions that future studies must 6 address. Some examples include the following: 1) it remains to be determined how activity in other

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1 higher-order oculomotor structures such as the frontal eye fields, which project to the OO muscles 2 (Gong et al., 2005 ), is modified during blink-perturbed saccades. 2) Another avenue of research 3 needs to consider whether trigeminally-induced and gaze-evoked blinks have similar neural signa- 4 tures. For example, the activity of superior colliculus neurons is briefly suppressed upon delivery of 5 a puff of air to the eye (Goossens and Van Opstal, 2000b ). To the best of our knowledge, no published 6 report describes the effect of gaze-evoked blinks on colliculus activity. A comparative approach may 7 help to clarify whether the activity reflects (trigeminal) feedback signals or a feedforward command 8 that already accounts for the dynamics associated with the combined blink-saccade movement. 9 3) Stimulation of the superior colliculus can introduce mono- and disynaptic potentials in parts of 10 the facial nucleus that contains motoneurons innervating the OO muscle (Vidal et al., 1988 ). 11 Furthermore, anatomy studies have identified tectofugal pathways that can mediate this response 12 (Dauvergne et al., 2004 ). Such results permit the possibility that the oculomotor output of the 13 colliculus is not limited to gaze shifts produced as coordinated eye-head movements, but that the 14 neural command may in fact also integrate activation of eyelid musculature (Evinger et al., 1994 ) as 15 well as other skeletomotor systems (Lünenburger et al., 2001 ). Additional studies are necessary to 16 understand the coordination of movements across many effectors. 4) The OPNs have long been 17 considered to gate both saccades and blinks. Support for this view comes from an anatomy study that 18 reported connectivity between the regions that house the OPNs and LP motoneurons (Horn and 19 Büttner-Ennever, 2008 ). A similar study is needed to check for connections between the OPNs and 20 facial nucleus motoneurons innervating the OO muscle. In contrast, a neurophysiological study 21 (Schultz et al., 2010 ) reported that the cessation of the tonic OPN activity is better synchronized with 22 the transient eye movement than with the blink itself. These seemingly conflicting conclusions of the 23 anatomical and electrophysiological studies need to be resolved. 24 The second major point of this chapter is to demonstrate the use of reflexive blinks as a tool to 25 probe the time-course of motor preparation of saccades. Gandhi and Bonadonna (2005 ) reasoned 26 that cessation of OPN activity during a blink would also remove its inhibition of the saccadic system. 27 If true, then the neural activity associated with the developing motor programme could be expressed 28 as a saccade accompanied with a blink, effectively offering an instantaneous behavioural readout of 29 the motor preparation process. As detailed earlier in the chapter, this was indeed the case, as long as 30 the animal was operating in a paradigm that required reflexive behaviour. Success with this approach 31 has also led to a characterization of the time-course of motor preparation during behaviours requir- 32 ing greater cognitive or top-down control; some examples include the countermanding task (Walton 33 and Gandhi, 2006 ) and generation of antisaccades within the context of a visual search paradigm 34 (Katnani and Gandhi, 2008 ). Future research questions can be extended in several directions: 1) one 35 conspicuous finding is that blink can only trigger saccades after the animal has the permission to 36 initiate it. In the delayed saccade task, for example, a blink evoked during the overlap period, before 37 the animal received the permission to initiate the eye movement, was not accompanied with a 38 saccade. One interpretation of this outcome is that the OPNs serve as a low-level gate. Investigations 39 that systematically manipulate higher-order gates (e.g. fixation-like neurons in the superior collicu- 40 lus and frontal eye fields, and global inhibition from the substantia nigra) may reveal a motor prepa- 41 ration process in tasks that require voluntary control. 2) Neural recordings in the frontal eye fields 42 during the visual search paradigm with pro- and antisaccades (Sato and Schall, 2003 ) have generated 43 exciting data on spatial attention and motor preparation. Incorporating the blink perturbation 44 approach with neurophysiological recordings during the visual search array can be a potentially 45 powerful test. The results should provide a temporal reference frame of the neural activity that corre- 46 lates with the blink perturbations behavioural readout. This information can provide crucial insight 47 to how and where attention and motor preparation unfold.

48 Acknowledgments

49 This work was supported by NIH grants R01-EY015485 (N.J.G), P30-DC0025205, and 50 T32-GM081760.

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