Decomposing the neural correlates of antisaccade eye movements using event-related FMRI

The antisaccade task is a model of the conflict between an unwantedreflexive response (which must be inhibited) and a complex volitionalresponse (which must be generated). The present experiment aimedto investigate separately the neural correlates of these cognitivecomponents using a delayed saccade paradigm to dissociate saccadeinhibition from generation. Seventeen healthy volunteers completedevent-related functional magnetic resonance imaging at 1.5 Tduring saccades to and away from a peripheral visual target(prosaccades and antisaccades, respectively). Saccades wererequested in response to an auditory go signal on average 12s after peripheral target appearance. It was found that theright supramarginal gyrus showed significantly greater activationduring the inhibition phase than the generation phase of theparadigm for both antisaccade and prosaccade trials, suggestinga role in saccade inhibition or stimulus detection. On the otherhand, the right lateral frontal eye field and bilateral intraparietalsulcus showed evidence of selective involvement in antisaccadegeneration. Ventrolateral and dorsolateral prefrontal corticesshowed comparable levels of activation in both phases of thetask. These areas likely fulfill a more general supervisoryrole in the volitional control of eye movements, such as stimulusappraisal, task set, and decision making.     

FEF TMS affects visual cortical activity

We tested whether the frontal eye field (FEF) is critical in controlling visual processing in posterior visual brain areas during the orienting of spatial attention. Short trains (5 pulses at 10 Hz) of transcranial magnetic stimulation (TMS) were applied to the right FEF during the cueing period of a covert attentional task while event-related potentials (ERPs) were simultaneously recorded from lateral posterior electrodes, where visual components are prominent. FEF TMS significantly affected the neural activity evoked by visual stimuli, as well as the ongoing neural activity recorded during earlier anticipation of the visual stimuli. The effects of FEF TMS started earlier and were greatest for brain activity recorded ipsilaterally to FEF TMS and contralaterally to the visual stimulus. The TMS-induced effect on visual ERPs occurred at the same time as ERPs were shown to be modulated by visual attention. Importantly, no similar effects were observed after TMS of a control site that was physically closer but not anatomically interconnected to the recording sites. The results show that the human FEF has a causal influence over the modulation of visual activity in posterior areas when attention is being allocated.     

Enhanced modulation of neuronal activity during antisaccades in the primate globus pallidus

The antisaccade task has been widely used to investigate theneural mechanisms underlying volitional movement control. Inthis task, subjects suppress reflexive saccades to the suddenappearance of peripheral visual stimuli (prosaccades) and generatea saccade in the opposite direction. Recent imaging studiessuggest that the globus pallidus (GP) is involved in the generationof antisaccades. To understand the roles of the GP, we examinedsingle neuron activity and the effects of local inactivation.Monkeys were trained to make either a pro- or antisaccade accordingto prior instruction provided by the color of the fixation pointin each trial. Among 119 saccade-related neurons, 55% showedincreased firing rates associated with saccades, whereas theremaining neurons showed decreased firing rates. For both populationsof neurons, the activity modulation was enhanced during thepreparation and execution of antisaccades, as compared withprosaccades. Inactivation of the recording sites in the externalsegment of the GP resulted in an increase in the number of errortrials in the antisaccade tasks, suggesting that signals inthe GP may play roles in suppressing inadequate prosaccadesin the task. Signals in the GP might regulate eye movementsthrough the nigro-collicular descending circuitry and throughthe basal ganglia–thalamocortical pathways.     

The location probability effects of saccade reaction times are modulated in the frontal eye fields but not in the supplementary eye field

The visual system constantly utilizes regularities that are embedded in the environment and by doing so reduces the computational burden of processing visual information. Recent findings have demonstrated that probabilistic information can override attentional effects, such as the cost of making an eye movement away from a visual target (antisaccade cost). The neural substrates of such probability effects have been associated with activity in the superior colliculus (SC). Given the immense reciprocal connections to SC, it is plausible that this modulation originates from higher oculomotor regions, such as the frontal eye field (FEF) and the supplementary eye field (SEF). To test this possibility, the present study employed theta burst transcranial magnetic stimulation (TMS) to selectively interfere with FEF and SEF activity. We found that TMS disrupted the effect of location probability when TMS was applied over FEF. This was not observed in the SEF TMS condition. Together, these 2 experiments suggest that the FEF plays a critical role not only in initiating saccades but also in modulating the effects of location probability on saccade production.     

Segregation of visual selection and saccades in human frontal eye fields

The premotor theory of attention suggests that target processing and generation of a saccade to the target are interdependent. Temporally precise transcranial magnetic stimulation (TMS) was delivered over the human frontal eye fields, the area most frequently associated with the premotor theory in association with eye movements, while subjects performed a visually instructed pro-/antisaccade task. Visual analysis and saccade preparation were clearly separated in time, as indicated by 2 distinct time points of TMS delivery that resulted in elevated saccade latencies. These results show that visual analysis and saccade preparation, although frequently enacted together, are dissociable processes.     

The planning and guiding of reading saccades: a repetitive transcranial magnetic stimulation study.

A previous positron emission tomography study that investigated the cortical areas involved in directing eye movements during text reading showed two areas of extra-occipital asymmetry: left > right posterior parietal cortex (PPC), and right > left frontal eye-field (FEF). We used the temporal resolution of repetitive TMS (rTMS) to isolate the contributions of the left and right PPC and FEF to the planning and execution of rightward reading saccades. We present eye-movement data collected during text reading, which involves the initiation and maintenance of a series of saccades (scanpath). rTMS over the left but not right PPC slowed reading speeds for the whole array of words, indicating that this area is involved throughout the scanpath. rTMS over the right but not the left FEF slowed the time to make the first saccade, but only when triggered before the stimuli appeared, demonstrating that the role of this region is in the preparation of the scanpath. Our results are compatible with the hypotheses that the left PPC maintains reading saccades along a line of text while the right FEF is involved in the preparation of the motor plan for the scanpath at the start of each new line of text.     

Simultaneous representation of saccade targets and visual onsets in monkey lateral intraparietal area

The monkey's lateral intraparietal area (LIP) has been associated with attention and saccades. LIP neurons have visual on-responses to objects abruptly appearing in their receptive fields (RFs) and sustained activity preceding saccades to the RF. We studied the relationship between the on-responses and delay activity in LIP using a 'stable-array' task. Monkeys viewed eight distinct, continuously illuminated objects, arranged in a circle with at least one object in the RF. A cue flashed instructing the monkey to make a saccade, after a delay, to the stable object physically matching the cue. The location of the cue was fixed in trial blocks, either in or out of the RF. If the cue was outside the RF, neurons developed delay-period activity tuned for the direction of the saccade target at approximately 190 ms after cue onset. If the cue appeared in the RF, neurons initially responded to cue onset and developed tuning for saccade direction only toward the end of the delay period, 390 ms after cue onset. The cue- and saccade-target responses coexisted throughout a significant portion of the delay period. The results show that visual-on responses and delay-period activity in LIP are functionally separable, and that, although highly selective, the salience representation in LIP can contain more than one object at a time.     

Distinct causal influences of parietal versus frontal areas on human visual cortex: evidence from concurrent TMS-fMRI

It has often been proposed that regions of the human parietal and/or frontal lobe may modulate activity in visual cortex, for example, during selective attention or saccade preparation. However, direct evidence for such causal claims is largely missing in human studies, and it remains unclear to what degree the putative roles of parietal and frontal regions in modulating visual cortex may differ. Here we used transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI) concurrently, to show that stimulating right human intraparietal sulcus (IPS, at a site previously implicated in attention) elicits a pattern of activity changes in visual cortex that strongly depends on current visual context. Increased intensity of IPS TMS affected the blood oxygen level-dependent (BOLD) signal in V5/MT+ only when moving stimuli were present to drive this visual region, whereas TMS-elicited BOLD signal changes were observed in areas V1-V4 only during the absence of visual input. These influences of IPS TMS upon remote visual cortex differed significantly from corresponding effects of frontal (eye field) TMS, in terms of how they related to current visual input and their spatial topography for retinotopic areas V1-V4. Our results show directly that parietal and frontal regions can indeed have distinct patterns of causal influence upon functional activity in human visual cortex.     

Functional neuroanatomy of anticipatory behavior: dissociation between sensory-driven and memory-driven systems

The ability to anticipate predictable stimuli allows faster responses. The predictive saccade (PRED) task has been shown to quickly induce such anticipatory behavior in humans. In a PRED task subjects track a visual target jumping back and forth between fixed positions at a fixed time interval. During this task, saccade latencies drop from approximately 200 ms to <80 ms as subjects anticipate target appearance. This change in saccade latency indicates that subjects' behavior shifts from being sensory driven to being memory driven. We conducted functional magnetic resonance imaging studies with 10 healthy adults performing the PRED task using a standard block design. We compared the PRED task with a visually guided saccade (VGS) task using unpredictable targets matched for number, direction and amplitude of required saccades. Our results show greater activation during the PRED task in the prefrontal, pre-supplementary motor and anterior cingulate cortices, hippocampus, mediodorsal thalamus, striatum and cerebellum. The VGS task elicited greater activation in the cortical eye fields and occipital cortex. These results demonstrate the important dissociation between sensory and predictive neural control of similar saccadic eye movements. Anticipatory behavior induced by the PRED task required less sensory-related processing activity and was subserved by a distributed cortico-subcortical memory system including prefronto-striatal circuitry.     

Priming of motion direction and area V5/MT: a test of perceptual memory

Presentation of supraliminal or subliminal visual stimuli that can (or cannot) be detected or identified can improve the probability of the same stimulus being detected over a subsequent period of seconds, hours or longer. The locus and nature of this perceptual priming effect was examined, using suprathreshold stimuli, in subjects who received repetitive pulse transcranial magnetic stimulation over the posterior occipital cortex, the extrastriate motion area V5/MT or the right posterior parietal cortex during the intertrial interval of a visual motion direction discrimination task. Perceptual priming observed in a control condition was abolished when area V5/MT was stimulated but was not affected by magnetic stimulation over striate or parietal sites. The effect of transcranial magnetic stimulation (TMS) on priming was specific to site (V5/MT) and to task - colour priming was unaffected by TMS over V5/MT. The results parallel, in the motion domain, recent demonstrations of the importance of macaque areas V4 and TEO for priming in the colour and form domains.     

Parietal damage dissociates saccade planning from presaccadic perceptual facilitation

A well-known theory in the field of attention today is the premotor theory of attention which suggests that the mechanisms involved in eye movements are the same as those for spatial attention shifts. We tested a parietal damaged patient with unilateral optic ataxia and 4 controls on a dual saccade/attentional task and show a dissociation between saccadic eye movements and presaccadic perceptual enhancement at the saccade goal. Remarkably, though the patient was able to make the appropriate saccades to the left, impaired visual field (undistinguishable from saccades to his right, intact visual field), he was unable to discriminate the letter at the saccade goal (whereas his performance was like controls for letter discrimination in his right visual field). This suggests that saccade planning and presaccadic perceptual facilitation are separable--planning a saccade to a location does not necessitate that the processing of this location is enhanced. Based on these results, we suggest that the parietal cortex is necessary for the coupling between saccade planning and presaccadic perceptual facilitation.     

The contribution of the human FEF and SEF to smooth pursuit initiation

Smooth pursuit eye movements function to keep moving targets foveated. Behavioral studies have shown that pursuit is particularly effective for predictable target motion. There is evidence that both the frontal eye field (FEF) and supplementary eye field (SEF) (also known as the dorsomedial frontal cortex) contribute to pursuit control. The goal of the current experiment was to determine whether these 2 areas made different contributions to the initiation of pursuit in response to predictable compared with unpredictable target motion. Transcranial magnetic stimulation (TMS) was used in 5 healthy human participants to temporarily disrupt each area around the time of target motion onset. TMS over the FEF delayed contraversive pursuit markedly more than ipsiversive pursuit and this direction-dependent difference was more deeply modulated during pursuit of unpredictable than predictable target motion. By contrast, TMS over the SEF resulted in a much more muted modulation of pursuit latency that was similar across both predictable and unpredictable conditions. Taken together, we conclude that the human FEF, but not the SEF, makes a significant contribution to the processing required during the preparation of contraversive pursuit responses to unpredictable target motion and this contribution is less vital during pursuit to predictable target motion.     

Smooth-pursuit eye movement representation in the primate frontal eye field.

Physiological and behavioral data reported here show an involvement of the primate frontal eye field (FEF) cortex in smooth-pursuit eye movements, in addition to its well-established role in saccadic eye movements. Microstimulation just ventral to the small saccade representation of the FEF elicits eye movements that, in contrast to elicited saccades, have low velocities, continue smoothly without interruption during prolonged stimulation, and are usually directed ipsilaterally to the stimulated hemisphere. Neurons in this region respond in association with smooth-pursuit eye movements and visual motion. Tracking deficits following experimental lesions of the FEF depend critically upon the status of this ventral region: superficial lesions sparing it leave smooth-pursuit eye movements intact, whereas lesions removing it produce substantial deficits in the anticipatory initiation, motion-induced acceleration, asymptotic velocity, and predictive continuation of ipsilateral smooth pursuit.     

The cross-modal interaction between pain-related and saccade-related cerebral activation: a preliminary study by event-related functional magnetic resonance imaging

Pain-related cerebral activation in functional magnetic resonance imaging shows less consistent signals that decay earlier than in conventional task-related activation. This may result from pain's top-down inhibition mediated by cognitive or hemodynamic interaction that could affect activation by other modalities. Using event-related functional magnetic resonance imaging, we examined whether pain affects cerebral activation by a saccade task through such cross-modal interaction. Six right-handed volunteers underwent whole-brain echo-planar imaging on a 3.0 T magnetic resonance imaging scanner while they received thermal pain stimulus at 50 degrees C on the right forearm (P; n = 6), performed a visually guided saccade task (V; n = 6), and went through a simultaneous pain-plus-saccade paradigm (PV; n = 5). Averaged functional activation maps were synthesized and signal time courses were analyzed at activation clusters. P activated the bilateral secondary somatosensory cortex (S2). V activated the posterior, supplementary, frontal eye fields, and visual areas. PV enhanced the S2 activation and activated additional pain-related areas, including the bilateral premotor area, right insula, anterior, and posterior cingulate cortices. In contrast, V-related activation was attenuated in PV. We propose that pain caused cross-modal suppression on the oculomotor activity and that an oculomotor task enhanced pain-related activation by triggering attention toward pain. IMPLICATIONS: Pain-related cerebral activation is enhanced by attention toward pain. It may involve top-down suppression over the unrelated neural networks of saccade.     

Neural activity in primate parietal area 7a related to spatial analysis of visual mazes

Cognitive psychological studies of humans and monkeys solving visual mazes have provided evidence that a covert analysis of the maze takes place during periods of eye fixation interspersed between saccades, or when mazes are solved without eye movements. We investigated the neural basis of this process in posterior parietal cortex by recording the activity of single neurons in area 7a during maze solution. Monkeys were required to determine from a single point of fixation whether a critical path through the maze reached an exit or a blind ending. We found that during this process the activity of approximately one in four neurons in area 7a was spatially tuned to maze path direction. We obtained evidence that path tuning did not reflect a covert saccade plan insofar as the majority of neurons active during maze solution were not active on a delayed-saccade control task, and the minority that were active on both tasks did not exhibit congruent spatial tuning in the two conditions. We also obtained evidence that path tuning during maze solution was not due to the locations of visual receptive fields mapped outside the behavioral context of maze solution, in that receptive field centers and preferred path directions were not spatially aligned. Finally, neurons tuned to path direction were not present in area 7a when a na?ve animal viewed the same visual maze stimuli but did not solve them. These data support the hypothesis that path tuning in parietal cortex is not due to the lower level visual features of the maze stimulus, but rather is associated with maze solution, and as such, reflects a cognitive process applied to a complex visual stimulus.     

Prefrontal delay-period activity reflects the decision process of a saccade direction during a free-choice ODR task

To examine how delay-period activity participates in the decision of a saccade direction, we analyzed prefrontal activity while monkeys performed 2 tasks: oculomotor delayed-response (ODR) and self-selection ODR (S-ODR) tasks. In the ODR task, monkeys were required to make a memory-guided saccade to the cue location after a 3-s delay. In the S-ODR task, 4 identical visual cues were presented simultaneously during the cue period and monkeys were required to make a saccade in any one direction after the delay. Delay-period activity was observed in both tasks in the same neuron with similar directional preferences. Neurons with delay-period activity were classified into several groups based on the temporal pattern of the activity itself and of the strength of the directional selectivity. Among these, neurons with an increasing type of delay-period activity with persistent directional selectivity throughout the delay period in the ODR task also showed directional delay-period activity in the S-ODR task. These results indicate that an increasing type of delay-period activity, which is thought to represent motor information, plays an important role in generating and enhancing directional bias in the S-ODR task and therefore contributes significantly to the decision process of the saccade direction in the S-ODR task.     

Dorsal posterior parietal rTMS affects voluntary orienting of visuospatial attention

Patients with lesions in posterior parietal cortex (PPC) are relatively unimpaired in voluntarily directing visual attention to different spatial locations, while many neuroimaging studies in healthy subjects suggest dorsal PPC involvement in this function. We used an offline repetitive transcranial magnetic stimulation (rTMS) protocol to study this issue further. Ten healthy participants performed a cue-target paradigm. Cues prompted covert orienting of spatial attention under voluntary control to either a left or right visual field position. Targets were flashed subsequently at the cued or uncued location, or bilaterally. Following rTMS over right dorsal PPC, (i) the benefit for target detection at cued versus uncued positions was preserved irrespective of cueing direction (left- or rightward), but (ii) leftward cueing was associated with a global impairment in target detection, at all target locations. This reveals that leftward orienting was still possible after right dorsal PPC stimulation, albeit at an increased overall cost for target detection. In addition, rTMS (iii) impaired left, but (iv) enhanced right target detection after rightward cueing. The finding of a global drop in target detection during leftward orienting with a spared, relative detection benefit at the cued (left) location (i-ii) suggests that right dorsal PPC plays a subsidiary rather than pivotal role in voluntary spatial orienting. This finding reconciles seemingly conflicting results from patients and neuroimaging studies. The finding of attentional inhibition and enhancement occurring contra- and ipsilaterally to the stimulation site (iii-iv) supports the view that spatial attention bias can be selectively modulated through rTMS, which has proven useful to transiently reduce visual hemispatial neglect.     

Cortical activity time locked to the shift and maintenance of spatial attention

Attention increases the gain of visual neurons, which improves visual performance. How attention is controlled, however, remains unknown. Clear correlations between attention and saccade planning indicate that the control of attention is mediated through mechanisms housed in the oculomotor network. Here, we used event-related functional magnetic resonance imaging to compare overt and covert attention shifts. Subjects covertly or overtly shifted attention based on an endogenous cue and maintained attention throughout a long and variable delay. To insure continued attention, subjects counted when the attended target dimmed at near-threshold contrast levels. Overt and covert tasks used identical stimuli and required identical motor responses. Additionally, a staircase procedure that adjusted the target-dimming contrast separately for covert and overt trials equated the difficulty between conditions and across subjects. We found that the same regions along the precentral and intraparietal sulci were active during shifts of covert and overt attention. We also found sustained activation in the hemisphere contralateral to the attended visual field. We conclude that maps of prioritized locations are represented in areas classically associated with oculomotor control. The readout of these spatial maps by posterior visual areas directs spatial attention just as the readout by downstream saccade generators directs saccades.     

The interaction of brain regions during visual search processing as revealed by transcranial magnetic stimulation

Although it has long been known that right posterior parietal cortex (PPC) has a role in certain visual search tasks, and human motion area V5 is involved in processing tasks requiring attention to motion, little is known about how these areas may interact during the processing of a task requiring the speciality of each. Using transcranial magnetic stimulation (TMS), this study first established the specialization of each area in the form of a double dissociation; TMS to right PPC disrupted processing of a color/form conjunction and TMS to V5 disrupted processing of a motion/form conjunction. The key finding of this study is, however, if TMS is used to disrupt processing of V5 at its critical time of activation during the motion/form conjunction task, concurrent disruption of right PPC now has a significant effect, where TMS at PPC alone does not. Our findings challenge the conventional interpretation of the role of right PPC in conjunction search and spatial attention.     

Monocular visual deprivation suppresses excitability in adult human visual cortex

The adult visual cortex maintains a substantial potential for plasticity in response to a change in visual input. For instance, transcranial magnetic stimulation (TMS) studies have shown that binocular deprivation (BD) increases the cortical excitability for inducing phosphenes with TMS. Here, we employed TMS to trace plastic changes in adult visual cortex before, during, and after 48 h of monocular deprivation (MD) of the right dominant eye. In healthy adult volunteers, MD-induced changes in visual cortex excitability were probed with paired-pulse TMS applied to the left and right occipital cortex. Stimulus-response curves were constructed by recording the intensity of the reported phosphenes evoked in the contralateral visual field at range of TMS intensities. Phosphene measurements revealed that MD produced a rapid and robust decrease in cortical excitability relative to a control condition without MD. The cortical excitability returned to preinterventional baseline levels within 3 h after the end of MD. The results show that in contrast to the excitability increase in response to BD, MD acutely triggers a reversible decrease in visual cortical excitability. This shows that the pattern of visual deprivation has a substantial impact on experience-dependent plasticity of the human visual cortex.