Contribution of the Primate Frontal Cortex to Eye Movements and Neuronal Activity in the Superior Colliculus

Humans and non-human primates must precisely align the eyes on an object to view it with high visual acuity. An important role of the oculomotor system is to generate accurate eye movements, such as saccades, toward a target. Given that each eye has only six muscles that rotate the eye in three degrees of freedom, this relatively simple volitional movement has allowed researchers to well-characterize the brain areas involved in their generation. In particular, the midbrain Superior Colliculus (SC), is recognized as having a primary role in the generation of visually-guided saccades via the integration of sensory and cognitive information. One important source of sensory and cognitive information to the SC is the Frontal Eye Fields (FEF). The role of the FEF and SC in visually-guided saccades has been well-studied using anatomical and functional techniques, but only a handful of studies have investigated how these areas work together to produce saccades. While it is assumed that the FEF exerts its influence on saccade generation though the SC, it remains unknown what happens in the SC when the FEF is suddenly inactivated. To test this prediction, I use the combined approach of FEF cryogenic inactivation and SC neuronal recordings, although it also provides a valuable opportunity to understand how FEF inputs to the SC govern saccade preparation. Nonetheless, it was first necessary to characterize the eye movement deficits following FEF inactivation, as it was unknown how a large and reversible FEF inactivation would influence saccade behaviour, or whether cortical areas influence fixational eye movements (e.g. microsaccades). Four major results emerged from this thesis. First, FEF inactivation delayed saccade reaction times (SRT) in both directions. Second, FEF inactivation impaired microsaccade generation and also selectively reduced microsaccades following peripheral cues. Third, FEF inactivation decreased visual, cognitive, and saccade-related activity in the ipsilesional SC. Fourth, the delayed onset of saccade-related SC activity best explained SRT increases during FEF inactivation, implicating one mechanism for how FEF inputs govern saccade preparation. Together, these results provide new insights into the FEF\u27s role in saccade and microsaccade behaviour, and how the oculomotor system commits to a saccade

Bilateral saccadic deficits following large and reversible inactivation of unilateral frontal eye field.

Inactivation permits direct assessment of the functional contribution of a given brain area to behavior. Previous inactivation studies of the frontal eye field (FEF) have either used large permanent ablations or reversible pharmacological techniques that only inactivate a small volume of tissue. Here we evaluated the impact of large, yet reversible, FEF inactivation on visually guided, delayed, and memory-guided saccades, using cryoloops implanted in the arcuate sulcus. While FEF inactivation produced the expected triad of contralateral saccadic deficits (increased reaction time, decreased accuracy and peak velocity) and performance errors (neglect or misdirected saccades), we also found consistent increases in reaction times of ipsiversive saccades in all three tasks. In addition, FEF inactivation did not increase the proportion of premature saccades to ipsilateral targets, as was predicted on the basis of pharmacological studies. Consistent with previous studies, greater deficits accompanied saccades toward extinguished visual cues. Our results attest to the functional contribution of the FEF to saccades in both directions. We speculate that the comparative effects of different inactivation techniques relate to the volume of inactivated tissue within the FEF. Larger inactivation volumes may reveal the functional contribution of more sparsely distributed neurons within the FEF, such as those related to ipsiversive saccades. Furthermore, while focal FEF inactivation may disinhibit the mirroring site in the other FEF, larger inactivation volumes may induce broad disinhibition in the other FEF that paradoxically prolongs oculomotor processing via increased competitive interactions

Global collision-risk hotspots of marine traffic and the world’s largest fish, the whale shark

© The Author(s), 2022. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Womersley, F. C., Humphries, N. E., Queiroz, N., Vedor, M., da Costa, I., Furtado, M., Tyminski, J. P., Abrantes, K., Araujo, G., Bach, S. S., Barnett, A., Berumen, M. L., Bessudo Lion, S., Braun, C. D., Clingham, E., Cochran, J. E. M., de la Parra, R., Diamant, S., Dove, A. D. M., Dudgeon, C. L., Erdmann, M. V., Espinoza, E., Fitzpatrick, R., González Cano, J., Green, J. R., Guzman, H. M., Hardenstine, R., Hasan, A., Hazin, F. H. V., Hearn, A. R., Hueter, R. E., Jaidah, M. Y., Labaja, J., Ladinol, F., Macena, B. C. L., Morris Jr., J. J., Norman, B. M., Peñaherrera-Palmav, C., Pierce, S. J., Quintero, L. M., Ramırez-Macías, D., Reynolds, S. D., Richardson, A. J., Robinson, D. P., Rohner, C. A., Rowat, D. R. L., Sheaves, M., Shivji, M. S., Sianipar, A. B., Skomal, G. B., Soler, G., Syakurachman, I., Thorrold, S. R., Webb, D. H., Wetherbee, B. M., White, T. D., Clavelle, T., Kroodsma, D. A., Thums, M., Ferreira, L. C., Meekan, M. G., Arrowsmith, L. M., Lester, E. K., Meyers, M. M., Peel, L. R., Sequeira, A. M. M., Eguıluz, V. M., Duarte, C. M., & Sims, D. W. Global collision-risk hotspots of marine traffic and the world’s largest fish, the whale shark. Proceedings of the National Academy of Sciences of the United States of America, 119(20), (2022): e2117440119, https://doi.org/10.1073/pnas.2117440119.Marine traffic is increasing globally yet collisions with endangered megafauna such as whales, sea turtles, and planktivorous sharks go largely undetected or unreported. Collisions leading to mortality can have population-level consequences for endangered species. Hence, identifying simultaneous space use of megafauna and shipping throughout ranges may reveal as-yet-unknown spatial targets requiring conservation. However, global studies tracking megafauna and shipping occurrences are lacking. Here we combine satellite-tracked movements of the whale shark, Rhincodon typus, and vessel activity to show that 92% of sharks’ horizontal space use and nearly 50% of vertical space use overlap with persistent large vessel (>300 gross tons) traffic. Collision-risk estimates correlated with reported whale shark mortality from ship strikes, indicating higher mortality in areas with greatest overlap. Hotspots of potential collision risk were evident in all major oceans, predominantly from overlap with cargo and tanker vessels, and were concentrated in gulf regions, where dense traffic co-occurred with seasonal shark movements. Nearly a third of whale shark hotspots overlapped with the highest collision-risk areas, with the last known locations of tracked sharks coinciding with busier shipping routes more often than expected. Depth-recording tags provided evidence for sinking, likely dead, whale sharks, suggesting substantial “cryptic” lethal ship strikes are possible, which could explain why whale shark population declines continue despite international protection and low fishing-induced mortality. Mitigation measures to reduce ship-strike risk should be considered to conserve this species and other ocean giants that are likely experiencing similar impacts from growing global vessel traffic.Funding for data analysis was provided by the UK Natural Environment Research Council (NERC) through a University of Southampton INSPIRE DTP PhD Studentship to F.C.W. Additional funding for data analysis was provided by NERC Discovery Science (NE/R00997/X/1) and the European Research Council (ERC-AdG-2019 883583 OCEAN DEOXYFISH) to D.W.S., Fundação para a Ciência e a Tecnologia (FCT) under PTDC/BIA/28855/2017 and COMPETE POCI-01–0145-FEDER-028855, and MARINFO–NORTE-01–0145-FEDER-000031 (funded by Norte Portugal Regional Operational Program [NORTE2020] under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund–ERDF) to N.Q. FCT also supported N.Q. (CEECIND/02857/2018) and M.V. (PTDC/BIA-COM/28855/2017). D.W.S. was supported by a Marine Biological Association Senior Research Fellowship. All tagging procedures were approved by institutional ethical review bodies and complied with all relevant ethical regulations in the jurisdictions in which they were performed. Details for individual research teams are given in SI Appendix, section 8. Full acknowledgments for tagging and field research are given in SI Appendix, section 7. This research is part of the Global Shark Movement Project (https://www.globalsharkmovement.org)

Impairment but not abolishment of express saccades after unilateral or bilateral inactivation of the frontal eye fields

Copyright © 2020 the American Physiological Society. Express saccades are a manifestation of a visual grasp reflex triggered when visual information arrives in the intermediate layers of the superior colliculus (SCi), which in turn orchestrates the lower level brainstem saccade generator to evoke a saccade with a very short latency (~100 ms or less). A prominent theory regarding express saccades generation is that they are facilitated by preparatory signals, presumably from cortical areas, which prime the SCi before the arrival of visual information. Here, we test this theory by reversibly inactivating a key cortical input to the SCi, the frontal eye fields (FEF), while monkeys perform an oculomotor task that promotes express saccades. Across three tasks with a different combination of potential target locations and unilateral or bilateral FEF inactivation, we found a spared ability for monkeys to generate express saccades, despite decreases in express saccade frequency during FEF inactivation. This result is consistent with the FEF having a facilitatory but not critical role in express saccade generation, likely because other cortical areas compensate for the loss of preparatory input to the SCi. However, we also found decreases in the accuracy and peak velocity of express saccades generated during FEF inactivation, which argues for an influence of the FEF on the saccadic burst generator even during express saccades. Overall, our results shed further light on the role of the FEF in the shortest-latency visually-guided eye movements. NEW & NOTEWORTHY Express saccades are the shortest-latency saccade. The frontal eye fields (FEF) are thought to promote express saccades by presetting the superior colliculus. Here, by reversibly inactivating the FEF either unilaterally or bilaterally via cortical cooling, we support this by showing that the FEF plays a facilitative but not critical role in express saccade generation. We also found that FEF inactivation lowered express saccade peak velocity, emphasizing a contribution of the FEF to express saccade kinematics

Frontal eye field inactivation reduces saccade preparation in the superior colliculus but does not alter how preparatory activity relates to saccades of a given latency

A neural correlate for saccadic reaction times (SRTs) in the gap saccade task is the level of low-frequency activity in the intermediate layers of the superior colliculus (iSC) just before visual target onset: greater levels of such preparatory iSC low-frequency activity precede shorter SRTs. The frontal eye fields (FEFs) are one likely source of iSC preparatory activity, since FEF preparatory activity is also inversely related to SRT. To better understand the FEF’s role in saccade preparation, and the way in which such preparation relates to SRT, in two male rhesus monkeys, we compared iSC preparatory activity across unilateral reversible cryogenic inactivation of the FEF. FEF inactivation increased contralesional SRTs, and lowered ipsilesional iSC preparatory activity. FEF inactivation also reduced rostral iSC activity during the gap period. Importantly, the distributions of SRTs generated with or without FEF inactivation overlapped, enabling us to conduct a novel population-level analyses examining iSC preparatory activity just before generation of SRT-matched saccades. When matched for SRTs, we observed no change during FEF inactivation in the relationship between iSC preparatory activity and SRT-matched saccades across a range of SRTs, even for the occasional express saccade. Thus, while our results emphasize that the FEF has an overall excitatory influence on preparatory activity in the iSC, the communication between the iSC and downstream oculomotor brainstem is unaltered for SRT-matched saccades

Frontal eye field inactivation diminishes superior colliculus activity, but delayed saccadic accumulation governs reaction time increases

Stochastic accumulator models provide a comprehensive framework for how neural activity could produce behavior. Neural activity within the frontal eye fields (FEFs) and intermediate layers of the superior colliculus (iSC) support such models for saccade initiation by relating variations in saccade reaction time (SRT) to variations in such parameters as baseline, rate of accumulation of activity, and threshold. Here, by recording iSC activity during reversible cryogenic inactivation of the FEF in four male nonhuman primates, we causally tested which parameter(s) best explains concomitant increases in SRT. While FEF inactivation decreased all aspects of ipsilesional iSC activity, decreases in accumulation rate and threshold poorly predicted accompanying increases in SRT. Instead, SRT increases best correlated with delays in the onset of saccade-related accumulation. We conclude that FEF signals govern the onset of saccade-related accumulation within the iSC, and that the onset of accumulation is a relevant parameter for stochastic accumulation models of saccade initiation

A Causal Role for the Cortical Frontal Eye Fields in Microsaccade Deployment

Microsaccades aid vision by helping to strategically sample visual scenes. Despite the importance of these small eye movements, no cortical area has ever been implicated in their generation. Here, we used unilateral and bilateral reversible inactivation of the frontal eye fields (FEF) to identify a cortical drive for microsaccades. Unexpectedly, FEF inactivation altered microsaccade metrics and kinematics. Such inactivation also impaired microsaccade deployment following peripheral cue onset, regardless of cue side or inactivation configuration. Our results demonstrate that the FEF provides critical top-down drive for microsaccade generation, particularly during the recovery of microsaccades after disruption by sensory transients. Our results constitute the first direct evidence, to our knowledge, for the contribution of any cortical area to microsaccade generation, and they provide a possible substrate for how cognitive processes can influence the strategic deployment of microsaccades

FEF inactivation decreased ipsilesional and contralesional microsaccade peak velocities, both before and after cue onset.

<p>(<b>A</b>) Unilateral (left) FEF inactivation reduced peak velocity for contralesional microsaccades independently of amplitude in our example monkey DZ and also decreased peak velocities for ipsilesional microsaccades. As shown in each inset, decreased peak velocities were associated with a downward shift in the main sequence relationship (+/- 95% confidence intervals). (<b>B</b>) FEF inactivation reduced peak velocity for microsaccades matched for radial amplitude, here shown for monkey DZ by averaging radial eye position and velocity traces (+/- standard error) aligned to microsaccade onset. As indicated by the shaded regions in <b>A</b>, we selected ipsilesional and contralesional microsaccades having radial amplitudes between 0.40° and 0.45°. The bilateral influence of FEF inactivation on amplitude-matched microsaccades is demonstrated by decreased peak velocity and increasing duration within the enlarged radial velocity traces (see arrows). (<b>C</b>) Peak velocity extracted at 2° decreased for contralesional microsaccades across monkeys and inactivation configurations and occasionally decreased for ipsilesional microsaccades. Distributions of peak velocities at 2° were obtained by bootstrapping 5,000 random samples of microsaccades and extracting the peak velocity at 2° from each linear regression. (<b>D</b>) Across monkeys, unilateral and bilateral FEF inactivation produced similar decreases in contralesional peak velocity at 2° in both the pre-cue and rebound periods. Filled symbols in <b>C</b> and <b>D</b> indicate statistically significant differences using a Welch's <i>t</i> test (<i>p</i> < 0.05) with 5,000 bootstrapped samples from each of the FEF warm and FEF cool conditions. Data in Supporting Information (see <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002531#pbio.1002531.s002" target="_blank">S2 Data</a>).</p

FEF inactivation markedly reduced microsaccades in the rebound period.

<p>(<b>A</b>) Microsaccade onset times relative to cue onset for individual pre-, peri-, and post-cooling trials from our example monkey with a unilateral (left) FEF inactivation. Each dot is a microsaccade onset time, and each row is a trial. (<b>B</b>) Corresponding time-courses of mean microsaccade rate (+/- 95% confidence intervals) for each of the pre-, peri-, and post-cooling sessions. In our example monkey, unilateral FEF inactivation exerted its greatest impact on microsaccade rate during the rebound period (i.e., 140–400 ms after cue onset), with no changes occurring in the pre-cue period (i.e., 200 ms period before cue onset) or the microsaccadic inhibition period (i.e., 60–140 ms after cue onset). (<b>C</b>) Across monkeys, we found consistent microsaccade rate decreases in the pre-cue period with bilateral but not unilateral inactivation configurations. (<b>D</b>) In contrast, both unilateral and bilateral FEF inactivation consistently decreased microsaccade rate in the rebound period. Same format as <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002531#pbio.1002531.g002" target="_blank">Fig 2C</a>. Data in Supporting Information (see <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002531#pbio.1002531.s003" target="_blank">S3 Data</a>).</p