Effects of Breast Cancer Treatment on Neural Noise: a Longitudinal Design.

OBJECTIVE: Cognitive dysfunction has been observed consistently in a subset of breast cancer survivors. Yet the precise neurophysiological origins of cancer-related cognitive decline remain unknown. The current study assessed neural noise (1/f activity in electroencephalogram [EEG]) in breast cancer survivors as a potential contributor to observed cognitive dysfunction from pre- to post-treatment. METHODS: We measured EEG in a longitudinal design during performance of the paired-click task and the revised Attention Network Test (ANT-R) to investigate pre- versus post-treatment effects of neural noise in breast cancer patients (n = 20 in paired click; n = 19 in ANT-R) compared with healthy controls (n = 32 in paired click; n = 29 in ANT-R). RESULTS: In both paradigms, one sensory (paired click) and one cognitive (ANT-R), we found that neural noise was significantly elevated after treatment in patients, remaining constant from pretest to posttest in controls. In the ANT-R, patients responded more slowly than controls on invalid cuing trials. Increased neural noise was associated with poorer alerting and poorer inhibitory control of attention (as measured by behavioral network scores), particularly for patients after treatment. CONCLUSIONS: The current study is the first to show a deleterious effect of breast cancer and/or cancer treatment on neural noise, pointing to alterations in the relative balance of excitatory and inhibitory synaptic inputs, while also suggesting promising approaches for cognitive rehabilitation.

Hypometria of saccadic eye movements to targets in rapid circular motion.

Saccades to objects moving on a straight trajectory take the velocity of the object into account. However, it is not known whether saccades can compensate for curved trajectories, nor is it known how they are affected by high target speeds. In Experiment 1, participants made a saccade in a delayed saccade task to a target moving in a circular trajectory. Surprisingly, saccades to high-speed moving targets were severely hypometric, with gains of only ∼55% for trajectories of the largest angular speed (2 revolutions per second) and eccentricity (12°). They also had unusually low peak velocities. In Experiment 2, the target jumped along a circular path around a central fixation point. Hypometria was still severe, except for very large jumps. Experiment 3 was like Experiment 1, except that a landmark was positioned on the trajectory of the target, and participants were instructed to make a saccade to the landmark or to its memorized location. This ameliorated hypometria considerably. Given the delayed nature of the tasks of Experiments 1 and 2, participants had considerable time to program a voluntary saccade to a location on the trajectory, if not to the rapidly moving target itself. Nevertheless, the abnormal saccade properties indicate that motor programming was compromised. These results indicate that motor output can be inextricably bound to sensory input to its detriment, even during a highly voluntary motor act; that apparent motion can produce this behavior; and that such abnormal saccades can be "rescued" by the presence of a stable visual goal.

The reduction of saccadic inhibition by distractor repetition.

When visual distractors are presented far from the goal of an impending voluntary saccadic eye movement, saccade execution will occur less frequently about 90 ms after distractor appearance, a phenomenon known as saccadic inhibition. However, it is also known that neural responses in visual and visuomotor areas of the brain will be attenuated if a visual stimulus appears several times in the same location in rapid succession. In particular, such visual adaptation can affect neurons in the mammalian superior colliculus (SC). As the SC is known to be intimately involved in the production of saccadic eye movements, and thus perhaps in saccadic inhibition, we used a memory-guided saccade task to test whether saccadic inhibition in humans would diminish if a distractor appeared several times in quick succession. We found that distractor repetition reduced saccadic inhibition considerably when distractors appeared opposite in space to the goal of the impending saccade. In addition, when three distractors appeared in quick succession but in different, spatially disparate locations, with only the final distractor appearing opposite the saccade goal, saccadic inhibition was reduced by an intermediate level, suggesting that its reduction due to distractor inhibition spatially generalizes. This suggests that distractor suppression can help reduce the impact that suddenly appearing visual stimuli have on purposive eye movement behavior.NEW & NOTEWORTHY This work combines approaches studying saccadic inhibition and visual adaptation to demonstrate that saccadic inhibition is largely eliminated with stimulus repetition. This is likely to be the largest demonstrated effect of visual stimulus context on saccadic inhibition. It also provides evidence for the existence of a mechanism that acts to suppress the effect of frequently appearing visual stimuli on purposive eye movement behavior in dynamic visual environments.

The effect of visual target presence and age on antisaccade performance.

Antisaccade and prosaccade (PS) performance were studied in a large cohort of females (age range 42-74 yr). Antisaccade performance was assessed in two variants of the task, a "traditional" antisaccade (TA) task, in which no visual stimuli were present at the saccade goal, and a visually guided antisaccade (VGA) task, in which small visual stimuli were present at the possible saccade goals prior to the imperative visual stimulus. Directional error frequency was similar in the two antisaccade tasks. However, reaction time (RT) was ∼33 ms longer in the VGA task than in the TA task. Across participants, the average saccade amplitudes of prosaccades and TAs were both correlated with those of VGAs but not with each other. TAs had a hypermetria that increased with age. Saccade amplitude variability was much higher for TAs than for PSs and VGAs. Saccade polar angle variability was low for all three tasks. Age diminished performance with modest task dependence, except for an increase in TA hypermetria. These results suggest that the generation of antisaccade directional errors does not depend on visual target presence at the saccade goal, that antisaccade RT can be affected by target presence, that age can increase saccade hypermetria in the absence of visual guidance, and that visually guided antisaccades are governed by distinct voluntary and visually guided saccade mechanisms. Moreover, these results suggest that an understanding of human motor performance benefits from the use of a participant pool with a larger age range than that used in most studies.NEW & NOTEWORTHY This study uses a visually guided antisaccade (VGA) task to determine whether poor performance in a large middle-aged participant pool on an antisaccade task results from problems with executive control or voluntary saccade generation. Spatial and temporal attributes of saccade performance as a function of task and age are analyzed comprehensively. Correlational analysis is used to determine how VGAs are governed jointly by voluntary and visually guided movement mechanisms.

Longitudinal Effects of Breast Cancer Treatment on Neural Correlates of Attention.

OBJECTIVE: Cognitive dysfunction has been observed consistently in a subset of breast cancer survivors. Yet, the precise physiological and processing origins of dysfunction remain unknown. The current study examined the utility of methods and procedures based on cognitive neuroscience to study cognitive change associated with cancer and cancer treatment. METHODS: We used electroencephalogram and behavioral measures in a longitudinal design to investigate pre- versus post-treatment effects on attention performance in breast cancer patients (n = 15) compared with healthy controls (n = 24), as participants completed the revised Attention Network Test, a cognitive measure of alerting, orienting, and inhibitory control of attention. RESULTS: We found no group differences in behavioral performance from pretest to posttest, but significant event-related potential effects of cancer treatment in processing cue validity: After treatment, patients revealed decreased N1 amplitude and increased P3 amplitude, suggesting a suppressed early (N1) response and an exaggerated late (P3) response to invalid cues. CONCLUSIONS: The results suggest that treatment-related attentional disruption begins in early sensory/perceptual processing and extends to compensatory top-down executive processes.

Impact of task-specific training on saccadic eye movement performance.

Prosaccades are saccadic eye movements made reflexively in response to the sudden appearance of visual stimuli, whereas antisaccades are saccades that are directed to a location opposite a stimulus. Bibi and Edelman (Bibi R, Edelman JA. J Neurophysiol 102: 3101-3110, 2009) demonstrated that decreases in reaction time resulting from training prosaccades along one spatial axis (horizontal or vertical) could transfer to prosaccades made along the other axis. To help determine whether visual or motor-related processes underlie this facilitation, in the present study we trained participants to make prosaccades and probed their performance (reaction time, error rate) on antisaccade trials and vice versa. Subjects were probed for the effects of training on saccade performance before, during, and after 12 sessions of training. Training on prosaccades improved performance on both pro- and antisaccade tasks. Antisaccade training, with either a classic step task or a gap task, improved performance on gap prosaccades, though by less than it improved antisaccade performance, but had limited effect on an overlap prosaccade task. Across all subjects, training on one task only rarely had an adverse impact on an untrained task. These findings suggest that the predominant effect of saccade training is to facilitate fixation disengagement and motor preparation processes while having little impact on visual input to the saccadic system.NEW & NOTEWORTHY This is the first systematic examination of whether training of prosaccades and antisaccades is task specific or instead transfers to the other saccade type. It finds that training tends to improve performance of all saccade types tested. These behavioral results provide insight into saccade neurophysiology, suggesting that saccade training enhances processes related to motor excitation and inhibition.

Effects of saccade training on express saccade proportions, saccade latencies, and peak velocities: an investigation of nasal/temporal differences.

Express saccades have very short latencies and are often considered a special population of saccadic eye movements. Recent evidence suggests that express saccade generation in humans increases with training, and that this training is independent of the actual saccade vector being trained. We assessed the time course of these training-induced increases in express saccade generation and how they differ between the nasal and temporal hemifields, and second whether they transfer from the trained to the untrained eye. We also measured the effects of training on saccade latencies more generally, and upon peak velocities. The training effect transferred between the nasal and temporal hemifields and between the trained and untrained eyes. More surprisingly, we found an asymmetric effect of training on express saccade proportions: Before training, express saccade proportions were higher for saccades made into the nasal hemifield but with training this reversed. This training-induced asymmetry was also observed in overall saccade latencies, showing how training can unmask nasal/temporal asymmetries in saccade latencies. Finally, we report for the first time that saccadic peak velocities increased with training, independently of changes in amplitude.

The effect of object-centered instructions in Cartesian and polar coordinates on saccade vector.

Express saccades (ES) are the most reflexive saccadic eye movements, with very short reaction times of 70-110 ms. It is likely that ES have the shortest saccade reaction times (SRTs) possible given the known physiological and anatomical delays present in sensory and motor systems. Nevertheless, it has been demonstrated that a vector displacement of ES to spatially extended stimuli can be influenced by spatial cognition. Edelman, Kristjansson, and Nakayama (2007) found that when two horizontally separated visual stimuli appear at a random location, the spatial vector, but not the reaction time, of human ES is strongly influenced by an instruction to make a saccade to one side (either left or right) of a visual stimulus array. Presently, we attempt to extend these findings of cognitive effects on saccades in three ways: (a) determining whether ES could be affected by other types of spatial instructions: vertical, polar amplitude, and polar direction; (b) determining whether these spatial effects increased with practice; and (c) determining how these effects depended on SRTs. The results demonstrate that both types of Cartesian as well as polar amplitude instructions strongly affect ES vector, but only modestly affect SRTs. Polar direction instructions had sizable effects only on nonreflexive saccades where the visual stimuli could be viewed for several hundred milliseconds prior to saccade execution. Short- (trial order within a block) and long-term (experience across several sessions) practice had little effect, though the effect of instruction increased with SRT. Such findings suggest a generalized, innate ability of cognition to affect the most reflexive saccadic eye movements.

Prepare for conflict: EEG correlates of the anticipation of target competition during overt and covert shifts of visual attention.

When preparing to make a saccadic eye movement in a cued direction, perception of stimuli at the target location is enhanced, just as it is when attention is covertly deployed there. Accordingly, the timing and anatomical sources of preparatory brain activity accompanying shifts of covert attention and saccade preparation tend to exhibit a large degree of overlap. However, there is evidence that preparatory processes are modulated by the foreknowledge of visual distractor competition during covert attention, and it is unknown whether eye movement preparation undergoes equivalent modulation. Here we examine preparatory processes in the electroencephalogram of human participants during four blocked versions of a spatial cueing task, requiring either covert detection or saccade execution, and either containing a distractor or not. As in previous work, a typical pattern of spatially selective occipital, parietal and frontal activity was seen in all task versions. However, whereas distractor presence called on an enhancement of spatially selective visual cortical modulation during covert attention, it instead called on increased activity over frontomedial oculomotor areas in the case of overt saccade preparation. We conclude that, although advance orienting signals may be similar in character during overt and covert conditions, the pattern by which these signals are modulated to ameliorate the behavioral costs of distractor competition is highly distinct, pointing to a degree of separability between the overt and covert systems.

The influence of motor training on human express saccade production.

Express saccadic eye movements are saccades of extremely short latency. In monkey, express saccades have been shown to occur much more frequently when the monkey has been trained to make saccades in a particular direction to targets that appear in predictable locations. Such results suggest that express saccades occur in large number only under highly specific conditions, leading to the view that vector-specific training and motor preparatory processes are required to make an express saccade of a particular magnitude and direction. To evaluate this hypothesis in humans, we trained subjects to make saccades quickly to particular locations and then examined whether the frequency of express saccades depended on training and the number of possible target locations. Training significantly decreased saccade latency and increased express saccade production to both trained and untrained locations. Increasing the number of possible target locations (two vs. eight possible targets) led to only a modest increase of saccade latency. For most subjects, the probability of express saccade occurrence was much higher than that expected if vector-specific movement preparation were necessary for their production. These results suggest that vector-specific motor preparation and vector-specific saccade training are not necessary for express saccade production in humans and that increases in express saccade production are due in part to a facilitation in fixation disengagement or else a general enhancement in the ability of the saccadic system to respond to suddenly appearing visual stimuli.

Inhibition of voluntary saccadic eye movement commands by abrupt visual onsets.

Saccadic eye movements are made both to explore the visual world and to react to sudden sensory events. We studied the ability for humans to execute a voluntary (i.e., nonstimulus-driven) saccade command in the face of a suddenly appearing visual stimulus. Subjects were required to make a saccade to a memorized location when a central fixation point disappeared. At varying times relative to fixation point disappearance a visual distractor appeared at a random location. When the distractor appeared at locations distant from the target virtually no saccades were initiated in a 30- to 40-ms interval beginning 70-80 ms after appearance of the distractor. If the distractor was presented slightly earlier relative to saccade initiation then saccades tended to have smaller amplitudes, with velocity profiles suggesting that the distractor terminated them prematurely. In contrast, distractors appearing close to the saccade target elicited express saccade-like movements 70-100 ms after their appearance, although the saccade endpoint was generally scarcely affected by the distractor. An additional experiment showed that these effects were weaker when the saccade was made to a visible target in a delayed task and still weaker when the saccade itself was made in response to the abrupt appearance of a visual stimulus. A final experiment revealed that the effect is smaller, but quite evident, for very small stimuli. These results suggest that the transient component of a visual response can briefly but almost completely suppress a voluntary saccade command, but only when the stimulus evoking that response is distant from the saccade goal.

The dependence of visual scanning performance on search direction and difficulty.

Phillips and Edelman [Phillips, M. H., & Edelman, J. A. (2008). The dependence of visual scanning performance on saccade, fixation, and perceptual metrics. Vision Research, 48(7), 926-936] presented evidence that performance variability in a visual scanning task depends on oculomotor variables related to saccade amplitude rather than fixation duration, and that saccade-related metrics reflects perceptual span. Here, we extend these results by showing that even for extremely difficult searches trial-to-trial performance variability still depends on saccade-related metrics and not fixation duration. We also show that scanning speed is faster for horizontal than for vertical searches, and that these differences derive again from differences in saccade-based metrics and not from differences in fixation duration. We find perceptual span to be larger for horizontal than vertical searches, and approximately symmetric about the line of gaze.

The dependence of visual scanning performance on saccade, fixation, and perceptual metrics.

We sought to understand the basis of performance variability and perceptual learning in saccadic visual search. Four subjects searched for a target based on its shape in a linear array of densely packed, regularly spaced items, a configuration used to simplify the analysis of performance and to minimize search strategy variability. We measured the dependence of performance-search speed-on the oculomotor variables of fixation duration and saccade amplitude, both within and across experimental sessions. We also measured perceptual span, the area in visual space in which subjects could identify the target above chance, with a modified version of the task using a gaze-contingent display with transiently appearing targets. The principal finding of this study was that both within and across sessions, saccade metrics accounted for much more of the variability and improvement in performance than did fixation duration. Increases in search speed were due primarily to subjects processing information from a greater area of the visual field, rather than processing information from a fixed area more quickly, though there was a small but consistent decrease in fixation duration across sessions. The increase in performance derived from an increase in perceptual span and not merely from an increase in subjects' efficiency in 'tiling' the search array with regions of visibility.

The influence of object-relative visuomotor set on express saccades.

Express saccades are considered to have the shortest latency (70-110 ms) of all saccadic eye movements. The influence of visuomotor set, preparatory processes that spatially affect a sensorimotor response, on express saccades was examined by instructing human subjects to make a saccade to one of two simultaneously appearing spots defined by its position relative to the other. A temporal gap between fixation point disappearance and target appearance was used to facilitate the production of express saccades. For all subjects, the instruction influenced the vector of express saccades without increasing saccade latency. The effect on express saccades was only slightly weaker than that for longer latency saccades. Saccade curvature was minimal and did not depend strongly on task. Further experiments demonstrated that the effect of instruction on express saccade vector was much weaker when saccades were instructed to be made to one side of a single small spot, that the effect of instruction was equally strong when directing saccades to the less salient of two stimuli, and that an instruction could not only determine the direction of the effect but also modulate the effect's magnitude. The effect of instruction on saccade vector was no higher when blocked than when varied across trials. These results suggest that express saccades are influenced by object-relative spatial preparatory processes without increasing their reaction time and, thus, that high-level cognitive processes can influence the most reflexive of saccadic eye movements.

Scan patterns during the processing of facial identity in prosopagnosia.

The scan patterns of ocular fixations made by prosopagnosic patients while they attempt to identify faces may provide insights into how they process the information in faces. Contrasts between their scanning of upright versus inverted faces may index the presence of a hypothesized orientation-dependent expert mechanism for processing faces, while contrasts between their scanning of familiar versus novel faces may index the influence of residual facial memories on their search for meaningful facial information. We recorded the eye movements of two prosopagnosics while they viewed faces. One patient, with acquired prosopagnosia from a right occipitotemporal lesion, showed degraded orientation effects but still with a normal distribution of fixations to more salient facial features. However, the dynamics of his global scan patterns were more chaotic for novel faces, suggesting degradation of an internal facial schema, and consistent with other evidence of impaired face configuration perception in this patient. His global scan patterns for famous faces differed from novel faces, suggesting the influence of residual facial memories, as indexed previously by his relatively good imagery for famous faces. The other patient, with a developmental prosopagnosia, showed anomalous orientation effects, abnormal distribution of fixations to less salient regions, and chaotic global scan patterns, in keeping with a more severe loss of face-expert mechanisms. The effects of fame on her scanning were weaker than those in the first subject and non-existent in her global scan patterns. We conclude that scan patterns in prosopagnosia can both reflect the loss of orientation-dependent expert mechanisms and index the covert influence of residual facial memories. In these two subjects the scanning data were consistent with other results from tests of configuration perception, imagery, and covert recognition.

Neural activity is modulated by trial history: a functional magnetic resonance imaging study of the effects of a previous antisaccade.

Saccadic latencies are influenced by what occurred during the previous trial. When the previous trial is an antisaccade, the latencies of both prosaccades and antisaccades are prolonged. The aim of this study was to identify neural correlates of this intertrial effect of antisaccades. Specifically, based on both monkey electrophysiology and human neuroimaging findings, we expected trials preceded by antisaccades to be associated with reduced frontal eye field (FEF) activity relative to those preceded by prosaccades. Twenty-one healthy participants performed pseudorandom sequences of prosaccade and antisaccade trials during functional magnetic resonance imaging (fMRI) with concurrent monitoring of eye position. We compared activity in trials preceded by an antisaccade with activity in trials preceded by a prosaccade. The primary result was that a previous antisaccade prolonged saccadic latency and reduced fMRI activity in the FEF and other regions. No regions showed increased activity. We interpret the reduced FEF activity and slower saccadic responses to reflect inhibitory influences on the response system as a consequence of performing an antisaccade in the previous trial. This demonstrates that neural activity is modulated by trial history, consistent with a rapid, dynamic form of learning. More generally, these results highlight the importance of trial history as a source of variability in both behavioral and neuroimaging studies.

Antisaccade velocity, but not latency, results from a lack of saccade visual guidance.

Antisaccades are slower in peak velocity, more dysmetric, and longer in latency than prosaccades. This study used a novel visually guided antisaccade task to determine how visual target presence affects antisaccade metrics. The results showed that peak velocity and endpoint error of visually guided antisaccades were more similar to prosaccades than to traditional antisaccades, whereas their latencies were similar to those of traditional antisaccades. The velocity of prosaccades, and to a lesser extent that of antisaccades, were boosted by the sudden appearance of a target. These results suggest that the lower velocity and increased dysmetria of traditional antisaccades result from the absence of a visual target, but their longer latency is more likely a result of suppressing a prosaccadic reflex.

Saccade-related activity in the primate superior colliculus depends on the presence of local landmarks at the saccade endpoint.

Saccade-related discharge in the superior colliculus is greater for saccades made to a spot of light than for saccades in complete darkness. However, it is unclear whether this enhancement is due to the discontinuity of the spot or due to its being a new object of fixation. In these experiments, we examined the saccade-related activity of intermediate-layer neurons in the primate superior colliculus during delayed saccades to the center or corner of a large, bright square, as well as for visual and memory-guided movements to small spots in isolation. The saccade-related discharge for movements made to a local visual landmark present at the time of the saccade, be it a corner of a square or a small spot, was higher than that for saccades made to the center of a square that contained no local visual landmarks within. Moreover, discharge for movements to the center of a square were very similar to that for saccades to blank, dark space. Saccade velocity was similarly dependent on the presence of such a landmark, though less dramatically. The endpoints of saccades directed toward a square's corner were slightly displaced toward the center of the square. Across all neurons, discharge and velocity for saccades to the center of a square increased as the square size was decreased, but were never greater than those for saccades to a small spot of light. These results suggest that both saccade-related discharge in the superior colliculus and saccade metrics are enhanced for movements directed to parts of the visual scene with high contrast, while shifting fixation to a new object is not itself sufficient to elevate discharge and metrics above those of saccades to blank space.

Effect of short-term saccadic adaptation on saccades evoked by electrical stimulation in the primate superior colliculus.

The brain maintains the accuracy of visually guided movements by using visual feedback to correct for changes in the nervous system and musculature that would otherwise result in dysmetria. In monkeys, evidence suggests that an adaptive mechanism can compensate for weakness in an extraocular muscle by changing the gain of the neural signal to the weakened muscle. The visual effects of such neuromuscular changes have been simulated using a short-term saccade adaptation paradigm, in which the target spot jumps to a new location during the initial saccade. Under these circumstances, over several hundred trials, monkeys gradually change the amplitude of their saccades so that the eye lands closer to the final location of the target spot. There is considerable evidence from lesion and single-unit recording studies that the locus of such saccade adaptation is downstream of the superior colliculus in the cerebellum. Paradoxically, previous research has indicated that saccades evoked by electrical stimulation in the superior colliculus are not modified by short-term saccade adaptation, suggesting that adaptation occurs in the oculomotor system upstream of the superior colliculus or else in a pathway that bypasses the superior colliculus. We tested whether this result was due to using suprathreshold stimulation currents. Stimulating at 44 low-threshold sites in the superior colliculi of three monkeys revealed that using low current levels evoked saccades that were modified by adaptation. Adaptation for visually guided and electrically evoked saccades had similar time courses and tended to be accomplished by a reduction in saccade velocity rather than a decrease in duration. Moreover, the more similar the velocity of electrically evoked and visually guided saccades prior to the start of saccadic adaptation the greater the effect of adaptation on electrically evoked saccades. These results suggest that the superior colliculus is indeed upstream of the locus of adaptation, corroborating previous lesion and single-cell recording studies, but that the mechanism mediating saccade adaptation is sensitive to the parameters of electrical stimulation.