Recipient Bone Marrow Engraftment in Donor Tissue After Long-term Tolerance to a Composite Tissue Allograft

Transplantation. Jun, 2002  |  Pubmed ID: 12131681

An important component of a composite tissue limb allograft (CTA) is the vascularized bone marrow and bone marrow stroma, which when transplanted could create immediate marrow space and engraftment. We have previously demonstrated that tolerance to musculoskeletal allografts can be achieved with a 12-day course of cyclosporine without the presence of long-term peripheral donor cell chimerism. The objective of this study was to determine the fate of the donor bone marrow after transplantation of a limb allograft in a miniature swine model.

Estimating Invisible Target Speed from Neuronal Activity in Monkey Frontal Eye Field

Nature Neuroscience. Jan, 2003  |  Pubmed ID: 12483216

Working memory involves transient storage of information and the ability to manipulate that information for short-range planning and prediction. The computational aspect of working memory can be probed using dynamic sensorimotor behavior requiring complex stimulus-response mappings. Such a transformation occurs when extrapolating the future location of a moving target that is rendered temporarily invisible. Estimating the trajectory of an invisible moving target requires encoding and storing several target features, including the direction and speed of motion. We trained monkeys to make saccades to the estimated position of invisible targets moving at various speeds. The activity of neurons in the frontal eye field (FEF) was consistently modulated according to the speed of target motion. A reconstruction algorithm showed that estimates of target speed based on FEF activity were similar to behavioral speed estimates. FEF may therefore be involved in updating an internal representation of target trajectory for predictive saccades.

Comparison of Performance on Memory-guided Saccade and Delayed Spatial Match-to-sample Tasks in Monkeys

Vision Research. Feb, 2003  |  Pubmed ID: 12535990

To investigate the sources of spatial error in memory-guided saccades (MGS), we have trained monkeys on two different tasks: a MGS task and a delayed spatial match-to-sample (MTS) task. We first tested the effect of introducing a post-saccadic visual feedback on the accuracy of MGS. We found that visual feedback had a pronounced effect on the systematic saccade error, but less of an effect on the variable error. Visual feedback can improve the accuracy of saccadic eye movements over several days, while feedback removal can decrease accuracy in a reversible way. These effects also depend both on target eccentricity and the duration of the memory delay. To test whether saccade error is due to the accuracy of spatial memory storage or arises downstream from that memory, we measured behavioral performance on a spatial MTS task both before and after training with visual feedback. The results showed no significant difference in performance of the MTS task before and after feedback training despite significant changes in MGS accuracy. The results suggest that the accuracy of spatial memory is not the source of the systematic errors that accompany MGS.

Effects of Gaze Shifts on Maintenance of Spatial Memory in Macaque Frontal Eye Field

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Jul, 2003  |  Pubmed ID: 12843243

The activity of 91 neurons in the frontal eye fields (FEFs) of two macaque monkeys was recorded while the animals performed a delayed spatial match-to-sample task. During the delay, the animals were required to shift their gaze to one of four eccentric locations. Neuronal activity during the delay was analyzed for sensitivity to cue location and eye position. One-third of the neurons showed significant delay activity selective for cue location, whereas slightly more than one-half of the neurons showed significant modulation of delay activity when the gaze was shifted to an eccentric location. Despite this modulation, the neurons continued to signal their preferred cue location during most of the delay. However, after recentering saccades, the memory signal was temporarily abolished and then reemerged over a period of few hundred milliseconds. This is consistent with the idea that spatial working memory is buffered outside of the FEF. For most neurons, delay activity tended to increase when the gaze was shifted away from the preferred location and to decrease when the gaze was shifted toward the preferred location. This pattern of modulation is consistent with a vector subtraction mechanism that allows for the superposition of multiple saccade plans.

Effects of Spontaneous Eye Movements on Spatial Memory in Macaque Periarcuate Cortex

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Dec, 2003  |  Pubmed ID: 14673003

Persistent activity in prefrontal cortex during delayed response tasks is a putative neural correlate of spatial working memory. We tested whether this activity was sensitive to eye movements made during the memory interval by recording from prefrontal neurons while monkeys performed a delayed spatial matching saccade task in which they were allowed to make eye movements freely. We found that eye movements degraded the spatial tuning of persistent activity even as there was an improvement in behavioral performance. Although the strength of the memory signal decreased, delay activity continued to signal the location of cue. The results suggest that free eye movements reduce neuronal gain rather than add variability. The saccades performed during the delay suggest the existence of a rehearsal mechanism that could contribute to working memory maintenance. The results do not provide support for a segregation of storage and executive functions in the periarcuate cortex.

Modification of Saccades Evoked by Stimulation of Frontal Eye Field During Invisible Target Tracking

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Mar, 2004  |  Pubmed ID: 15056705

We investigated the internal representation of invisible moving targets using electrical microstimulation in the prefrontal cortex. Monkeys were trained to make saccades to the extrapolated position of a small moving target that was rendered invisible during part of its trajectory. Although the target was invisible, involuntary saccades were evoked by electrical microstimulation of the frontal eye field. Stimulation was applied at different times relative to the disappearance of the target while the monkey fixated. When stimulation was applied immediately after target disappearance, electrically evoked saccades were biased toward the starting point of the target trajectory. When stimulation was applied later in the trial, evoked saccades were biased toward the end of the trajectory. The bias in evoked saccade direction changed continuously over time. The magnitude and statistical significance of the electrically evoked saccade deviation depended on the accuracy of the monkeys' voluntary saccades relative to the invisible target. The results suggest that covert tracking is accompanied by a continuously shifting saccade plan that moves along the target path.

Effects of Electrical Microstimulation in Monkey Frontal Eye Field on Saccades to Remembered Targets

Vision Research. Dec, 2005  |  Pubmed ID: 15893784

Spatially selective delay activity in the frontal eye field (FEF) is hypothesized to be part of a mechanism for the transformation of visual signals into instructions for voluntary movements. To understand the linkage between FEF activity and eye movement planning, we recorded neuronal responses of FEF neurons while monkeys performed a memory-saccade task. We then electrically stimulated the same sites during the memory-delay epoch of the task. The stimulation currents used were subthreshold for evoking saccades during a gap-fixation task. Microstimulation resulted in changes in the spatial and temporal components of saccade parameters: an increase in latency, and a shift in amplitude and direction. We performed a vector analysis to determine the relative influence of the visual cue and electrical stimulus on the memory-saccade. In general, the memory-saccade was strongly weighted toward the visual cue direction, yet the electrical stimulus introduced a consistent bias away from the receptive/movement field of the stimulation site. The effects of sub-threshold stimulation were consistent with a combination of vector subtraction and averaging, but not with vector summation. Vector subtraction may play a role in spatial updating of movement plans for memory-guided saccades when eye position changes during the memory period.

Microstimulation of the Dorsolateral Prefrontal Cortex Biases Saccade Target Selection

Journal of Cognitive Neuroscience. Jun, 2005  |  Pubmed ID: 15969908

A long-standing issue concerning the executive function of the primate dorsolateral prefrontal cortex is how the activity of prefrontal neurons is linked to behavioral response selection. To establish a functional relationship between prefrontal memory fields and saccade target selection, we trained three macaque monkeys to make saccades to the remembered location of a visual cue in a delayed spatial match-to-sample saccade task. We electrically stimulated sites in the prefrontal cortex with subthreshold currents during the delay epoch while monkeys performed this task. Our results show that the artificially injected signal interacts with the neural activity responsible for target selection, biasing saccade choices either towards the receptive/movement field (RF/MF) or away from the RF/MF, depending on the stimulation site. These findings might reflect a functional link between prefrontal signals responsible for the selection bias by modulating the balance between excitation and inhibition in the competitive interactions underlying behavioral selection.

Motion Processing in Macaque V4

Nature Neuroscience. Sep, 2005  |  Pubmed ID: 16127440

A Flashing Line Can Warp Your Mind

Neuron. Feb, 2006  |  Pubmed ID: 16446136

Keeping pace with a constantly changing world requires the ability to make predictions about the future on a variety of timescales. A very basic example of this is the ability to predict the future location of a moving object in the brief time that it takes to perceive and respond to that object. In this issue of Neuron, experiments by Sundberg, Fallah, and Reynolds reveal a potential neural substrate for making short-range predictions about motion in visual area V4.

A Neural Representation of Categorization Uncertainty in the Human Brain

Neuron. Mar, 2006  |  Pubmed ID: 16504950

The ability to classify visual objects into discrete categories ("friend" versus "foe"; "edible" versus "poisonous") is essential for survival and is a fundamental cognitive function. The cortical substrates that mediate this function, however, have not been identified in humans. To identify brain regions involved in stimulus categorization, we developed a task in which subjects classified stimuli according to a variable categorical boundary. Psychophysical functions were used to define a decision variable, categorization uncertainty, which was systematically manipulated. Using event-related functional MRI, we discovered that activity in a fronto-striatal-thalamic network, consisting of the medial frontal gyrus, anterior insula, ventral striatum, and dorsomedial thalamus, was modulated by categorization uncertainty. We found this network to be distinct from the frontoparietal attention network, consisting of the frontal and parietal eye fields, where activity was not correlated with categorization uncertainty.

Perception, Memory, and Action in Frontal and Parietal Cortex. Focus on "Selection and Maintenance of Saccade Goals in the Human Frontal Eye Fields"

Journal of Neurophysiology. Jun, 2006  |  Pubmed ID: 16510779

Radial Motion Bias in Macaque Frontal Eye Field

Visual Neuroscience. Jan-Feb, 2006  |  Pubmed ID: 16597350

The visual responsiveness and spatial tuning of frontal eye field (FEF) neurons were determined using a delayed memory saccade task. Neurons with visual responses were then tested for direction selectivity using moving random dot patterns centered in the visual receptive field. The preferred axis of motion showed a significant tendency to be aligned with the receptive-field location so as to favor motion toward or away from the center of gaze. Centrifugal (outward) motion was preferred over centripetal motion. Motion-sensitive neurons in FEF thus appear to have a direction bias at the population level. This bias may facilitate the detection or discrimination of expanding optic flow patterns. The direction bias is similar to that seen in visual area MT and in posterior parietal cortex, from which FEF receives afferent projections. The outward motion bias may explain asymmetries in saccades made to moving targets. A representation of optic flow in FEF might be useful for planning eye movements during navigation.

Walk the Line: Parietal Neurons Respect Category Boundaries

Nature Neuroscience. Oct, 2006  |  Pubmed ID: 17001336

Computing Vector Differences Using a Gain Field-like Mechanism in Monkey Frontal Eye Field

The Journal of Physiology. Jul, 2007  |  Pubmed ID: 17510192

Signals related to eye position are essential for visual perception and eye movements, and are powerful modulators of sensory responses in many regions of the visual and oculomotor systems. We show that visual and pre-saccadic responses of frontal eye field (FEF) neurons are modulated by initial eye position in a way suggestive of a multiplicative mechanism (gain field). Furthermore the slope of the eye position sensitivity tends to be negatively correlated with preferred retinal position across the population. A model with Gaussian visual receptive fields and linear-rectified eye position gain fields accounts for a large portion of the variance in the recorded data. Using physiologically derived parameters, this model is able to subtract the gaze shift from the vector representing the retinal location of the target. This computation might be used to maintain a memory of target location in space during ongoing eye movements. This updated spatial memory can be read directly from the locus of the peak of activity across the retinotopic map of FEF and it is the result of a vector subtraction between retinal target location when flashed and subsequent eye displacement in the dark.

Visual Remapping by Vector Subtraction: Analysis of Multiplicative Gain Field Models

Neural Computation. Sep, 2007  |  Pubmed ID: 17650063

Saccadic eye movements remain spatially accurate even when the target becomes invisible and the initial eye position is perturbed. The brain accomplishes this in part by remapping the remembered target location in retinal coordinates. The computation that underlies this visual remapping is approximated by vector subtraction: the original saccade vector is updated by subtracting the vector corresponding to the intervening eye movement. The neural mechanism by which vector subtraction is implemented is not fully understood. Here, we investigate vector subtraction within a framework in which eye position and retinal target position signals interact multiplicatively (gain field). When the eyes move, they induce a spatial modulation of the firing rates across a retinotopic map of neurons. The updated saccade metric can be read from the shift of the peak of the population activity across the map. This model uses a quasi-linear (half-rectified) dependence on the eye position and requires the slope of the eye position input to be negatively proportional to the preferred retinal position of each neuron. We derive analytically this constraint and study its range of validity. We discuss how this mechanism relates to experimental results reported in the frontal eye fields of macaque monkeys.

Coordination of Smooth Pursuit and Saccade Target Selection in Monkeys

Journal of Neurophysiology. Oct, 2007  |  Pubmed ID: 17715189

The coordination of saccadic and smooth pursuit eye movements in macaque monkeys was investigated using a target selection paradigm with two moving targets crossing at a center fixation point. A task in which monkeys selected a target based on its color was used to test the hypothesis that common neural signals underlie target selection for pursuit and saccades, as well as testing whether target selection signals are available to the saccade and pursuit systems simultaneously or sequentially. Several combinations of target color, speed, and direction were used. In all cases, smooth pursuit was highly selective for the rewarded target before any saccade occurred. On >80% of the trials, the saccade was directed toward the same target as both pre- and postsaccadic pursuit. The results favor a model in which a shared target selection signal is simultaneously available to both the saccade and pursuit systems, rather than a sequential model.

Modulation of Visual Responses in Macaque Frontal Eye Field During Covert Tracking of Invisible Targets

Cerebral Cortex (New York, N.Y. : 1991). Apr, 2007  |  Pubmed ID: 16723405

The purpose of this study was to investigate the interaction between internal representations of invisible moving targets and visual responses of neurons in frontal eye fields (FEFs). Monkeys were trained to make saccades to the extrapolated position of a target that was temporarily rendered invisible for variable durations as if it had passed behind an occluder. Flashed, task-irrelevant visual probe stimuli were used to study the visual responsiveness of FEF neurons during this task. Probes were flashed at various times and locations during the occlusion interval. Net changes in neuronal activity were obtained by comparing the activity on trials with probes with randomly interleaved trials without any probe. Most neurons showed an increase in firing rate in response to the probe, but some showed a decrease. Both types of responses were enhanced when the invisible target moved toward the receptive field (RF) as compared with trials on which the target moved away from the RF. Some neurons showed a spatial shift in the visual response during the occlusion interval. For cells that were excited by the probe, the shift tended to be correlated with the direction of motion of the target, whereas for cells that were inhibited the shift tended to be in the opposite direction. These results suggest that the role of FEF in predicting invisible target motion includes a sensory/perceptual component.

Neuronal Responses to Moving Targets in Monkey Frontal Eye Fields

Journal of Neurophysiology. Sep, 2008  |  Pubmed ID: 18632886

Due to delays in visuomotor processing, eye movements directed toward moving targets must integrate both target position and velocity to be accurate. It is unknown where and how target velocity information is incorporated into the planning of rapid (saccadic) eye movements. We recorded the activity of neurons in frontal eye fields (FEFs) while monkeys made saccades to stationary and moving targets. A substantial fraction of FEF neurons was found to encode not only the initial position of a moving target, but the metrics (amplitude and direction) of the saccade needed to intercept the target. Many neurons also encoded target velocity in a nearly linear manner. The quasi-linear dependence of firing rate on target velocity means that the neuronal response can be directly read out to compute the future position of a target moving with constant velocity. This is demonstrated using a quantitative model in which saccade amplitude is encoded in the population response of neurons tuned to retinal target position and modulated by target velocity.

Detection of Time-varying Signals in Event-related FMRI Designs

NeuroImage. Nov, 2008  |  Pubmed ID: 18775784

In neuroimaging research on attention, cognitive control, decision-making, and other areas where response time (RT) is a critical variable, the temporal variability associated with the decision is often assumed to be inconsequential to the hemodynamic response (HDR) in rapid event-related designs. On this basis, the majority of published studies model brain activity lasting less than 4 s with brief impulses representing the onset of neural or cognitive events, which are then convolved with the hemodynamic impulse response function (HRF). However, electrophysiological studies have shown that decision-related neuronal activity is not instantaneous, but in fact, often lasts until the motor response. It is therefore possible that small differences in neural processing durations, similar to human RTs, will produce noticeable changes in the HDR, and therefore in the results of regression analyses. In this study we compare the effectiveness of traditional models that assume no temporal variance with a model that explicitly accounts for the duration of very brief epochs of neural activity. Using both simulations and fMRI data, we show that brief differences in duration are detectable, making it possible to dissociate the effects of stimulus intensity from stimulus duration, and that optimizing the model for the type of activity being detected improves the statistical power, consistency, and interpretability of results.

Frontal Eye Field Neurons Signal Changes in Decision Criteria

Nature Neuroscience. Nov, 2009  |  Pubmed ID: 19855389

Flexible links between sensory stimuli and behavioral responses underlie many cognitive processes. One process that contributes to flexible decision-making is categorization. Some categories are innate or overlearned, but, in many cases, category boundaries represent flexible decision criteria that can shift on the fly to adapt to changes in the environment. The ability to shift category boundaries allows decision-making to adapt to changing circumstances. We found that monkeys were able to switch rapidly between two category boundaries when classifying the speed of a moving dot pattern and that neurons in monkey frontal eye field (FEF) changed their activity when the boundary changed. The responses of a subpopulation of FEF neurons that were sensitive to both stimulus and boundary speed were used to classify the stimuli as accurately as the monkeys' performance.

Effects of Heartbeat and Respiration on Macaque FMRI: Implications for Functional Connectivity

Neuropsychologia. Jun, 2010  |  Pubmed ID: 19969009

The use of functional magnetic resonance imaging (fMRI) in non-human primates is on the increase. It is known that the blood-oxygen-level-dependent (BOLD) signal varies not only as a function of local neuronal energy consumption but also as a function of cardiac and respiratory activity. We mapped these cyclic cardiac and respiratory artifacts in anesthetized macaque monkeys and present an objective analysis of their impact on estimates of functional connectivity (fcMRI). Voxels with significant cardiac and respiratory artifacts were found in much the same regions as previously reported for awake humans. We show two example seeds where removing the artifacts clearly decreased the number of false positive and false negative correlations. In particular, removing the artifacts reduced correlations in the so-called resting state network. Temporal bandpass filtering or spatial smoothing may help to reduce the effects of artifacts in some cases but are not an adequate replacement for an algorithm that explicitly models and removes cyclic cardiac and respiratory artifacts.

Internally Generated Error Signals in Monkey Frontal Eye Field During an Inferred Motion Task

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Sep, 2010  |  Pubmed ID: 20810882

An internal model for predictive saccades in frontal cortex was investigated by recording neurons in monkey frontal eye field (FEF) during an inferred motion task. Monkeys were trained to make saccades to the extrapolated position of a small moving target that was rendered temporarily invisible and whose trajectory was altered. On approximately two-thirds of the trials, monkeys made multiple saccades while the target was invisible. Primary saccades were correlated with extrapolated target position. Secondary saccades significantly reduced residual errors resulting from imperfect accuracy of the first saccade. These observations suggest that the second saccade was corrective. Because there was no visual feedback, corrective saccades could only be driven by an internally generated error signal. Neuronal activity in the frontal eye field was directionally tuned before both primary and secondary saccades. Separate subpopulations of cells encoded either saccade direction or direction error before the second saccade. These results suggest that FEF neurons encode the error after the first saccade, as well as the direction of the second saccade. Hence, FEF appears to contribute to detecting and correcting movement errors based on internally generated signals.

Suboptimal Integration of Reward Magnitude and Prior Reward Likelihood in Categorical Decisions by Monkeys

Frontiers in Neuroscience. 2010  |  Pubmed ID: 21151367

Sensory decisions may be influenced by non-sensory information regarding reward magnitude or reward likelihood. Given identical sensory information, it is more optimal to choose an option if it is a priori more likely to be correct and hence rewarded (prior reward likelihood bias), or if it yields a larger reward, given that it is the correct choice (reward magnitude bias). Here, we investigated the ability of macaque monkeys to integrate reward magnitude and prior reward likelihood information into a categorical decision about stimuli with high signal strength but variable decision uncertainty. In the asymmetric reward magnitude condition, monkeys over-adjusted their decision criterion such that they chose the highly rewarded alternative far more often than was optimal; in contrast, monkeys did not adjust their decision criterion in response to asymmetric reward likelihood. This finding shows that in this setting, monkeys did not adjust their decision criterion based on the product of reward likelihood and reward magnitude as has been reported to be the case in value-based decisions that do not involve decision uncertainty due to stimulus categorization.

The Dorsal Medial Frontal Cortex is Sensitive to Time on Task, Not Response Conflict or Error Likelihood

NeuroImage. Jul, 2011  |  Pubmed ID: 21168515

The dorsal medial frontal cortex (dMFC) is highly active during choice behavior. Though many models have been proposed to explain dMFC function, the conflict monitoring model is the most influential. It posits that dMFC is primarily involved in detecting interference between competing responses thus signaling the need for control. It accurately predicts increased neural activity and response time (RT) for incompatible (high-interference) vs. compatible (low-interference) decisions. However, it has been shown that neural activity can increase with time on task, even when no decisions are made. Thus, the greater dMFC activity on incompatible trials may stem from longer RTs rather than response conflict. This study shows that (1) the conflict monitoring model fails to predict the relationship between error likelihood and RT, and (2) the dMFC activity is not sensitive to congruency, error likelihood, or response conflict, but is monotonically related to time on task.

Conflict, Error Likelihood, and RT: Response to Brown & Yeung Et Al

NeuroImage. Jul, 2011  |  Pubmed ID: 21554960

Feasibility of Noninvasive Cavitation-guided Blood-brain Barrier Opening Using Focused Ultrasound and Microbubbles in Nonhuman Primates

Applied Physics Letters. Apr, 2011  |  Pubmed ID: 21580802

In vivo transcranial and noninvasive cavitation detection with blood-brain barrier (BBB) opening in nonhuman primates is hereby reported. The BBB in monkeys was opened transcranically using focused ultrasound (FUS) in conjunction with microbubbles. A passive cavitation detector, confocal with the FUS transducer, was used to identify and monitor the bubble behavior. During sonication, the cavitation spectrum, which was found to be region-, pressure-, and bubble-dependent, provided real-time feedback regarding the opening occurrence and its properties. These findings demonstrate feasibility of transcranial, cavitation-guided BBB opening using FUS and microbubbles in noninvasive human applications.

Noninvasive, Transient and Selective Blood-brain Barrier Opening in Non-human Primates in Vivo

PloS One. 2011  |  Pubmed ID: 21799913

The blood-brain barrier (BBB) is a specialized vascular system that impedes entry of all large and the vast majority of small molecules including the most potent central nervous system (CNS) disease therapeutic agents from entering from the lumen into the brain parenchyma. Microbubble-enhanced, focused ultrasound (ME-FUS) has been previously shown to disrupt noninvasively, selectively, and transiently the BBB in small animals in vivo. For the first time, the feasibility of transcranial ME-FUS BBB opening in non-human primates is demonstrated with subsequent BBB recovery. Sonications were combined with two different types of microbubbles (customized 4-5 µm and Definity®). 3T MRI was used to confirm the BBB disruption and to assess brain damage.