An Open Resource for Non-human Primate Optogenetics.

Optogenetics has revolutionized neuroscience in small laboratory animals, but its effect on animal models more closely related to humans, such as non-human primates (NHPs), has been mixed. To make evidence-based decisions in primate optogenetics, the scientific community would benefit from a centralized database listing all attempts, successful and unsuccessful, of using optogenetics in the primate brain. We contacted members of the community to ask for their contributions to an open science initiative. As of this writing, 45 laboratories around the world contributed more than 1,000 injection experiments, including precise details regarding their methods and outcomes. Of those entries, more than half had not been published. The resource is free for everyone to consult and contribute to on the Open Science Framework website. Here we review some of the insights from this initial release of the database and discuss methodological considerations to improve the success of optogenetic experiments in NHPs.

Fast Compensatory Functional Network Changes Caused by Reversible Inactivation of Monkey Parietal Cortex.

The brain has a remarkable capacity to recover after lesions. However, little is known about compensatory neural adaptations at the systems level. We addressed this question by investigating behavioral and (correlated) functional changes throughout the cortex that are induced by focal, reversible inactivations. Specifically, monkeys performed a demanding covert spatial attention task while the lateral intraparietal area (LIP) was inactivated with muscimol and whole-brain fMRI activity was recorded. The inactivation caused LIP-specific decreases in task-related fMRI activity. In addition, these local effects triggered large-scale network changes. Unlike most studies in which animals were mainly passive relative to the stimuli, we observed heterogeneous effects with more profound muscimol-induced increases of task-related fMRI activity in areas connected to LIP, especially FEF. Furthermore, in areas such as FEF and V4, muscimol-induced changes in fMRI activity correlated with changes in behavioral performance. Notably, the activity changes in remote areas did not correlate with the decreased activity at the site of the inactivation, suggesting that such changes arise via neuronal mechanisms lying in the intact portion of the functional task network, with FEF a likely key player. The excitation-inhibition dynamics unmasking existing excitatory connections across the functional network might initiate these rapid adaptive changes.

Selective TMS-induced modulation of functional connectivity correlates with changes in behavior.

Despite the increasing use of functional connectivity (FC) studies in fundamental and clinical research, the link between FC and behavior is still poorly understood. To test the hypothesis that artificial modulation of FC correlates with changes in behavior in a quantitative manner, we performed behavioral and resting state fMRI experiments in monkeys while perturbing, offline, the frontal eye fields (FEF) using unilateral continuous theta burst transcranial magnetic stimulation (FEF-cTBS). Stimulation of left and right FEF caused remarkably specific decreases in FC, which were symmetric for intra-hemispheric and asymmetric for inter-hemispheric FC. Surprisingly, FEF-cTBS improved the performance and compensated intrinsic choice biases in saccadic behavior of four monkeys, independent of the initial bias direction. Moreover, the direction of the stimulation-induced effects on both behavior (i.e. bias compensation) and FC (i.e. decrease) were independent of the stimulated hemisphere, while their magnitude depended on the side of stimulation, choice bias and monkey. Overall, the naturally-occurring saccade biases determined the FC changes following FEF-cTBS. Finally, we showed that the average decreases in FC in the FEF network induced by cTBS can be used to predict, with high specificity, both the direction (opposite to the saccadic biases) and the magnitude of the shift in saccadic choice preference relative to the unperturbed state. To reconcile the apparent contradiction between improved performance and bias compensation vs. decrease in functional connectivity, we propose that the main functional consequences of FEF-cTBS relate to adjusting inter-hemispheric imbalances.

A practical application of text mining to literature on cognitive rehabilitation and enhancement through neurostimulation.

The exponential growth in publications represents a major challenge for researchers. Many scientific domains, including neuroscience, are not yet fully engaged in exploiting large bodies of publications. In this paper, we promote the idea to partially automate the processing of scientific documents, specifically using text mining (TM), to efficiently review big corpora of publications. The "cognitive advantage" given by TM is mainly related to the automatic extraction of relevant trends from corpora of literature, otherwise impossible to analyze in short periods of time. Specifically, the benefits of TM are increased speed, quality and reproducibility of text processing, boosted by rapid updates of the results. First, we selected a set of TM-tools that allow user-friendly approaches of the scientific literature, and which could serve as a guide for researchers willing to incorporate TM in their work. Second, we used these TM-tools to obtain basic insights into the relevant literature on cognitive rehabilitation (CR) and cognitive enhancement (CE) using transcranial magnetic stimulation (TMS). TM readily extracted the diversity of TMS applications in CR and CE from vast corpora of publications, automatically retrieving trends already described in published reviews. TMS emerged as one of the important non-invasive tools that can both improve cognitive and motor functions in numerous neurological diseases and induce modulations/enhancements of many fundamental brain functions. TM also revealed trends in big corpora of publications by extracting occurrence frequency and relationships of particular subtopics. Moreover, we showed that CR and CE share research topics, both aiming to increase the brain's capacity to process information, thus supporting their integration in a larger perspective. Methodologically, despite limitations of a simple user-friendly approach, TM served well the reviewing process.

Functional significance of nonspatial information in monkey lateral intraparietal area.

Although the parietal cortex is traditionally associated with spatial perception and motor planning, recent evidence shows that neurons in the lateral intraparietal area (LIP) carry both spatial and nonspatial signals. The functional significance of the nonspatial information in the parietal cortex is not understood. To address this question, we tested the effect of unilateral reversible inactivation of LIP on three behavioral tasks known to evoke nonspatial responses. Each task included a spatial component (target selection in the hemifield contralateral or ipsilateral to the inactivation) and a nonspatial component, namely limb motor planning, the estimation of elapsed time, and reward-based decisions. Although inactivation reliably impaired performance on all tasks, the deficits were spatially specific (restricted to contralateral target locations), and there were no effects on nonspatial aspects on performance. This suggests that modulatory nonspatial signals in LIP represent feedback about computations performed elsewhere rather than a primary role of LIP in these computations.

Task specific computations in attentional maps.

The lateral intraparietal area (LIP), a portion of monkey posterior parietal cortex, has been implicated in spatial attention. We review recent evidence from our laboratory showing that LIP encodes a priority map of the external environment that specifies the momentary locus of attention and is activated in a variety of behavioral tasks. The priority map in LIP is shaped by task-specific variables. We suggest that the multifaceted responses in LIP represent mechanisms for allocating attention, and that the attentional system may flexibly configure itself to meet the cognitive, motor and motivational demands of individual tasks.

Neuronal correlates of the set-size effect in monkey lateral intraparietal area.

It has long been known that the brain is limited in the amount of sensory information that it can process at any given time. A well-known form of capacity limitation in vision is the set-size effect, whereby the time needed to find a target increases in the presence of distractors. The set-size effect implies that inputs from multiple objects interfere with each other, but the loci and mechanisms of this interference are unknown. Here we show that the set-size effect has a neural correlate in competitive visuo-visual interactions in the lateral intraparietal area, an area related to spatial attention and eye movements. Monkeys performed a covert visual search task in which they discriminated the orientation of a visual target surrounded by distractors. Neurons encoded target location, but responses associated with both target and distractors declined as a function of distractor number (set size). Firing rates associated with the target in the receptive field correlated with reaction time both within and across set sizes. The findings suggest that competitive visuo-visual interactions in areas related to spatial attention contribute to capacity limitations in visual searches.

Integration of exogenous input into a dynamic salience map revealed by perturbing attention.

Although it is widely accepted that exogenous and voluntary factors jointly determine the locus of attention, the rules governing the integration of these factors are poorly understood. We investigated neural responses in the lateral intraparietal area (LIP) to transient, distracting visual perturbations presented during task performance. Monkeys performed a covert search task in which they discriminated the orientation of a target embedded among distractors, and brief visual perturbations were presented at various moments and locations during task performance. LIP neurons responded to perturbations consisting of the appearance of new objects, as well as to abrupt changes in the color, luminance, or position of existing objects. The LIP response correlated with the bottom-up behavioral effects of different perturbation types. In addition, neurons showed two types of top-down modulations. One modulation was a context-specific multiplicative gain that affected perturbation, target, and distractor activity in a spatially nonspecific manner. Gain was higher in blocks of trials in which perturbations directly marked target location than in blocks in which they invariably appeared opposite the target, thus encoding a behavioral context defined by the statistical contingency between target and perturbation location. A second modulation reflected local competitive interactions with search-related activity, resulting in the converse effect: weaker perturbation-evoked responses if perturbations appeared at the location of the target than if they appeared opposite the target. Thus, LIP encodes an abstract dimension of salience, which is shaped by local and global top-down mechanisms. These interacting mechanisms regulate responsiveness to external input as a function of behavioral context and momentary task demands.

Integration of visuospatial and effector information during symbolically cued limb movements in monkey lateral intraparietal area.

Natural behavior requires close but flexible coordination between attention, defined as selection for perception, and action. In recent years a distributed network including the lateral intraparietal area (LIP) has been implicated in visuospatial selection for attention and rapid eye movements (saccades), but the relation between the attentional and motor functions of this area remains unclear. Here we tested LIP neurons in a task that involved not an ocular but a manual operant response. Monkeys viewed a display containing one cue and several distractors and reported the orientation of the cue (right- or left-facing) by releasing one of two bars grasped, respectively, with the right or left hand. The movement in this task thus was associated with (cued by), but not directed toward, the visual stimulus. A large majority of neurons responded more when the cue rather than when a distractor was in their receptive field, suggesting that they contribute to the attentional selection of the cue. A fraction of these neurons also was modulated by limb release, thus simultaneously encoding cue location and the active limb. The results suggest that the LIP links behaviorally relevant visual information with motor variables relevant for solving a task in a wide range of circumstances involving goal-directed or symbolically cued movements and eye as well as limb movements. A central function of the LIP may be to coordinate visual and motor selection during a wide variety of behaviors.

Effects of spontaneous eye movements on spatial memory in macaque periarcuate cortex.

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.

Effects of gaze shifts on maintenance of spatial memory in macaque frontal eye field.

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.