Differential clustering of visual and choice- and saccade-related activity in macaque V3A and CIP.

Neurons in sensory and motor cortices tend to aggregate in clusters with similar functional properties. Within the primate dorsal ("where") pathway, an important interface between three-dimensional (3-D) visual processing and motor-related functions consists of two hierarchically organized areas: V3A and the caudal intraparietal (CIP) area. In these areas, 3-D visual information, choice-related activity, and saccade-related activity converge, often at the single-neuron level. Characterizing the clustering of functional properties in areas with mixed selectivity, such as these, may help reveal organizational principles that support sensorimotor transformations. Here we quantified the clustering of visual feature selectivity, choice-related activity, and saccade-related activity by performing correlational and parametric comparisons of the responses of well-isolated, simultaneously recorded neurons in macaque monkeys. Each functional domain showed statistically significant clustering in both areas. However, there were also domain-specific differences in the strength of clustering across the areas. Visual feature selectivity and saccade-related activity were more strongly clustered in V3A than in CIP. In contrast, choice-related activity was more strongly clustered in CIP than in V3A. These differences in clustering may reflect the areas' roles in sensorimotor processing. Stronger clustering of visual and saccade-related activity in V3A may reflect a greater role in within-domain processing, as opposed to cross-domain synthesis. In contrast, stronger clustering of choice-related activity in CIP may reflect a greater role in synthesizing information across functional domains to bridge perception and action.NEW & NOTEWORTHY The occipital and parietal cortices of macaque monkeys are bridged by hierarchically organized areas V3A and CIP. These areas support 3-D visual transformations, carry choice-related activity during 3-D perceptual tasks, and possess saccade-related activity. This study quantifies the functional clustering of neuronal response properties within V3A and CIP for each of these domains. The findings reveal domain-specific cross-area differences in clustering that may reflect the areas' roles in sensorimotor processing.

Perspective Cues Make Eye-specific Contributions to 3-D Motion Perception.

Robust 3-D visual perception is achieved by integrating stereoscopic and perspective cues. The canonical model describing the integration of these cues assumes that perspective signals sensed by the left and right eyes are indiscriminately pooled into a single representation that contributes to perception. Here, we show that this model fails to account for 3-D motion perception. We measured the sensitivity of male macaque monkeys to 3-D motion signaled by left-eye perspective cues, right-eye perspective cues, stereoscopic cues, and all three cues combined. The monkeys exhibited idiosyncratic differences in their biases and sensitivities for each cue, including left- and right-eye perspective cues, suggesting that the signals undergo at least partially separate neural processing. Importantly, sensitivity to combined cue stimuli was greater than predicted by the canonical model, which previous studies found to account for the perception of 3-D orientation in both humans and monkeys. Instead, 3-D motion sensitivity was best explained by a model in which stereoscopic cues were integrated with left- and right-eye perspective cues whose representations were at least partially independent. These results indicate that the integration of perspective and stereoscopic cues is a shared computational strategy across 3-D processing domains. However, they also reveal a fundamental difference in how left- and right-eye perspective signals are represented for 3-D orientation versus motion perception. This difference results in more effective use of available sensory information in the processing of 3-D motion than orientation and may reflect the temporal urgency of avoiding and intercepting moving objects.

Mapping functional gradients of the striatal circuit using simultaneous microelectric stimulation and ultrahigh-field fMRI in non-human primates.

Advances in functional magnetic resonance imaging (fMRI) have significantly enhanced our understanding of the striatal system of both humans and non-human primates (NHP) over the last few decades. However, its circuit-level functional anatomy remains poorly understood, partly because in-vivo fMRI cannot directly perturb a brain system and map its casual input-output relationship. Also, routine 3T fMRI has an insufficient spatial resolution. We performed electrical microstimulation (EM) of the striatum in lightly-anesthetized NHPs while simultaneously mapping whole-brain activation, using contrast-enhanced fMRI at ultra-high-field 7T. By stimulating multiple positions along the striatum's main (dorsal-to-ventral) axis, we revealed its complex functional circuit concerning mutually connected subsystems in both cortical and subcortical areas. Indeed, within the striatum, there were distinct brain activation patterns across different stimulation sites. Specifically, dorsal stimulation revealed a medial-to-lateral elongated shape of activation in upper caudate and putamen areas, whereas ventral stimulation evoked areas confined to the medial and lower caudate. Such dorsoventral gradients also appeared in neocortical and thalamic activations, indicating consistent embedding profiles of the striatal system across the whole brain. These findings reflect different forms of within-circuit and inter-regional neuronal connectivity between the dorsal and ventromedial striatum. These patterns both shared and contrasted with previous anatomical tract-tracing and in-vivo resting-state fMRI studies. Our approach of combining microstimulation and whole-brain fMRI mapping in NHPs provides a unique opportunity to integrate our understanding of a targeted brain area's meso- and macro-scale functional systems.

Hierarchical computation of 3D motion across macaque areas MT and FST.

Computing behaviorally relevant representations of three-dimensional (3D) motion from two-dimensional (2D) retinal signals is critical for survival. To ascertain where and how the primate visual system performs this computation, we recorded from the macaque middle temporal (MT) area and its downstream target, the fundus of the superior temporal sulcus (area FST). Area MT is a key site of 2D motion processing, but its role in 3D motion processing is controversial. The functions of FST remain highly underexplored. To distinguish representations of 3D motion from those of 2D retinal motion, we contrast responses to multiple motion cues during a motion discrimination task. The results reveal a hierarchical transformation whereby many FST but not MT neurons are selective for 3D motion. Modeling results further show how generalized, cue-invariant representations of 3D motion in FST may be created by selectively integrating the output of 2D motion selective MT neurons.

Associations Between Smartphone Use for Physical Activity by South Korean College Students and Behavioral Change Constructs of the Transtheoretical Model.

We examined associations between smartphone uses to assist physical activity (PA) and change constructs of the transtheoretical model (TTM) among Korean college students. Our participants were 242 college students who completed a cross-sectional survey of their smartphone use, PA, and TTM constructs. We applied Poisson regression models to test the associations between stages of change and smartphone PA use frequencies in four categories over the previous week: 1= watching PA instruction videos; 2 = tracking PA; 3 = searching and booking sites for PA; and 4 = finding and making appointments with PA partners. The associations between these smartphone uses and participants' self-efficacy, decisional balance, processes of change, and PA were tested via ordinary least squares regression models. Results were that participants in the precontemplation and maintenance stages were the least and most frequent users of the smartphones in all four categories, respectively. Category one usage was positively associated with participants' scores on pros (ß = .22, p = .004), cognitive processes of change (ß = .30, p < .001), and behavioral processes of change (ß = .28, p < .001). Category two usage was positively associated with PA (ß = .06, p = .048). While category three usage was not significantly associated with any TTM constructs except for stages of change, category four usage was positively associated with self-efficacy (ß = .28, p < .001), pros (ß = .30, p < .001), cognitive processes of change (ß = .31, p < .001), behavioral processes of change (ß = .06, p <. 001), and PA (ß = .45, p < .001). These findings suggest that (a) active college students are likely to take advantage of smartphone to assist their PA, and (b) smartphones can help motivate college students toward regular PA.

Parallel processing, hierarchical transformations, and sensorimotor associations along the 'where' pathway.

Visually guided behaviors require the brain to transform ambiguous retinal images into object-level spatial representations and implement sensorimotor transformations. These processes are supported by the dorsal 'where' pathway. However, the specific functional contributions of areas along this pathway remain elusive due in part to methodological differences across studies. We previously showed that macaque caudal intraparietal (CIP) area neurons possess robust 3D visual representations, carry choice- and saccade-related activity, and exhibit experience-dependent sensorimotor associations (Chang et al., 2020b). Here, we used a common experimental design to reveal parallel processing, hierarchical transformations, and the formation of sensorimotor associations along the 'where' pathway by extending the investigation to V3A, a major feedforward input to CIP. Higher-level 3D representations and choice-related activity were more prevalent in CIP than V3A. Both areas contained saccade-related activity that predicted the direction/timing of eye movements. Intriguingly, the time course of saccade-related activity in CIP aligned with the temporally integrated V3A output. Sensorimotor associations between 3D orientation and saccade direction preferences were stronger in CIP than V3A, and moderated by choice signals in both areas. Together, the results explicate parallel representations, hierarchical transformations, and functional associations of visual and saccade-related signals at a key juncture in the 'where' pathway.

A probabilistic strategy for understanding action selection.

Brain regions involved in transforming sensory signals into movement commands are the likely sites where decisions are formed. Once formed, a decision must be read out from the activity of populations of neurons to produce a choice of action. How this occurs remains unresolved. We recorded from four superior colliculus neurons simultaneously while monkeys performed a target selection task. We implemented three models to gain insight into the computational principles underlying population coding of action selection. We compared the population vector average (PVA)/optimal linear estimator (OLE) and winner-takes-all (WTA) models and a Bayesian model, maximum a posteriori estimate (MAP), to determine which predicted choices most often. The probabilistic model predicted more trials correctly than both the WTA and the PVA. The MAP model predicted 81.88%, whereas WTA predicted 71.11% and PVA/OLE predicted the least number of trials at 55.71 and 69.47%. Recovering MAP estimates using simulated, nonuniform priors that correlated with monkeys' choice performance, improved the accuracy of the model by 2.88%. A dynamic analysis revealed that the MAP estimate evolved over time and the posterior probability of the saccade choice reached a maximum at the time of the saccade. MAP estimates also scaled with choice performance accuracy. Although there was overlap in the prediction abilities of all the models, we conclude that movement choice from populations of neurons may be best understood by considering frameworks based on probability.

MRI Compatible, Customizable, and 3D-Printable Microdrive for Neuroscience Research.

The effective connectivity of brain networks can be assessed using functional magnetic resonance imaging (fMRI) to quantify the effects of local electrical microstimulation (EM) on distributed neuronal activity. The delivery of EM to specific brain regions, particularly with layer specificity, requires MRI compatible equipment that provides fine control of a stimulating electrode's position within the brain while minimizing imaging artifacts. To this end, we developed a microdrive made entirely of MRI compatible materials. The microdrive uses an integrated penetration grid to guide electrodes and relies on a microdrilling technique to eliminate the need for large craniotomies, further reducing implant maintenance and image distortions. The penetration grid additionally serves as a built-in MRI marker, providing a visible fiducial reference for estimating probe trajectories. Following the initial implant procedure, these features allow for multiple electrodes to be inserted, removed, and repositioned with minimal effort, using a screw-type actuator. To validate the design of the microdrive, we conducted an EM-coupled fMRI study with a male macaque monkey. The results verified that the microdrive can be used to deliver EM during MRI procedures with minimal imaging artifacts, even within a 7 Tesla (7T) environment. Future applications of the microdrive include neuronal recordings and targeted drug delivery. We provide computer aided design (CAD) templates and a parts list for modifying and fabricating the microdrive for specific research needs. These designs provide a convenient, cost-effective approach to fabricating MRI compatible microdrives for neuroscience research.

Optimized but Not Maximized Cue Integration for 3D Visual Perception.

Reconstructing three-dimensional (3D) scenes from two-dimensional (2D) retinal images is an ill-posed problem. Despite this, 3D perception of the world based on 2D retinal images is seemingly accurate and precise. The integration of distinct visual cues is essential for robust 3D perception in humans, but it is unclear whether this is true for non-human primates (NHPs). Here, we assessed 3D perception in macaque monkeys using a planar surface orientation discrimination task. Perception was accurate across a wide range of spatial poses (orientations and distances), but precision was highly dependent on the plane's pose. The monkeys achieved robust 3D perception by dynamically reweighting the integration of stereoscopic and perspective cues according to their pose-dependent reliabilities. Errors in performance could be explained by a prior resembling the 3D orientation statistics of natural scenes. We used neural network simulations based on 3D orientation-selective neurons recorded from the same monkeys to assess how neural computation might constrain perception. The perceptual data were consistent with a model in which the responses of two independent neuronal populations representing stereoscopic cues and perspective cues (with perspective signals from the two eyes combined using nonlinear canonical computations) were optimally integrated through linear summation. Perception of combined-cue stimuli was optimal given this architecture. However, an alternative architecture in which stereoscopic cues, left eye perspective cues, and right eye perspective cues were represented by three independent populations yielded two times greater precision than the monkeys. This result suggests that, due to canonical computations, cue integration for 3D perception is optimized but not maximized.

Functional links between sensory representations, choice activity, and sensorimotor associations in parietal cortex.

Three-dimensional (3D) representations of the environment are often critical for selecting actions that achieve desired goals. The success of these goal-directed actions relies on 3D sensorimotor transformations that are experience-dependent. Here we investigated the relationships between the robustness of 3D visual representations, choice-related activity, and motor-related activity in parietal cortex. Macaque monkeys performed an eight-alternative 3D orientation discrimination task and a visually guided saccade task while we recorded from the caudal intraparietal area using laminar probes. We found that neurons with more robust 3D visual representations preferentially carried choice-related activity. Following the onset of choice-related activity, the robustness of the 3D representations further increased for those neurons. We additionally found that 3D orientation and saccade direction preferences aligned, particularly for neurons with choice-related activity, reflecting an experience-dependent sensorimotor association. These findings reveal previously unrecognized links between the fidelity of ecologically relevant object representations, choice-related activity, and motor-related activity.

Saccade target selection in the superior colliculus: a signal detection theory approach.

How the brain selects one action from among multiple options is unknown. A main tenet of signal detection theory (SDT) is that sensory stimuli are represented as noisy information channels. Therefore, the accuracy of selection might be predicted by how well neuronal activity representing alternatives can be distinguished. Here, we apply an SDT framework to a motor system by recording from superior colliculus (SC) neurons during performance of a color, oddball selection task. We recorded from sets of four neurons simultaneously, each of the four representing one of the four possible targets. Because the electrode placement constrained the position of the stimuli in the visual field, the stimulus arrangement varied across experiments. This variability in stimulus arrangement led to variability in choices allowing us to explore the relationship between SC neuronal activity and performance accuracy. SC target neurons had higher levels of discharge than SC distractor neurons in subsets of trials when selection performance was very accurate. In subsets of trials when performance was poor, the discharge level decreased in target neurons and increased in distractor neurons. Accurate performance was associated with larger separations between neuronal activity from targets and distractors as quantified by the receiver operating characteristic (ROC) area and d' (an index of discriminability). Poorer performance was associated with less separation of target and distractor neuronal activity. ROC area and d' scaled approximately linearly with performance accuracy. Furthermore, ROC area and d' increased as saccade onset approached. Together, the results indicate that SC buildup neuronal activity signals the saccadic eye movement decision.

Real-time experimental control using network-based parallel processing.

Modern neuroscience research often requires the coordination of multiple processes such as stimulus generation, real-time experimental control, as well as behavioral and neural measurements. The technical demands required to simultaneously manage these processes with high temporal fidelity is a barrier that limits the number of labs performing such work. Here we present an open-source, network-based parallel processing framework that lowers this barrier. The Real-Time Experimental Control with Graphical User Interface (REC-GUI) framework offers multiple advantages: (i) a modular design that is agnostic to coding language(s) and operating system(s) to maximize experimental flexibility and minimize researcher effort, (ii) simple interfacing to connect multiple measurement and recording devices, (iii) high temporal fidelity by dividing task demands across CPUs, and (iv) real-time control using a fully customizable and intuitive GUI. We present applications for human, non-human primate, and rodent studies which collectively demonstrate that the REC-GUI framework facilitates technically demanding, behavior-contingent neuroscience research. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

Gravity orientation tuning in macaque anterior thalamus.

Gravity may provide a ubiquitous allocentric reference to the brain's spatial orientation circuits. Here we describe neurons in the macaque anterior thalamus tuned to pitch and roll orientation relative to gravity, independently of visual landmarks. We show that individual cells exhibit two-dimensional tuning curves, with peak firing rates at a preferred vertical orientation. These results identify a thalamic pathway for gravity cues to influence perception, action and spatial cognition.

An online questionnaire survey on preferred timing for the diagnosis and management of thyroid carcinoma in general population in Korea.

PURPOSE: An optimal timing for diagnosis and management of papillary thyroid microcarcinoma (PTMC) has become the subject for much controversy. The aim of the present study is to analyze people's preference in Korea for timing of diagnosis and management of PTMC using an online questionnaire. METHODS: The questionnaire consists of 3 questions about preference for the diagnosis and management of PTMC and 3 additional questions about respondents' personal information. An online survey was conducted from March 3 to June 3 in 2015 using Google Survey (http://goo.gl/forms/b81yEjqNUA). RESULTS: A total 2,308 persons (1,246 males, 1,053 females) answered the questionnaire. Respondents' ages varied widely from teenagers to 70-year-olds. If there was a suspicious thyroid nodule from PTMC measuring less than 1 cm in diameter, 95.7% of respondents want to know a cytological diagnosis for it. If a thyroid nodule turned out to be a PTMC, 59.5% of respondents wanted it removed immediately. For surgical management of PTMC, 53.0% of respondents were worried more about recurrences than complications. In subgroup analyses, respondents younger than 40 years old more often want immediate surgery than others: 66.7% vs. 32.7% (P < 0.05). Respondents who underwent thyroid cancer surgery (n = 91) were worried more about recurrences than others: 69.2% vs. 52.4% (P < 0.05). CONCLUSION: Almost all respondents in the present study wanted diagnosis of suspicious thyroid nodules immediately. However, there were opposing opinions about the preferred timing for surgical treatment and surgical extents. A patient's right to know their disease status and decision on treatments should be emphasized all the more.

Amelioration of dural granulation tissue growth for primate neurophysiology.

Four methods were tried in order to reduce the growth of granulation tissue on the dura. The best results were obtained using white petrolatum jelly, which almost completely suppressed the growth of granulation tissue when the recording chamber was filled with petrolatum. Collagen and acrylic seals were very effective in one monkey. Panalog ointment slowed the growth of granulation tissue; preformed silicon sheets had no apparent effect. We conclude that long-term application of petrolatum jelly has no adverse effects and achieves striking suppression of the growth of granulation tissue.

Spatially directed movement and neuronal activity in freely moving monkey.

The abilities to plan a series of movements and to navigate within the environment require the functions of the frontal and ventromedial temporal lobes, respectively. Neuropsychological studies posit the existence of egocentric (prefrontal) and allocentric (ventromedial temporal) spatial frames of reference that mediate these functions. To examine neural mechanisms underlying egocentric and allocentric guidance of movement, we have developed behavioral and neurophysiological techniques for freely moving monkey. In this chapter, we provide evidence that the dorsolateral prefrontal cortex is important for egocentric spatial tasks in both the visual and tactile modalities, but it does not contribute to performance of an allocentric spatial task. Moreover, neurophysiological recordings indicate that prefrontal neurons are involved in monitoring the spatial nature of behavioral sequences in an egocentric memory task. In contrast, hippocampal neurons are active during spatially directed locomotion, apparently reflecting the monkey's location in a testing room. This discharge is independent of the task's contingencies.

Phase II study of weekly carboplatin and irinotecan as first-line chemotherapy for patients with advanced non-small cell lung cancer.

PURPOSE: Platinum-based doublet chemotherapy has a major role in the treatment of patients with advanced non-small cell lung cancer (NSCLC). The weekly fractionated administration of cisplatin for patients with NSCLC has been shown to be active. Irinotecan and carboplatin are effective against NSCLC and demonstrated synergism with non-cross-resistance in preclinical studies. We conducted a phase II study of weekly combination of carboplatin and irinotecan as first-line chemotherapy for patients with advanced NSCLC. METHODS: From March 2009 to November 2011, 24 patients who were diagnosed with inoperable or metastatic NSCLC were enrolled. Treatment consisted of carboplatin at an AUC 2.5 mg/mL/min over 30-min intravenous infusion and irinotecan 65 mg/m(2) over 90-min intravenous infusion on day 1 and day 8, respectively. The treatment was repeated every 3 weeks. RESULTS: One patient (4.2 %) achieved complete response, and seven (29.2 %) showed partial response. Overall response rate was 33.3 %, with median response duration of 4.55 months. Nine patients had stable disease, and disease control rate was 70.8 %. With median follow-up of 12.8 months, median progression-free survival was 4.5 months (95 % CI 1.8-7.2), and median overall survival was 15.5 months (95 % CI 6.9-24.1). Major toxicity was myelosuppression. Grade 3-4 neutropenia and thrombocytopenia occurred in 50 and 20.8 % of patients, respectively. Two patients experienced febrile neutropenia. Non-hematologic toxicities were generally mild. One patient suffered grade 4 diarrhea, and one treatment-related death due to pneumonia was occurred. CONCLUSION: The weekly combination of carboplatin and irinotecan showed favorable activity and manageable toxicity profiles in chemo-naïve patients with advanced NSCLC. Our results suggest that this regimen can be a reasonable chemotherapeutic option for patients with advanced NSCLC.

Transient pauses in delay-period activity of superior colliculus neurons.

A feature of neurons in the mammalian superior colliclus (SC) is the robust discharge of action potentials preceding the onset of rapid eye movements called saccades. The burst, which commands ocular motoneurons, is often preceded by persistent, low-level activity, likely reflecting neuronal processes such as target selection, saccade selection and preparation. Here, we report on a transient pause in persistent activity of SC neurons. We trained monkeys to make or withhold saccades based on the shape of a centrally located cue. We found that after the cue changed shape, there was a measurable pause in persistent activity of SC neurons, even though the cue was located well outside the response field of the neurons. We show here that this pause is not a simple, transient inhibitory drive from neurons representing the central visual field. Rather, the occurrence of the pause depends on the occurrence of saccades made much later in the trial. The characteristics of the pause such as magnitude or duration are not predictable from the task condition, rather the occurrence of the pause across the SC neuronal population varies with whether a saccade is made much later in the trial. We developed a model that accounts for our results and makes testable predictions about the effects of signals related to inhibition in SC neuronal populations.

Neurophysiological recordings in freely moving monkeys.

Recordings of neuronal activity in freely moving rats are common in experiments where electrical signals are transmitted using cables. Such techniques are not common in monkeys because their prehensile abilities are thought to preclude such techniques. However, analysis of brain mechanisms underlying spatial navigation and cognition require the subject to walk. We have developed techniques for recordings in freely moving monkeys in two different situations: a 5 x 5 m testing laboratory and in a 50 m2 open field environment. Neuronal signals are sent to amplifiers and data acquisition systems using cables or telemetry. These techniques provide high quality recordings of single neurons during behaviors such as foraging, walking, and the performance of memory tasks and thus provide a unique opportunity to study primate behavior in a semi-natural situation.

Objective measures of health and well-being in laboratory rhesus monkeys (Macaca mulatta).

BACKGROUND: Non-human primates are an invaluable part of biomedical research. Strict regulations insure animals have a maximum likelihood of well-being and optimum health during the course of experimental procedures. Objective assessment of well-being is a critical component of these assurances. METHODS: Here we describe an objective and quantitative system we used to identify two well-being concerns in laboratory rhesus monkeys (Macaca mulatta). We provide a series of indicators for use by laboratory personnel to promote laboratory primate well-being. The indicators measure (1) potentially life threatening clinical concerns, (2) developing clinical issues, (3) atypical behaviors, and (4) laboratory performance. We include specific criteria to facilitate veterinary intervention. RESULTS: The assessment, applied to two case studies reported here, enabled swift veterinary intervention returning the animals to a healthy state. CONCLUSIONS: The measures described here provide a battery of observable and objective measures across multiple dimensions that can further ensure both excellent science and veterinary care.