Crucial information for efficient face searching by humans and Japanese macaques.

Humans can efficiently detect a face among non-face objects, but few studies of this ability have been conducted in animals. Here, in Japanese macaques and humans, we examined visual searching for a face and explored what factors contribute to efficient facial information processing. Subjects were asked to search for an odd target among the different numbers of distracters. Faces of the subjects' own species, the backs of the head of the subjects' own species, faces of the subjects' closely related species or race, and faces of species that are clearly different from the subjects' own species were used as the target. Both the macaques and humans detected a face of their own species more efficiently than a face from a clearly different species. Similar efficient detections were confirmed for the faces of the subjects' closely related species or race. These results suggest that conspecific faces and faces that share morphological similarity with conspecific faces can be detected efficiently among non-face objects by both humans and Japanese macaques. In another experiment, facial recognition efficiency was observed when the subjects searched for own-species faces that had lower-spatial-frequency components compared to faces with higher-spatial-frequency components. It seems reasonable that the ability to search efficiently for faces by using holistic face processing is derived from fundamental social cognition abilities that are broadly shared among species.

Effects of tilted orientations and face-like configurations on visual search asymmetry in macaques.

Visual search asymmetry has been used as an important tool for exploring cognitive mechanisms in humans. Here, we examined visual search asymmetry in two macaques toward two types of stimulus: the orientation of line stimuli and face-like stimuli. In the experiment, the monkeys were required to detect an odd target among numerous uniform distracters. The monkeys detected a tilted-lines target among horizontal- or vertical-lined distracters significantly faster than a horizontal- or vertical-lined target among tilted-lined distracters, regardless of the display size. However, unlike the situation in which inverted-face stimuli were introduced as distracters, this effect was diminished if upright-face stimuli were used as distracters. Additionally, monkeys detected an upright-face target among inverted-face distracters significantly faster than an inverted-face target among upright-face distracters, regardless of the display size. These results demonstrate that macaques can search a target efficiently to detect both tilted lines among non-tilted lines and upright faces among inverted faces. This clarifies that there are several types of visual search asymmetry in macaques.

Wireless system for recording evoked potentials.

Experiments measuring evoked potentials require flexible and rapid adjustment of stimulation and recording parameters. In this study, we have developed a recording system and an associated Android application that allow making such adjustments wirelessly. The system consists of 3 units: for stimulation, recording and control. Most of the modules in this system are custom made, although the stimulator and tablet are off-the-shelf products. When installed on the tablet, our Android application allows wireless communication with the control unit from a distance of 5 m. In testing, the recording unit had low internal noise and displayed signals faithfully. Upon receiving commands from the control unit, the stimulation unit produced precisely timed pulse outputs. Using this system, we were able to record evoked field potentials in the dentate gyrus of a rat; responses increased as expected with increasing stimulation pulse amplitude and duration.

Relationships between fusional convergence, suppression depth, and exotropia control in intermittent exotropia.

Purpose: To assess the correlation between the contribution rates of fusional convergence from the dominant and non-dominant eye and suppression depth and exotropia control. Study design: Cross-sectional prospective study. Methods: The fusional convergence of 25 participants with intermittent exotropia (mean age 10.8 ± 3.4; range 6-18 years) was measured with an eye-tracking system. The contribution rate was defined based on the amplitude of fusional convergence during refusion relative to the exo-deviation angle. The suppression depth was assessed, and exotropia control was evaluated using the intermittent exotropia Office Control Score. We analyzed the correlations between the contribution rate from the dominant and non-dominant eyes and the suppression depth or control score. Results: There was a negative correlation between the dominant eye's contribution rate and the suppression depth in both eyes (r = -0.85, 95% confidence interval [CI]: -0.97 to - 0.20 in the fixated dominant eye and r = -0.91, 95%CI: -0.95 to - 0.40 in the fixated non-dominant eye). There was a negative correlation between the dominant eye's contribution rate and the control score at a 4-meter distance (r = -0.53, 95%CI: -0.76 to - 0.17). Conclusion: Suppression in intermittent exotropia patients could affect the fusional convergence in the dominant eye.

Changes in saccadic eye movement and smooth pursuit gain in patients with acquired comitant esotropia after strabismus surgery.

This study investigates the change in horizontal saccadic eye movement and smooth pursuit in patients with acquired comitant esotropia (ACE), before and after strabismus surgery. The horizontal saccades and pursuit in 11 patients with ACE were recorded using a video eye-tracker under binocular viewing before and after strabismus surgery. Participants were instructed to fixate on the new target as rapidly as possible when it randomly appeared at either 18.3° rightward or 18.3° leftward. For smooth pursuit, participants were asked to track, as accurately as possible, a step-ramp target moving at ±6.1°/s. The asymmetry of adduction-abduction and the binocular coordination in gains of saccade and pursuit were compared between the pre- and post-surgical data. The asymmetry of adduction-abduction saccade gain in each eye after surgery tended to be smaller than that before surgery. The binocular coordination of saccade showed significant improvement after surgery in only the non-dominant eye direction. Adduction-abduction asymmetry in the smooth pursuit gain in each eye after surgery tended to be smaller than before surgery. After surgery, the binocular coordination of pursuit was improved significantly in both directions. In patients with ACE, binocular coordination of saccade and smooth pursuit was poor. Binocular coordination of saccade and pursuit seems to be improved due to the improvement in ocular deviation angle and binocular visual function after surgery.

Correlation of saccade amplitude during refusion with the fusional convergence amplitude in patients with intermittent exotropia.

In patients with intermittent exotropia (IXT), to investigate the correlation between fusional convergence amplitude and saccade during refusion, as well as the differences in saccade caused by suppression.We measured the fusional convergence amplitude using a synoptophore. Suppression was assessed in 15 patients with IXT (mean age 18.1 ± 11.0 yrs, range 8-54 yrs) having diplopia during exotropia. We performed the cover-uncover test and recorded the saccade during the shift from exotropia to binocular fixation using an eye-tracking system. We analyzed the correlation between the fusional convergence amplitude on the one hand and the saccade peak velocity (PV), the saccade amplitude, and the saccade amplitude of the fusion on the other. We also investigated the difference of those saccade variables between patients with and without suppression.In 15 patients with IXT, the median fusional convergence amplitude was 14 (range 0-60) °, and suppression was confirmed in 11 patients. When the cover was removed from the dominant eye, the fusional convergence amplitude showed a positive correlation with the saccade PV and the amplitude in non-dominant eye (r = 0.570, p = 0.042 and r = 0.669, p = 0.012, respectively). The mean saccade PV, the mean saccade amplitude and the mean saccade amplitude of the fusion were not significantly different with the presence or the absence of the suppression.The fusional convergence amplitude was correlated with saccade in patients with IXT. The saccade during refusion can thus be used to quantitatively evaluate sensory and/or motor fusion.

Neural correlates of associative face memory in the anterior inferior temporal cortex of monkeys.

To investigate the neural basis of the associative aspects of facial identification, we recorded neuronal activity from the ventral, anterior inferior temporal cortex (AITv) of macaque monkeys during the performance of an asymmetrical paired-association (APA) task that required associative pairing between an abstract pattern and five different facial views of a single person. In the APA task, after one element of a pair (either an abstract pattern or a face) was presented as a sample cue, the reward-seeking monkey correctly identified the other element of the pair among various repeatedly presented test stimuli (faces or patterns) that were temporally separated by interstimulus delays. The results revealed that a substantial number of AITv neurons responded both to faces and abstract patterns, and the majority of these neurons responded selectively to a particular associative pair. It was demonstrated that in addition to the view-invariant identity of faces used in the APA task, the population of AITv neurons was also able to represent the associative pairing between faces and abstract patterns, which was acquired by training in the APA task. It also appeared that the effect of associative pairing was not so strong that the abstract pattern could be treated in a manner similar to a series of faces belonging to a unique identity. Together, these findings indicate that the AITv plays a crucial role in both facial identification and semantic associations with facial identities.

A method for recording evoked local field potentials in the primate dentate gyrus in vivo.

Recording evoked local field potentials (LFPs) in the hippocampus in vivo has yielded us useful information about the neural mechanisms of learning and memory. Although this technique has been used in studies of the hippocampus of rodents, lagomorphs, and felines, it has not yet been applied to the primate hippocampus. Here, we report a method for recording evoked LFPs in the hippocampus of monkeys. A stimulation electrode and a recording electrode were implanted in the perforant pathway and dentate gyrus, respectively, under the guidance of electrophysiological recording. With a low stimulus intensity just above the threshold, the potential appeared as a slow positive-wave component, which was regarded as field excitatory postsynaptic potential (putative fEPSP); as stimulation intensity increased, the fEPSP amplitude increased, followed by a sharp negative component which was regarded as putative population spike. When the coordinates of the recording or stimulation electrode were moved stepwise, we observed a systematic change in the waveforms of evoked LFPs; this change corresponded to the structural arrangement through which the electrode passed. In a test for short-term synaptic plasticity by paired-pulse stimulation, potentials evoked by the second pulse were influenced by the first one in a manner dependent on interpulse intervals. In a test for long-term synaptic plasticity by high-frequency stimulation, the slopes of the fEPSPs and the area of population spikes were increased for more than 1 h. These results indicate that the method developed in the present study is useful for testing theories of hippocampal functions in primates.

Longitudinal changes in binocular coordination of smooth pursuit in patients with intermittent exotropia after strabismus surgery.

PURPOSE: To observe the change in horizontal smooth pursuit in patients with intermittent exotropia before and after strabismus surgery. METHODS: The smooth pursuit of patients with intermittent exotropia was recorded using a video eye-tracker before and 1 week, and 1, 3, and 6 months after strabismus surgery. Subjects were asked to track a step-ramp target moving at ±6.1°/sec horizontally as accurately as possible under binocular viewing. The differences in gain (eye velocity divided by target velocity) and amplitude of smooth pursuit between right and left eyes before and after surgery were compared. RESULTS: A total of 9 patients (mean age, 22.2 ± 13.9 years) were included. Mean preoperative ocular alignment at near was 59.1Δ ± 34.7Δ. The difference in gain between the left and right eyes before surgery was 0.23 ± 0.1; in amplitude, 3.0° ± 3.7°. These values were improved at 1 week after surgery (gain, 0.08 ± 0.06; amplitude, 0.9° ± 0.65°) and continued to improve for 6 months after surgery; however, ocular alignment at near reverted from 5.9Δ ± 10.5Δ to 18.9Δ ± 17.5Δ by 6 months after surgery. CONCLUSIONS: In this small patient cohort, surgical correction of ocular alignment improved binocular coordination of smooth pursuit in intermittent exotropia. In the long term, the improvement of the binocular coordination of smooth pursuit tended to remain, although the eye position partially reverted to the presurgical state.

Auditory thalamus integrates visual inputs into behavioral gains.

By binding multisensory signals, we get robust percepts and respond to our surroundings more correctly and quickly. How and where does the brain link cross-modal sensory information to produce such behavioral advantages? The classical role of sensory thalamus is to relay modality-specific information to the cortex. Here we find that, in the rat thalamus, visual cues influence auditory responses, which have two distinct components: an early phasic one followed by a late gradual buildup that peaks before reward. Although both bimodal presentation and reward value had similar effects on behavioral performance, the cross-modal effect on neural activity showed unique temporal dynamics: it affected the amplitude of the early component and starting level of the late component, whereas reward value affected only the slope of the late component. These results demonstrate that cross-modal cueing modulates gain in the sensory thalamus, potentially providing a priming influence on the choice of an optimal behavior.

Effects of self-locomotion on the activity of place cells in the hippocampus of a freely behaving monkey.

The activity of hippocampal cell assemblies is considered to function as the neural substrate for a cognitive map in various animal species. The firing rate of hippocampal place cells increases when an individual animal reaches a specific location in an environment. Although cumulative views on place cells have been revealed by studies using rodents under free-behavior conditions, few studies have addressed the spatial representation provided by hippocampal neurons in primates. Moreover, although previous work in rats has demonstrated the importance of locomotion velocity and direction in the spatially selective discharge of hippocampal neurons, it remains unknown whether a corresponding phenomenon exists in the primate hippocampus. In the present study, we recorded the activity and investigated the spatial representation of the hippocampal neurons in a freely behaving monkey performing a shuttle-movement task. We observed increased activity in a subset of hippocampal neurons (place cells) when the monkey crossed a particular location. Many of the monkey place cells exhibited sensitivity to locomotion velocity rather than to locomotion direction. These results suggest the existence of primate hippocampal place cells comparable to those in rodents, with the exception that, in primates, velocity information has a stronger impact on place cell activity than directional information.

Data on the activity of place cells in the hippocampal CA1 subfield of a monkey performing a shuttling task.

This data article provides spike-timestamps of place cells recorded in a male Japanese monkey and the animal's sequential positions during the performance of a shuttling task on a rectangular track. All data were recorded in the right hippocampal CA1 subfield, while the monkey performed the task under a freely behaving condition. These were the source data on the monkey place cells in our related research article entitled "Effects of self-locomotion on the activity of place cells in the hippocampus of a freely behaving monkey" [1]. In addition, here we show a movement directional activity of a place cell in two-dimensional space as an example of data utilization. The source data are freely accessible [2] and can be used by other researchers to obtain new insights into place cells, such as functional differences between animal species.

Horizontal Saccadic Velocity in Patients with Exotropia before and after Unilateral Resection and Recession Surgery.

PURPOSE: The effects of strabismus surgery on eye movement are not known in detail, as few studies have compared saccade velocities before and after strabismus surgery. In this study, horizontal saccades were recorded using an eye-tracker in patients with only exotropia to compare the peak velocities (PVs), before and after undergoing strabismus surgery of the same type (unilateral resection and recession). METHODS: Horizontal saccades of monocular vision were recorded using an eye-tracking device in 18 patients with exotropia and 20 normal subjects. All patients were examined using the same method after strabismus surgery. RESULTS: The PVs of adduction and abduction in the patients were higher than those in the normal subjects (in dominant eye, P=0.032 for adduction and P=0.049 for abduction; in nondominant eye, P=0.016 for adduction and P=0.037 for abduction). Following the surgery, the PVs of abduction of the surgical eye (nondominant eye) decreased to the level of the normal subjects (P=0.016). However, there were no correlations between changes in the PVs and the extent of surgery (resection and recession). CONCLUSION: Strabismus surgery normalized the patient's increased PV in the operated eye for abduction of horizontal saccade. Not only peripheral (extraocular muscle) but also central sensory-motor mechanisms may be involved in the changes in PV of horizontal saccades, both of which could result from the improvement of the primary eye position.

The combined efficacy of OTS964 and temozolomide for reducing the size of power-law coded heterogeneous glioma stem cell populations.

Glioblastoma resists chemotherapy then recurs as a fatal space-occupying lesion. To improve the prognosis, the issues of chemoresistance and tumor size should be addressed. Glioma stem cell (GSC) populations, a heterogeneous power-law coded population in glioblastoma, are believed to be responsible for the recurrence and progressive expansion of tumors. Thus, we propose a therapeutic strategy of reducing the initial size and controlling the regrowth of GSC populations which directly facilitates initial and long-term control of glioblastoma recurrence. In this study, we administered an anti-glioma/GSC drug temozolomide (TMZ) and OTS964, an inhibitor for T-Lak cell originated protein kinase, in combination (T&O), investigating whether together they efficiently and substantially shrink the initial size of power-law coded GSC populations and slow the long-term re-growth of drug-resistant GSC populations. We employed a detailed quantitative approach using clonal glioma sphere (GS) cultures, measuring sphere survivability and changes to growth during the self-renewal. T&O eliminated self-renewing GS clones and suppressed their growth. We also addressed whether T&O reduced the size of self-renewed GS populations. T&O quickly reduced the size of GS populations via efficient elimination of GS clones. The growth of the surviving T&O-resistant GS populations was continuously disturbed, leading to substantial long-term shrinkage of the self-renewed GS populations. Thus, T&O reduced the initial size of GS populations and suppressed their later regrowth. A combination therapy of TMZ and OTS964 would represent a novel therapeutic paradigm with the potential for long-term control of glioblastoma recurrence via immediate and sustained shrinkage of power-law coded heterogeneous GSC populations.

Targeting the T-Lak cell originated protein kinase by OTS964 shrinks the size of power-law coded heterogeneous glioma stem cell populations.

Glioblastoma resists chemoradiotherapy, then, recurs to be a fatal space-occupying lesion. The recurrence is caused by re-growing cell populations such as glioma stem cells (GSCs), suggesting that GSC populations should be targeted. This study addressed whether a novel anti-cancer drug, OTS964, an inhibitor for T-LAK cell originated protein kinase (TOPK), is effective in reducing the size of the heterogeneous GSC populations, a power-law coded heterogeneous GSC populations consisting of glioma sphere (GS) clones, by detailing quantitative growth properties. We found that OTS964 killed GS clones while suppressing the growth of surviving GS clones, thus identifying clone-eliminating and growth-disturbing efficacies of OTS964. The efficacies led to a significant size reduction in GS populations in a dose-dependent manner. The surviving GS clones reconstructed GS populations in the following generations; the recovery of GS populations fits a recurrence after the chemotherapy. The recovering GS clones resisted the clone-eliminating effect of OTS964 in sequential exposure during the growth recovery. However, surprisingly, the resistant properties of the recovered-GS clones had been plastically canceled during self-renewal, and then the GS clones had become re-sensitive to OTS964. Thus, OTS964 targets GSCs to eliminate them or suppress their growth, resulting in shrinkage of the power-law coded GSC populations. We propose a therapy focusing on long-term control in recurrence of glioblastoma via reducing the size of the GSC populations by OTS964.

Neural correlates of stimulus-reward association in the rat mediodorsal thalamus.

Neural activity was recorded from the mediodorsal thalamic nucleus of behaving rats during the discrimination of olfactory cues associated with or without a reward. Approximately 10% of mediodorsal thalamic neurons showed significant responses during the presentation of cues. Most of these neurons responded strongly to cues associated with a reward. These neurons also differentiated between cues, even in the same reinforcement (reward/nonreward) group. All of the neurons tested in extinction, relearning, and/or new-learning trials changed their responses flexibly according to the reward contingency. These neurons were located primarily in the central and medial segments of the mediodorsal thalamus. These results suggest that these mediodorsal thalamic neurons are the neural substrates for association learning of olfactory stimuli with rewards.

Fixation stability of the upward gaze in patients with myasthenia gravis: an eye-tracker study.

OBJECTIVE: To quantify fixation stability of the upward gaze in patients with myasthenia gravis (MG) using an eye tracker. METHODS AND ANALYSIS: In this study, 21 normal subjects, 5 patients with MG with diplopia, 5 patients with MG without diplopia and 6 patients with superior oblique (SO) palsy were included. Subjects fixated on a target in the upward direction for 1 min. The horizontal (X) and vertical (Y) eye positions were recorded using an eye tracker. Fixation stability was first quantified using the bivariate contour ellipse areas (BCEA) of fixation points as an index of whole stability. Then, the SDs of the X and Y eye positions (SDX and SDY, respectively) were quantified as indices of directional stability, with the data divided into three 20 s fractions to detect temporal fixation fluctuation. RESULTS: BCEAs were larger in patients with MG (both with and without diplopia) than normal subjects and patients with SO palsy, without significant differences among the three 20 s fractions. Compared with normal subjects, SDXs were larger only in patients with MG with diplopia; SDYs were larger in both patients with MG with and without diplopia. In addition, SDYs in patients with MG with diplopia were larger than those in patients with MG without diplopia and patients with SO palsy. Furthermore, a significant difference among the three 20 s fractions was detected for SDYs in patients with MG with diplopia. CONCLUSION: Patients with MG, especially those with diplopia, exhibit fixation instability in the upward gaze. Non-invasive quantification of fixation stability with an eye tracker is useful for precisely identifying MG-specific fatigue characteristics. TRIAL REGISTRATION NUMBER: UMIN000023468; pre-results.

Discovery of Power-Law Growth in the Self-Renewal of Heterogeneous Glioma Stem Cell Populations.

BACKGROUND: Accumulating evidence indicates that cancer stem cells (CSCs) drive tumorigenesis. This suggests that CSCs should make ideal therapeutic targets. However, because CSC populations in tumors appear heterogeneous, it remains unclear how CSCs might be effectively targeted. To investigate the mechanisms by which CSC populations maintain heterogeneity during self-renewal, we established a glioma sphere (GS) forming model, to generate a population in which glioma stem cells (GSCs) become enriched. We hypothesized, based on the clonal evolution concept, that with each passage in culture, heterogeneous clonal sublines of GSs are generated that progressively show increased proliferative ability. METHODOLOGY/PRINCIPAL FINDINGS: To test this hypothesis, we determined whether, with each passage, glioma neurosphere culture generated from four different glioma cell lines become progressively proliferative (i.e., enriched in large spheres). Rather than monitoring self-renewal, we measured heterogeneity based on neurosphere clone sizes (#cells/clone). Log-log plots of distributions of clone sizes yielded a good fit (r>0.90) to a straight line (log(% total clones) = k*log(#cells/clone)) indicating that the system follows a power-law (y = xk) with a specific degree exponent (k = -1.42). Repeated passaging of the total GS population showed that the same power-law was maintained over six passages (CV = -1.01 to -1.17). Surprisingly, passage of either isolated small or large subclones generated fully heterogeneous populations that retained the original power-law-dependent heterogeneity. The anti-GSC agent Temozolomide, which is well known as a standard therapy for glioblastoma multiforme (GBM), suppressed the self-renewal of clones, but it never disrupted the power-law behavior of a GS population. CONCLUSIONS/SIGNIFICANCE: Although the data above did not support the stated hypothesis, they did strongly suggest a novel mechanism that underlies CSC heterogeneity. They indicate that power-law growth governs the self-renewal of heterogeneous glioma stem cell populations. That the data always fit a power-law suggests that: (i) clone sizes follow continuous, non-random, and scale-free hierarchy; (ii) precise biologic rules that reflect self-organizing emergent behaviors govern the generation of neurospheres. That the power-law behavior and the original GS heterogeneity are maintained over multiple passages indicates that these rules are invariant. These self-organizing mechanisms very likely underlie tumor heterogeneity during tumor growth. Discovery of this power-law behavior provides a mechanism that could be targeted in the development of new, more effective, anti-cancer agents.

Effects of a novel arginine-vasopressin derivative, NC-1900, on the spatial memory impairment of rats with transient forebrain ischemia.

NC-1900, an arginine-vasopressin derivative, has been reported to enhance memory for avoidance behavior. Specifically, NC-1900 ameliorated cycloheximide-induced learning impairments in a passive avoidance test in rats. In the present study, we investigated that effects of NC-1900 on place learning in rats with selective lesions in the CA1 subfield of the hippocampal formation produced by transient forebrain ischemia. NC-1900 was administered daily (1 microg/kg, p.o.) 1 h before the place learning task. A rat was required to alternate between 2 small circular areas located diametrically opposite each other on the circumference of an open field in order to obtain intracranial electrical stimulation reward (the spatial navigation task). Rats with hippocampal lesions showed severe place learning impairments both in task performance (indicated by number of rewards obtained per a session) and in navigation performance (forming efficient trails) over the 30-day test period. Treatment with NC-1900 ameliorated deficits in the place learning exhibited by rats with the same hippocampal lesions, such that their performance reached normal levels. There were no significant differences in the ischemic hippocampal lesions, spontaneous locomotor activity, and stimulation current intensity between the treated and untreated rats. The results demonstrated that NC-1900 reduced place learning impairments produced by hippocampal lesions.

A method for accurate determination of stereotaxic coordinates in single-unit recording studies in monkeys by high-resolution three-dimensional magnetic resonance imaging.

For single-unit recording from the brain in monkeys, the precise determination of recording targets is essential. Although magnetic resonance imaging (MRI) has been used recently in several laboratories, it has been difficult to obtain three-dimensional information on a target from two-dimensional pictures, and, therefore, it has also been difficult to determine precise coordinates. We developed a new method for precisely determining target-area coordinates based on reconstructed rendering pictures made from three-dimensional MRI data. We also combined this method with magnetic resonance angiography to avoid severe vessel complications in recording experiments.