An easy-to-implement, non-invasive head restraint method for monkey fMRI.

Functional magnetic resonance imaging (fMRI) in behaving monkeys has a strong potential to bridge the gap between human neuroimaging and primate neurophysiology. In monkey fMRI, to restrain head movements, researchers usually surgically implant a plastic head-post on the skull. Although time-proven to be effective, this technique could create burdens for animals, including a risk of infection and discomfort. Furthermore, the presence of extraneous objects on the skull, such as bone screws and dental cement, adversely affects signals near the cortical surface. These side effects are undesirable in terms of both the practical aspect of efficient data collection and the spirit of "refinement" from the 3R's. Here, we demonstrate that a completely non-invasive fMRI scan in awake monkeys is possible by using a plastic head mask made to fit the skull of individual animals. In all of the three monkeys tested, longitudinal, quantitative assessment of head movements showed that the plastic mask has effectively suppressed head movements, and we were able to obtain reliable retinotopic BOLD signals in a standard retinotopic mapping task. The present, easy-to-make plastic mask has a strong potential to simplify fMRI experiments in awake monkeys, while giving data that is as good as or even better quality than that obtained with the conventional head-post method.

Ready to detect a reversal of time's arrow: a psychophysical study using short video clips in daily scenes.

It is generally believed that time flows in one direction and that a reversal of time's arrow would render the external world non-sensical. We evaluated our ability to tell the direction of time's arrow in a wide range of dynamic scenes in our daily life by presenting 360 video clips in the correct or incorrect direction. Participants, who judged the direction in a speeded manner, erred in 39% of trials when a video was played in reverse, but in only 9% when it was played normally. Due to the bias favouring the 'forward' judgement, the reaction was generally faster for the forward response. However, the reaction became paradoxically faster and more synchronous for the detection of reversal in some critical occasions such as forward motion, free fall, diffusion, division and addition of materials by hand. Another experiment with a fraction of the video clips revealed that reversal replay of these videos provided instantaneous evidence strong enough to overtake the forward judgement bias. We suggest that our brain is equipped with a system that predicts how the external organisms behave or move in these critical occasions and that the prediction error of the system contributes to the fast 'reversal' detection.

Distinctive modes of cortical communications in tactile temporal order judgment.

Temporal order judgment of two successive tactile stimuli delivered to our hands is often inverted when we cross our hands. The present study aimed to identify time-frequency profiles of the interactions across the cortical network associated with the crossed-hand tactile temporal order judgment task using magnetoencephalography. We found that the interactions across the cortical network were channeled to a low-frequency band (5-10 Hz) when the hands were uncrossed. However, the interactions became activated in a higher band (12-18 Hz) when the hands were crossed. The participants with fewer inverted judgments relied mainly on the higher band, whereas those with more frequent inverted judgments (reversers) utilized both. Moreover, reversers showed greater cortical interactions in the higher band when their judgment was correct compared to when it was inverted. Overall, the results show that the cortical network communicates in two distinctive frequency modes during the crossed-hand tactile temporal order judgment task. A default mode of communications in the low-frequency band encourages inverted judgments, and correct judgment is robustly achieved by recruiting the high-frequency mode.

What Underlies a Greater Reversal in Tactile Temporal Order Judgment When the Hands Are Crossed? A Structural MRI Study.

Our subjective temporal order of two successive tactile stimuli, delivered one to each hand, is often inverted when our hands are crossed. However, there is great variability among different individuals. We addressed the question of why some show almost complete reversal, but others show little reversal. To this end, we obtained structural magnetic resonance imaging data from 42 participants who also participated in the tactile temporal order judgment (TOJ) task. We extracted the cortical thickness and the convoluted surface area as cortical characteristics in 68 regions. We found that the participants with a thinner, larger, and more convoluted cerebral cortex in 10 regions, including the right pars-orbitalis, right and left postcentral gyri, left precuneus, left superior parietal lobule, right middle temporal gyrus, left superior temporal gyrus, right cuneus, left supramarginal gyrus, and right rostral middle frontal gyrus, showed a smaller degree of judgment reversal. In light of major theoretical accounts, we suggest that cortical elaboration in the aforementioned regions improve the crossed-hand TOJ performance through better integration of the tactile stimuli with the correct spatial representations in the left parietal regions, better representation of spatial information in the postcentral gyrus, or improvement of top-down inhibitory control by the right pars-orbitalis.

Neural Correlates of Temporal Presentness in the Precuneus: A Cross-linguistic fMRI Study based on Speech Stimuli.

The position of any event in time could be in the present, past, or future. This temporal discrimination is vitally important in our daily conversations, but it remains elusive how the human brain distinguishes among the past, present, and future. To address this issue, we searched for neural correlates of presentness, pastness, and futurity, each of which is automatically evoked when we hear sentences such as "it is raining now," "it rained yesterday," or "it will rain tomorrow." Here, we show that sentences that evoked "presentness" activated the bilateral precuneus more strongly than those that evoked "pastness" or "futurity." Interestingly, this contrast was shared across native speakers of Japanese, English, and Chinese languages, which vary considerably in their verb tense systems. The results suggest that the precuneus serves as a key region that provides the origin (that is, the Now) of our time perception irrespective of differences in tense systems across languages.

Automatic encoding of a target position relative to a natural scene.

We previously showed that the brain automatically represents a target position for reaching relative to a large square in the background. In the present study, we tested whether a natural scene with many complex details serves as an effective background for representing a target. In the first experiment, we used upright and inverted pictures of a natural scene. A shift of pictures significantly attenuated prism adaptation of reaching movements as long as they were upright. In one-third of participants, adaptation was almost completely cancelled whether the pictures were upright or inverted. It was remarkable that there were two distinct groups of participants, one who relies fully on the allocentric coordinate and the other who depended only when the scene was upright. In the second experiment, we examined how long it takes for a novel upright scene to serve as a background. A shift of the novel scene had no significant effects when it was presented for 500 ms before presenting a target, but significant effects were recovered when presented for 1,500 ms. These results show that a natural scene serves as a background against which a target is automatically represented once we spend 1,500 ms in the scene.NEW & NOTEWORTHY Prism adaptation of reaching was attenuated by a shift of natural scenes as long as they were upright. In one-third of participants, adaptation was fully canceled whether the scene was upright or inverted. When an upright scene was novel, it took 1,500 ms to prepare the scene for allocentric coding. These results show that a natural scene serves as a background against which a target is automatically represented once we spend 1,500 ms in the scene.

Motor Error in Parietal Area 5 and Target Error in Area 7 Drive Distinctive Adaptation in Reaching.

Errors in reaching drive trial-by-trial adaptation to compensate for the error. Parietal association areas are implicated in error coding, but whether the parietal error signals directly drive adaptation remains unknown. We first examined the activity of neurons in areas 5 and 7 while two monkeys performed rapid target reaching to clarify whether and how the parietal error signals drive adaptation in reaching. We introduced random errors using a motor-driven prism device to augment random motor errors in reaching. Neurons in both regions encoded information on the target position prior to reaching and information on the motor error after reaching. However, post-movement microstimulation caused trial-by-trial adaptation to cancel the motor error only when it was delivered to area 5. By contrast, stimulation to area 7 caused trial-by-trial adaptation so that the reaching endpoint was adjusted toward the target position. We further hypothesized that area 7 would encode target error that is caused by a target jump during the reach, and our results support this hypothesis. Area 7 neurons encoded target error information, but area 5 neurons did not encode this information. These results suggest that area 5 provides signals for adapting to motor errors and that area 7 provides signals to adapt to target errors.

[Neural Basis for Producing Temporal Order].

It has been proposed that a position in time can be discriminated in two ways. First, each position is either past, present, or future (A series). Second, each position is either before or after another (B series). In this review, we aim to infer how the two series are represented in the brain on the basis of findings from clinical, neurophysiological, and neuroimaging studies. We suggest that the precuneus and posterior cingulate cortex are critically involved in the A series. In the B series, we suggest that a group of events are represented in space around the intraparietal cortex and are combined with the temporal directional cue provided by the motion signals in the left temporo-parietal junction. We also review a report that states that the B series is affected by alpha rhythm, the source of which is located in the precuneus. Taken together, we suggest that the precuneus and the regions adjacent to it play key roles in representing the A and B series.

Modulation of Illusory Reversal in Tactile Temporal Order by the Phase of Posterior α Rhythm.

The subjective temporal order of tactile stimuli, delivered sequentially to each hand with an interval of 100-300 ms, is often inverted when the arms are crossed. Based on data from behavioral and neuroimaging studies, it has been proposed that the reversal is due to a conflict between anatomical and spatial representations of the tactile signal or to the production of an inverted apparent motion signal. Because the α rhythms, which consist of a few distinct components, reportedly modulate tactile perception and apparent motion and serve as a 10 Hz timer, we hypothesized that the illusory reversal would be regulated by some of the α rhythms. To test this hypothesis, we conducted magnetoencephalographic recordings in both male and female participants during the tactile temporal order judgment task. We decomposed the α rhythms into five independent components and discovered that the illusory reversal was modulated by the phase of one independent component with strong current sources near the parieto-occipital (PO) sulcus (peri-PO component). As expected, the estimated current sources distributed over the human MST implicated to represent tactile apparent motion, in addition to the intraparietal region implicated in mapping tactile signals in space. However, the strongest source was located in the precuneus that occupies a central hub region in the cortical networks and receives tactile inputs through a tecto-thalamic pathway. These results suggest that the peri-PO component plays an essential role in regulating tactile temporal perception by modulating the thalamic nuclei that interconnect the superior colliculus with the cortical networks.SIGNIFICANCE STATEMENT Despite a long-held hypothesis that the posterior α rhythm serves as a 10 Hz timer that regulates human temporal perception, the contribution of the α rhythms in temporal perception is still unclear. We examined how the α rhythms influence tactile temporal order judgment. Judgment reversal depended on the phase of one particular α rhythm with its source near the parieto-occipital sulcus. The peri-parieto-occipital α rhythm may play a crucial role in organizing tactile temporal perception.

Development of long-term event memory in preverbal infants: an eye-tracking study.

The development of long-term event memory in preverbal infants remains elusive. To address this issue, we applied an eye-tracking method that successfully revealed in great apes that they have long-term memory of single events. Six-, 12-, 18- and 24-month-old infants watched a video story in which an aggressive ape-looking character came out from one of two identical doors. While viewing the same video again 24 hours later, 18- and 24-month-old infants anticipatorily looked at the door where the character would show up before it actually came out, but 6- and 12-month-old infants did not. Next, 12-, 18- and 24-month-old infants watched a different video story, in which a human grabbed one of two objects to hit back at the character. In their second viewing after a 24-hour delay, 18- and 24-month-old infants increased viewing time on the objects before the character grabbed one. In this viewing, 24-month-old infants preferentially looked at the object that the human had used, but 18-month-old infants did not show such preference. Our results show that infants at 18 months of age have developed long-term event memory, an ability to encode and retrieve a one-time event and this ability is elaborated thereafter.

Short-latency allocentric control of saccadic eye movements.

It is generally accepted that the neural circuits that are implicated in saccade control use retinotopically coded target locations. However, several studies have revealed that nonretinotopic representation is also used. This idea raises a question about whether nonretinotopic coding is egocentric (head or body centered) or allocentric (environment centered). In the current study, we hypothesized that allocentric coding may play a crucial role in immediate saccade control. To test this hypothesis, we used an immediate double-step saccade task toward two sequentially flashed targets with a frame in the background, and we examined whether the end point of the second saccade was affected by a transient shift of the background that participants were told to ignore. When the background was shifted transiently upward (or downward) during the flash of the second target, the second saccade generally erred the target downward (or upward), which was in the direction opposite to the shift of the background. The effect on the second saccade became significant within 150 ms after the frame was presented for decoding and was built up for 200 ms thereafter. When the second saccade was not adjusted, a small, corrective saccade followed within 300 ms. The effect scaled linearly with the shift size up to 3° for a noncorrective second saccade and up to 6° for a corrective saccade. The present results show that an allocentric location of a target is rapidly represented by the brain and used for controlling saccades. NEW & NOTEWORTHY: We found that the saccade end point was shifted from the actual target position toward the direction expected from allocentric coding when a large frame in the background was transiently shifted during the period of target presentation. The effect occurred within 150 ms. The present study provides direct evidence that the brain rapidly uses allocentric coding of a target to control immediate saccades.

A group of very preterm children characterized by atypical gaze patterns.

OBJECTIVE: Very preterm (VP) children are at risk for social difficulties, including autism spectrum disorder (ASD). This study used eye tracking to determine viewing behaviors that may reflect these difficulties. DESIGN: The gaze patterns of 47 VP (mean gestational age: 28weeks, mean birth weight: 948g, and mean chronological age: 49months) were assessed while viewing dynamic social scenes and compared with those of 25 typically developing (TD) and 25 children with ASD. The temporo-spatial gaze patterns were summarized on a two-dimensional plane using multidimensional scaling (MDS) and the median of the TD children was used to characterize the gazes of the VP children. Time spent viewing the face was also compared. RESULTS: The VP children formed two clusters: one had a mean MDS distance comparable to that of TD group (n=32; VP-small), and the other had a larger mean distance comparable to that of ASD group (n=15; VP-large). The VP-large were similar to the ASD group by spending significantly less time viewing the face. Their performance was comparable to the TD during the initial 1s, but they could not remain focused on the face thereafter. CONCLUSIONS: The VP children were objectively classified into two groups based on gaze behaviors. One group was comparable to TD children, whereas the other had difficulty maintaining attention and exhibited atypical viewing behaviors similar to those of the ASD group. Our method may be useful in identifying VP children at higher risk for experiencing social difficulties.

Error Signals in Motor Cortices Drive Adaptation in Reaching.

Reaching movements are subject to adaptation in response to errors induced by prisms or external perturbations. Motor cortical circuits have been hypothesized to provide execution errors that drive adaptation, but human imaging studies to date have reported that execution errors are encoded in parietal association areas. Thus, little evidence has been uncovered that supports the motor hypothesis. Here, we show that both primary motor and premotor cortices encode information on end-point errors in reaching. We further show that post-movement microstimulation to these regions caused trial-by-trial increases in errors, which subsided exponentially when the stimulation was terminated. The results indicate for the first time that motor cortical circuits provide error signals that drive trial-by-trial adaptation in reaching movements.

Modulation of prism adaptation by a shift of background in the monkey.

Recent human behavioral studies have shown that the position of a visual target is instantly represented relative to the background (e.g., a large square) and used for evaluating the error in reaching the target. In the present study, we examined whether the same allocentric mechanism is shared by the monkey. We trained two monkeys to perform a fast and accurate reaching movement toward a visual target with a square in the background. Then, a visual shift (20mm or 4.1°) was introduced by wedge prisms to examine the process of decreasing the error during an exposure period (30 trials) and the size of the error upon removal of the prisms (aftereffect). The square was shifted during each movement, either in the direction of the visual displacement or in the opposite direction, by an amount equal to the size of the visual shift. The ipsilateral shift of the background increased the asymptote during the exposure period and decreased the aftereffect, i.e., prism adaptation was attenuated by the ipsilateral shift. By contrast, a contralateral shift enhanced adaptation. We further tested whether the shift of the square alone could cause an increase in the motor error. Although the target did not move, the shift of the square increased the motor error in the direction of the shift. These results were generally consistent with the results reported in human subjects, suggesting that the monkey and the human share the same neural mechanisms for representing a target relative to the background.

Modulation of error-sensitivity during a prism adaptation task in people with cerebellar degeneration.

Cerebellar damage can profoundly impair human motor adaptation. For example, if reaching movements are perturbed abruptly, cerebellar damage impairs the ability to learn from the perturbation-induced errors. Interestingly, if the perturbation is imposed gradually over many trials, people with cerebellar damage may exhibit improved adaptation. However, this result is controversial, since the differential effects of gradual vs. abrupt protocols have not been observed in all studies. To examine this question, we recruited patients with pure cerebellar ataxia due to cerebellar cortical atrophy (n = 13) and asked them to reach to a target while viewing the scene through wedge prisms. The prisms were computer controlled, making it possible to impose the full perturbation abruptly in one trial, or build up the perturbation gradually over many trials. To control visual feedback, we employed shutter glasses that removed visual feedback during the reach, allowing us to measure trial-by-trial learning from error (termed error-sensitivity), and trial-by-trial decay of motor memory (termed forgetting). We found that the patients benefited significantly from the gradual protocol, improving their performance with respect to the abrupt protocol by exhibiting smaller errors during the exposure block, and producing larger aftereffects during the postexposure block. Trial-by-trial analysis suggested that this improvement was due to increased error-sensitivity in the gradual protocol. Therefore, cerebellar patients exhibited an improved ability to learn from error if they experienced those errors gradually. This improvement coincided with increased error-sensitivity and was present in both groups of subjects, suggesting that control of error-sensitivity may be spared despite cerebellar damage.

Decoding the timing and target locations of saccadic eye movements from neuronal activity in macaque oculomotor areas.

OBJECTIVE: The control of movement timing has been a significant challenge for brain-machine interfaces (BMIs). As a first step toward developing a timing-based BMI, we aimed to decode movement timing and target locations in a visually guided saccadic eye movement task using the activity of neurons in the primate frontal eye field (FEF) and supplementary eye field (SEF). APPROACH: For this purpose, we developed a template-matching method that could recruit a variety of neurons in these areas. MAIN RESULTS: As a result, we were able to achieve a favorable estimation of saccade onset: for example, data from 20 randomly sampled FEF neurons or 40 SEF neurons achieved a median estimation error of ∼10 ms with an interquartile range less than 50 ms (± ∼25 ms). In the best case, seven simultaneously recorded SEF neurons using a multi-electrode array achieved a comparable accuracy (10 ± 30 ms). The method was significantly better than a heuristic method that used only a group of movement cells with sharp discharges at the onset of saccades. The estimation of target location was less accurate but still favorable, especially when we estimated target location at a timing of 200 ms after the onset of saccade: the method was able to discriminate 16 targets with an accuracy of 90%, which differed not only in their directions (eight directions) but also in amplitude (10/20°) when we used data from 61 randomly sampled FEF neurons. SIGNIFICANCE: The results show that the timing, amplitude and direction of saccades can be decoded from neuronal activity in the FEF and SEF and further suggest that timing-based BMIs can be developed by decoding timing information using the template-matching method.

Automatic representation of a visual stimulus relative to a background in the right precuneus.

Our brains represent the position of a visual stimulus egocentrically, in either retinal or craniotopic coordinates. In addition, recent behavioral studies have shown that the stimulus position is automatically represented allocentrically relative to a large frame in the background. Here, we investigated neural correlates of the 'background coordinate' using an fMRI adaptation technique. A red dot was presented at different locations on a screen, in combination with a rectangular frame that was also presented at different locations, while the participants looked at a fixation cross. When the red dot was presented repeatedly at the same location relative to the rectangular frame, the fMRI signals significantly decreased in the right precuneus. No adaptation was observed after repeated presentations relative to a small, but salient, landmark. These results suggest that the background coordinate is implemented in the right precuneus.

Effects of aging and idiopathic Parkinson's disease on tactile temporal order judgment.

It is generally accepted that the basal ganglia play an important role in interval timing that requires the measurement of temporal durations. By contrast, it remains controversial whether the basal ganglia play an essential role in temporal order judgment (TOJ) of successive stimuli, a behavior that does not necessarily require the measurement of durations in time. To address this issue, we compared the effects of idiopathic Parkinson's disease (PD) on the TOJ of two successive taps delivered to each hand, with the arms uncrossed in one condition and crossed in another. In addition to age-matched elderly participants without PD (non-PD), we examined young healthy participants so that the effect of aging could serve as a control for evaluating the effects of PD. There was no significant difference between PD and non-PD participants in any parameter of TOJ under either arm posture, although reaction time was significantly longer in PD compared with non-PD participants. By contrast, the effect of aging was apparent in both conditions. With their arms uncrossed, the temporal resolution (the interstimulus interval that yielded 84% correct responses) in elderly participants was significantly worse compared with young participants. With their arms crossed, elderly participants made more errors at longer intervals (~1 s) than young participants, although both age groups showed similar judgment reversal at moderately short intervals (~200 ms). These results indicate that the basal ganglia and dopaminergic systems do not play essential roles in tactile TOJ involving both hands and that the effect of aging on TOJ is mostly independent of the dopaminergic systems.