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Master

Affiliation (Master)

  • Faculty of Medicine　Physiological Science　Physiology

Affiliation (Master)

  • Faculty of Medicine　Physiological Science　Physiology

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Profile and Settings

Profile and Settings

  • Name (Japanese)

    tanaka

  • Name (Kana)

    masaki

  • Name

    200901053615140966

Alternate Names

Achievement

Research Interests

  • 包括脳ネットワーク・研究集会委員会   包括脳ネットワーク   統合脳・脳の高次機能学   大脳皮質   選択的注意   前頭連合野   背側視床   タイミング   機能脱落   運動発現   神経生理学   運動性視床   霊長類   神経活動   眼球運動   

Research Areas

  • Life sciences / Clinical pharmacy
  • Life sciences / Physiology
  • Life sciences / Neuroscience - general

Research Experience

  • 2017/04 - Today 北海道大学 医学研究院 神経生理学教室 教授（改組による名称変更）
  • 2022/04 - 2024/03 北海道大学脳科学研究教育センター センター長（兼任）
  • 2010/11 - 2017/03 Systems Neuroscience Laboratory, Hokkaido Univ Sch Med Professor of Physiology
  • 2001/09 - 2010/10 北海道大学 医学研究科 助手・講師・助教授・准教授
  • 2006/10 - 2010/03 Japan Science and Technology Agency
  • 1998/09 - 2001/08 米国ハワードヒューズ医学研究所（UCSF） Research Associate

Education

  •        - 1998/03  北海道大学大学院 修了
  •        - 1994/03  Hokkaido University  School of Medicine
  •        - 1988/03  甲陽学院高校 卒業

Awards

  • 2016 平成27年度 北海道大学教育総長賞（奨励賞）
  • 2013 平成25年度 北海道大学医学研究科優秀研究賞
  • 2008 平成20年度 文部科学大臣表彰若手科学者賞
  • 2006 平成18年度 日本神経科学学会奨励賞
  • 2005 平成17年度 フラテ研究奨励賞

Published Papers

  • Masaki Tanaka, Masashi Kameda, Ken-Ichi Okada
    Advances in experimental medicine and biology 1455 95 - 116 2024 
    Temporal information processing in the range of a few hundred milliseconds to seconds involves the cerebellum and basal ganglia. In this chapter, we present recent studies on nonhuman primates. In the studies presented in the first half of the chapter, monkeys were trained to make eye movements when a certain amount of time had elapsed since the onset of the visual cue (time production task). The animals had to report time lapses ranging from several hundred milliseconds to a few seconds based on the color of the fixation point. In this task, the saccade latency varied with the time length to be measured and showed stochastic variability from one trial to the other. Trial-to-trial variability under the same conditions correlated well with pupil diameter and the preparatory activity in the deep cerebellar nuclei and the motor thalamus. Inactivation of these brain regions delayed saccades when asked to report subsecond intervals. These results suggest that the internal state, which changes with each trial, may cause fluctuations in cerebellar neuronal activity, thereby producing variations in self-timing. When measuring different time intervals, the preparatory activity in the cerebellum always begins approximately 500 ms before movements, regardless of the length of the time interval being measured. However, the preparatory activity in the striatum persists throughout the mandatory delay period, which can be up to 2 s, with different rate of increasing activity. Furthermore, in the striatum, the visual response and low-frequency oscillatory activity immediately before time measurement were altered by the length of the intended time interval. These results indicate that the state of the network, including the striatum, changes with the intended timing, which lead to different time courses of preparatory activity. Thus, the basal ganglia appear to be responsible for measuring time in the range of several hundred milliseconds to seconds, whereas the cerebellum is responsible for regulating self-timing variability in the subsecond range. The second half of this chapter presents studies related to periodic timing. During eye movements synchronized with alternating targets at regular intervals, different neurons in the cerebellar nuclei exhibit activity related to movement timing, predicted stimulus timing, and the temporal error of synchronization. Among these, the activity associated with target appearance is particularly enhanced during synchronized movements and may represent an internal model of the temporal structure of stimulus sequence. We also considered neural mechanism underlying the perception of periodic timing in the absence of movement. During perception of rhythm, we predict the timing of the next stimulus and focus our attention on that moment. In the missing oddball paradigm, the subjects had to detect the omission of a regularly repeated stimulus. When employed in humans, the results show that the fastest temporal limit for predicting each stimulus timing is about 0.25 s (4 Hz). In monkeys performing this task, neurons in the cerebellar nuclei, striatum, and motor thalamus exhibit periodic activity, with different time courses depending on the brain region. Since electrical stimulation or inactivation of recording sites changes the reaction time to stimulus omission, these neuronal activities must be involved in periodic temporal processing. Future research is needed to elucidate the mechanism of rhythm perception, which appears to be processed by both cortico-cerebellar and cortico-basal ganglia pathways.
  • Masashi Kameda, Koichiro Niikawa, Akiko Uematsu, Masaki Tanaka
    Proceedings of the National Academy of Sciences of the United States of America 120 (24) e2221641120  2023/06/13 
    Both the cerebellum and basal ganglia are involved in rhythm processing, but their specific roles remain unclear. During rhythm perception, these areas may be processing purely sensory information, or they may be involved in motor preparation, as periodic stimuli often induce synchronized movements. Previous studies have shown that neurons in the cerebellar dentate nucleus and the caudate nucleus exhibit periodic activity when the animals prepare to respond to the random omission of regularly repeated visual stimuli. To detect stimulus omission, the animals need to learn the stimulus tempo and predict the timing of the next stimulus. The present study demonstrates that neuronal activity in the cerebellum is modulated by the location of the repeated stimulus and that in the striatum (STR) by the direction of planned movement. However, in both brain regions, neuronal activity during movement and the effect of electrical stimulation immediately before stimulus omission were largely dependent on the direction of movement. These results suggest that, during rhythm processing, the cerebellum is involved in multiple stages from sensory prediction to motor control, while the STR consistently plays a role in motor preparation. Thus, internalized rhythms without movement are maintained as periodic neuronal activity, with the cerebellum and STR preferring sensory and motor representations, respectively.
  • Ryo Sawagashira, Masaki Tanaka
    Psychopharmacology 2022/07/08 
    RATIONALE: The central cholinergic system is a major therapeutic target for restoring cognitive functions. Although manipulation of cholinergic signaling is known to alter working memory (WM), the underlying mechanism remains unclear. It is widely accepted that WM consists of multiple functional modules, one storing short-term memory and the other manipulating and utilizing it. A recently developed visual search task and a relevant model can be used to assess multiple components of WM during administration of acetylcholine receptor (AChR)-related substances. OBJECTIVES: The effects of systemic administration of AChR-related agents on WM and eye movements were examined during the oculomotor foraging task. METHODS: Three monkeys performing the task received an intramuscular injection of saline or the following AChR-related agents: nicotine (24 or 56 μg/kg), mecamylamine (nicotinic AChR antagonist, 1.0 mg/kg), oxotremorine (muscarinic AChR agonist, 3.0 µg/kg), and scopolamine (muscarinic AChR antagonist, 20 μg/kg). The task was to find a target among 15 identical objects by making eye movements within 6 s. The data were analyzed according to the foraging model that incorporated three parameters. RESULTS: Nicotine and mecamylamine significantly increased the utility but not the capacity of short-term memory, while muscarinic AChR-related agents did not alter any WM parameters. Further regression analyses with a mixed-effect model showed that the beneficial effect of nicotine on memory utility remained after considering eye movement variability, but the beneficial effect of mecamylamine disappeared. CONCLUSIONS: Nicotine improves visual search, mainly by increasing the utility of short-term memory, with minimal changes in oculomotor parameters.
  • Ken-ichi Okada, Ryuji Takeya, Masaki Tanaka
    Nature Communications 13 (1) 2022/05/06 
    AbstractMovements synchronized with external rhythms are ubiquitous in our daily lives. Despite the involvement of the cerebellum, the underlying mechanism remains unclear. In monkeys performing synchronized saccades to periodically alternating visual stimuli, we found that neuronal activity in the cerebellar dentate nucleus correlated with the timing of the next saccade and the current temporal error. One-third of the neurons were active regardless of saccade direction and showed greater activity for synchronized than for reactive saccades. During the transition from reactive to predictive saccades in each trial, the activity of these neurons coincided with target onset, representing an internal model of rhythmic structure rather than a specific motor command. The behavioural changes induced by electrical stimulation were explained by activating different groups of neurons at various strengths, suggesting that the lateral cerebellum contains multiple functional modules for the acquisition of internal rhythms, predictive motor control, and error detection during synchronized movements.
  • Akiko Uematsu, Masaki Tanaka
    Neuroscience 482 161 - 171 2022/02/01 
    The cerebellum has been shown to be involved in temporal information processing. We recently demonstrated that neurons in the cerebellar dentate nucleus exhibited periodic activity predicting stimulus timing when monkeys attempted to detect a single omission of isochronous repetitive visual stimulus. In this study, we assessed the relative contribution of signals from Purkinje cells and mossy and climbing fibers to the periodic activity by comparing single neuronal firing before and during local infusion of GABA or glutamate receptor antagonists (gabazine or a mixture of 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide hydrate (NBQX) and (±)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP)). Gabazine application reduced the magnitude of periodic activity and increased the baseline firing rate in most neurons. In contrast, during the blockade of glutamate receptors, both the magnitude of periodic firing modulation and the baseline activity remained unchanged in the population, while a minority of neurons significantly altered their activity. Furthermore, the amounts of changes in the baseline activity and the magnitude of periodic activity were inversely correlated in the gabazine experiments but not in the NBQX + CPP experiments. We also found that the variation of baseline activity decreased during gabazine application but sometimes increased during the blockade of glutamate receptors. These changes were not observed during prolonged recording without drug administration. These results suggest that the predictive neuronal activity in the dentate nucleus may mainly attribute to the inputs from the cerebellar cortex, while the signals from both mossy fibers and Purkinje cells may play a role in setting the level and variance of baseline activity during the task.
  • Ryo Sawagashira, Masaki Tanaka
    eNeuro 2021/03/09 
    Impairments of working memory are commonly observed in a variety of neurodegenerative disorders but they are difficult to quantitatively assess in clinical cases. Recent studies in experimental animals have used low-dose ketamine (an NMDA receptor antagonist) to disrupt working memory, partly mimicking the pathophysiology of schizophrenia. Here, we developed a novel behavioral paradigm to assess multiple components of working memory and applied it to monkeys with and without ketamine administration. In an oculomotor foraging task, the animals were presented with 15 identical objects on the screen. One of the objects was associated with a liquid reward, and monkeys were trained to search for the target by generating sequential saccades under a time constraint. We assumed that the occurrence of recursive movements to the same object might reflect working memory dysfunction. We constructed a "foraging model" that incorporated 1) memory capacity, 2) memory decay and 3) utility rate; this model was able to explain more than 92% of the variations in behavioral data obtained from three monkeys. Following systemic administration of low dosages of ketamine, the memory capacity and utility rate were dramatically reduced by 15% and 57%, respectively, while memory decay remained largely unchanged. These results suggested that the behavioral deficits during the blockade of NMDA receptors were mostly due to the decreased usage of short-term memory. Our oculomotor paradigm and foraging model appear to be useful for quantifying multiple components of working memory and could be applicable to clinical cases in future studies.Significance StatementWorking memory is often difficult to quantitatively assess in clinical cases, although deficiencies in working memory have been reported in a variety of disorders. Here, we developed a novel oculomotor foraging paradigm and devised a relevant model for accurately evaluating several parameters of working memory during visual search. We applied it to monkeys with and without administration of low-dose ketamine, which has been used to produce animal models of schizophrenia. Subanesthetic doses of ketamine dramatically reduced the use of short-term memory and increased the rate of exploratory choice, whereas the changes in memory capacity and memory decay were only modest. Our behavioral paradigm and the proposed model will provide a better understanding of the pathophysiology of working memory dysfunction.
  • Kei Matsuyama, Masaki Tanaka
    The Journal of neuroscience : the official journal of the Society for Neuroscience 41 (9) 1917 - 1927 2021/03/03 
    Prediction of periodic event timing is an important function for everyday activities, while the exact neural mechanism remains unclear. Previous studies in nonhuman primates have demonstrated that neurons in the cerebellar dentate nucleus and those in the caudate nucleus exhibit periodic firing modulation when the animals attempt to detect a single omission of isochronous repetitive audiovisual stimuli. To understand how these subcortical signals are sent and processed through the thalamocortical pathways, we examined single-neuron activities in the central thalamus of two macaque monkeys (one female and one male). We found that three types of neurons responded to each stimulus in the sequence in the absence of movements. Reactive-type neurons showed sensory adaptation and gradually waned the transient response to each stimulus. Predictive-type neurons steadily increased the magnitude of the suppressive response, similar to neurons previously reported in the cerebellum. Switch-type neurons initially showed a transient response, but after several cycles, the direction of firing modulation reversed and the activity decreased for each repetitive stimulus. The time course of Switch-type activity was well explained by the weighted sum of activities of the other types of neurons. Furthermore, for only Switch-type neurons the activity just before stimulus omission significantly correlated with behavioral latency, indicating that this type of neuron may carry a more advanced signal in the system detecting stimulus omission. These results suggest that the central thalamus may transmit integrated signals to the cerebral cortex for temporal information processing, which are necessary to accurately predict rhythmic event timing.SIGNIFICANCE STATEMENT Several cortical and subcortical regions are involved in temporal information processing, and the thalamus will play a role in functionally linking them. The present study aimed to clarify how the paralaminar part of the thalamus transmits and modifies signals for temporal prediction of rhythmic events. Three types of thalamic neurons exhibited periodic activity when monkeys attempted to detect a single omission of isochronous repetitive stimuli. The activity of one type of neuron correlated with the behavioral latency and appeared to be generated by integrating the signals carried by the other types of neurons. Our results revealed the neuronal signals in the thalamus for temporal prediction of sensory events, providing a clue to elucidate information processing in the thalamocortical pathways.
  • Tomoki W Suzuki, Ken-Ichi Inoue, Masahiko Takada, Masaki Tanaka
    eNeuro 2021/03/03 
    The motor thalamus relays signals from subcortical structures to the motor cortical areas. Previous studies in songbirds and rodents suggest that cortical feedback inputs crucially contribute to the generation of movement-related activity in the motor thalamus. In primates, however, it remains uncertain whether the corticothalamic projections may play a role in shaping neuronal activity in the motor thalamus. Here, using an optogenetic inactivation technique with the viral vector system expressing halorhodopsin, we investigated the role of cortical input in modulating thalamic neuronal activity during goal-directed behavior. In particular, we assessed whether suppression of signals originating from the supplementary eye field at the corticothalamic terminals could change the task-related neuronal modulation in the oculomotor thalamus in monkeys performing a self-initiated saccade task. We found that many thalamic neurons exhibited changes in their firing rates depending on saccade direction or task event, indicating that optical stimulation exerted task-specific effects on neuronal activity beyond the global changes in baseline activity. These results suggest that the corticothalamic projections might be actively involved in signal processing necessary for goal-directed behavior. However, we also found that some thalamic neurons exhibited overall, non-task-specific changes in the firing rate during optical stimulation, even in control animals without vector injections. The stimulation effects in these animals started with longer latency, implying a possible thermal effect on neuronal activity. Thus, our results not only reveal the importance of direct cortical input in neuronal activity in the primate motor thalamus, but also provide useful information for future optogenetic studies.Significance statementAlthough previous studies in songbirds and rodents have shown that corticothalamic inputs are essential for generating movement-related activity in the motor thalamus, their role in primates remains largely unknown. Here, we attempted to optogenetically suppress the corticothalamic terminals during neuronal recording from theoculomotor thalamus in monkeys performing a saccade task. We found that optical stimulation resulted in task-specific changes in the firing rate, indicating that thecorticothalamic projections are engaged in neural computations for goal-directed behavior. We also observed non-task-specific changes in baseline activity that mightbe caused by local heating of surrounding tissue, which underscores the importance of control experiments in animals without opsin expression.
  • Ryuji Takeya, Shuntaro Nakamura, Masaki Tanaka
    PloS one 16 (3) e0248530  2021 
    Sequential movements are often grouped into several chunks, as evidenced by the modulation of the timing of each elemental movement. Even during synchronized tapping with a metronome, we sometimes feel subjective accent for every few taps. To examine whether motor segmentation emerges during synchronized movements, we trained monkeys to generate a series of predictive saccades synchronized with visual stimuli which sequentially appeared for a fixed interval (400 or 600 ms) at six circularly arranged landmark locations. We found two types of motor segmentations that featured periodic modulation of saccade timing. First, the intersaccadic interval (ISI) depended on the target location and saccade direction, indicating that particular combinations of saccades were integrated into motor chunks. Second, when a task-irrelevant rectangular contour surrounding three landmarks ("inducer") was presented, the ISI significantly modulated depending on the relative target location to the inducer. All patterns of individual differences seen in monkeys were also observed in humans. Importantly, the effects of the inducer greatly decreased or disappeared when the animals were trained to generate only reactive saccades (latency >100 ms), indicating that the motor segmentation may depend on the internal rhythms. Thus, our results demonstrate two types of motor segmentation during synchronized movements: one is related to the hierarchical organization of sequential movements and the other is related to the spontaneous grouping of rhythmic events. This experimental paradigm can be used to investigate the underlying neural mechanism of temporal grouping during rhythm production.
  • Masaki Tanaka, Jun Kunimatsu, Tomoki W Suzuki, Masashi Kameda, Shogo Ohmae, Akiko Uematsu, Ryuji Takeya
    Neuroscience 462 220 - 234 2020/04/30 [Refereed][Not invited]
     
    The cerebellum is thought to have a variety of functions because it developed with the evolution of the cerebrum and connects with different areas in the frontoparietal cortices. Like neurons in the cerebral cortex, those in the cerebellum also exhibit strong activity during planning in addition to the execution of movements. However, their specific roles remain elusive. In this article, we review recent findings focusing on preparatory activities found in the primate deep cerebellar nuclei during tasks requiring deliberate motor control and temporal prediction. Neurons in the cerebellum are active during anti-saccade preparation and their inactivation impairs proactive inhibitory control for saccades. Experiments using a self-timing task show that there are mechanisms for tracking elapsed time and regulating trial-by-trial variation in timing, and that the cerebellum is involved in the latter. When predicting the timing of periodic events, the cerebellum provides more accurate temporal information than the striatum. During a recently developed synchronized eye movement task, cerebellar nuclear neurons exhibited periodic preparatory activity for predictive synchronization. In all cases, the cerebellum generated preparatory activity lasting for several hundred milliseconds. These signals may regulate neuronal activity in the cerebral cortex that adjusts movement timing and predicts the timing of rhythmic events.
  • Takeshi D Itoh, Ryuji Takeya, Masaki Tanaka
    Scientific reports 10 (1) 5280 - 5280 2020/03/24 [Refereed][Not invited]
     
    Moving objects are often occluded behind larger, stationary objects, but we can easily predict when and where they reappear. Here, we show that the prediction of object reappearance is subject to adaptive learning. When monkeys generated predictive saccades to the location of target reappearance, systematic changes in the location or timing of target reappearance independently altered the endpoint or latency of the saccades. Furthermore, spatial adaptation of predictive saccades did not alter visually triggered reactive saccades, whereas adaptation of reactive saccades altered the metrics of predictive saccades. Our results suggest that the extrapolation of motion trajectory may be subject to spatial and temporal recalibration mechanisms located upstream from the site of reactive saccade adaptation. Repetitive exposure of visual error for saccades induces qualitatively different adaptation, which might be attributable to different regions in the cerebellum that regulate learning of trajectory prediction and saccades.
  • Lauren N Miterko, Kenneth B Baker, Jaclyn Beckinghausen, Lynley V Bradnam, Michelle Y Cheng, Jessica Cooperrider, Mahlon R DeLong, Simona V Gornati, Mark Hallett, Detlef H Heck, Freek E Hoebeek, Abbas Z Kouzani, Sheng-Han Kuo, Elan D Louis, Andre Machado, Mario Manto, Alana B McCambridge, Michael A Nitsche, Nordeyn Oulad Ben Taib, Traian Popa, Masaki Tanaka, Dagmar Timmann, Gary K Steinberg, Eric H Wang, Thomas Wichmann, Tao Xie, Roy V Sillitoe
    Cerebellum (London, England) 18 (6) 1064 - 1097 1473-4222 2019/12 [Refereed][Not invited]
     
    The cerebellum is best known for its role in controlling motor behaviors. However, recent work supports the view that it also influences non-motor behaviors. The contribution of the cerebellum towards different brain functions is underscored by its involvement in a diverse and increasing number of neurological and neuropsychiatric conditions including ataxia, dystonia, essential tremor, Parkinson's disease (PD), epilepsy, stroke, multiple sclerosis, autism spectrum disorders, dyslexia, attention deficit hyperactivity disorder (ADHD), and schizophrenia. Although there are no cures for these conditions, cerebellar stimulation is quickly gaining attention for symptomatic alleviation, as cerebellar circuitry has arisen as a promising target for invasive and non-invasive neuromodulation. This consensus paper brings together experts from the fields of neurophysiology, neurology, and neurosurgery to discuss recent efforts in using the cerebellum as a therapeutic intervention. We report on the most advanced techniques for manipulating cerebellar circuits in humans and animal models and define key hurdles and questions for moving forward.
  • Kameda M, Ohmae S, Tanaka M
    eLife 8 2019/09 [Refereed][Not invited]
     
    Rhythmic events recruit neuronal activity in the basal ganglia and cerebellum, but their roles remain elusive. In monkeys attempting to detect a single omission of isochronous visual stimulus, we found that neurons in the caudate nucleus showed increased activity for each stimulus in sequence, while those in the cerebellar dentate nucleus showed decreased activity. Firing modulation in the majority of caudate neurons and all cerebellar neurons was proportional to the stimulus interval, but a quarter of caudate neurons displayed a clear duration tuning. Furthermore, the time course of population activity in the cerebellum well predicted stimulus timing, whereas that in the caudate reflected stochastic variation of response latency. Electrical stimulation to the respective recording sites confirmed a causal role in the detection of stimulus omission. These results suggest that striatal neurons might represent periodic response preparation while cerebellar nuclear neurons may play a role in temporal prediction of periodic events.
  • Tomoki W Suzuki, Masaki Tanaka
    Communications biology 2 102 - 102 2019 [Refereed][Not invited]
     
    When measuring time, neuronal activity in the cortico-basal ganglia pathways has been shown to be temporally scaled according to the interval, suggesting that signal transmission within the pathways is flexibly controlled. Here we show that, in the caudate nuclei of monkeys performing a time production task with three different intervals, the magnitude of visually-evoked potentials at the beginning of an interval differed depending on the conditions. Prior to this response, the power of low frequency components (6-20 Hz) significantly changed, showing inverse correlation with the visual response gain. Although these components later exhibited time-dependent modification during self-timed period, the changes in spectral power for interval conditions qualitatively and quantitatively differed from those associated with the reward amount. These results suggest that alteration of network state in the cortico-basal ganglia pathways indexed by the low frequency oscillations may be crucial for the regulation of signal transmission and subsequent timing behavior.
  • Jun Kunimatsu, Tomoki W Suzuki, Shogo Ohmae, Masaki Tanaka
    eLife 7 2018/07/02 [Refereed][Not invited]
     
    The ability to flexibly adjust movement timing is important for everyday life. Although the basal ganglia and cerebellum have been implicated in monitoring of supra- and sub-second intervals, respectively, the underlying neuronal mechanism remains unclear. Here, we show that in monkeys trained to generate a self-initiated saccade at instructed timing following a visual cue, neurons in the caudate nucleus kept track of passage of time throughout the delay period, while those in the cerebellar dentate nucleus were recruited only during the last part of the delay period. Conversely, neuronal correlates of trial-by-trial variation of self-timing emerged earlier in the cerebellum than the striatum. Local inactivation of respective recording sites confirmed the difference in their relative contributions to supra- and sub-second intervals. These results suggest that the basal ganglia may measure elapsed time relative to the intended interval, while the cerebellum might be responsible for the fine adjustment of self-timing.
  • Ryuji Takeya, Aniruddh D Patel, Masaki Tanaka
    Frontiers in psychology 9 2172 - 2172 2018 [Refereed][Not invited]
     
    Synchronized movements with external periodic rhythms, such as dancing to a beat, are commonly observed in daily life. Although it has been well established that some vocal learning species (including parrots and humans) spontaneously develop this ability, it has only recently been shown that monkeys are also capable of predictive and tempo-flexible synchronization to periodic stimuli. In our previous study, monkeys were trained to make predictive saccades for alternately presented visual stimuli at fixed stimulus onset asynchronies (SOAs) to obtain a liquid reward. The monkeys generalized predictive synchronization to novel SOAs in the middle of trained range, suggesting a capacity for tempo-flexible synchronization. However, it is possible that when encountering a novel tempo, the monkeys might sample learned saccade sequences from those for the short and long SOAs so that the mean saccade interval matched the untrained SOA. To eliminate this possibility, in the current study we tested monkeys on novel SOAs outside the trained range. Animals were trained to generate synchronized eye movements for 600 and 900-ms SOAs for a few weeks, and then were tested for longer SOAs. The accuracy and precision of predictive saccades for one untrained SOA (1200 ms) were comparable to those for the trained conditions. On the other hand, the variance of predictive saccade latency and the proportion of reactive saccades increased significantly in the longer SOA conditions (1800 and 2400 ms), indicating that temporal prediction of periodic stimuli was difficult in this range, similar to previous results on synchronized tapping in humans. Our results suggest that monkeys might share similar synchronization mechanisms with humans, which can be subject to physiological examination in future studies.
  • Tomoki W Suzuki, Masaki Tanaka
    Neuroscience 366 15 - 22 0306-4522 2017/12/16 [Refereed][Not invited]
     
    We recently found that when monkeys performed an oculomotor version of the time production task, the trial-by-trial latency of self-timed saccades was negatively correlated with pupil diameter just before the delay period (Suzuki et al., 2016). Since pupil diameter has been shown to correlate with neuronal activity in the locus coeruleus, the level of noradrenaline (NA) in the brain might regulate the subjective passage of time. To examine this, we orally administered a selective noradrenaline reuptake inhibitor (reboxetine, 0.4-0.8 mg) when animals made a self-initiated memory-guided saccade >1 s following the appearance of a brief visual cue. We found that reboxetine delayed self-timed saccades, while the latency of visually triggered saccades remained unchanged. Because the changes in proportions and latencies of early impulsive saccades were comparable between conditions with and without drug administration, alteration of self-timing might not result from reduced impulsivity. We also assessed other behavioral parameters (saccade accuracy, velocity, and latency variance), but failed to find any drug effect except for the accuracy of visually triggered saccades in the high-dose condition, indicating that reboxetine specifically altered self-timing under our experimental conditions. Our results suggest that NA-related internal states may causally regulate temporal information processing in the brain.
  • Ryuji Takeya, Masashi Kameda, Aniruddh D Patel, Masaki Tanaka
    Scientific reports 7 (1) 6127 - 6127 2045-2322 2017/07/21 [Refereed][Not invited]
     
    Predictive and tempo-flexible synchronization to an auditory beat is a fundamental component of human music. To date, only certain vocal learning species show this behaviour spontaneously. Prior research training macaques (vocal non-learners) to tap to an auditory or visual metronome found their movements to be largely reactive, not predictive. Does this reflect the lack of capacity for predictive synchronization in monkeys, or lack of motivation to exhibit this behaviour? To discriminate these possibilities, we trained monkeys to make synchronized eye movements to a visual metronome. We found that monkeys could generate predictive saccades synchronized to periodic visual stimuli when an immediate reward was given for every predictive movement. This behaviour generalized to novel tempi, and the monkeys could maintain the tempo internally. Furthermore, monkeys could flexibly switch from predictive to reactive saccades when a reward was given for each reactive response. In contrast, when humans were asked to make a sequence of reactive saccades to a visual metronome, they often unintentionally generated predictive movements. These results suggest that even vocal non-learners may have the capacity for predictive and tempo-flexible synchronization to a beat, but that only certain vocal learning species are intrinsically motivated to do it.
  • Shogo Ohmae, Jun Kunimatsu, Masaki Tanaka
    The Journal of neuroscience : the official journal of the Society for Neuroscience 37 (13) 3511 - 3522 0270-6474 2017/03/29 [Refereed][Not invited]
     
    Previous studies suggest that the cerebellum and basal ganglia are involved in sub-second and supra-second timing, respectively. To test this hypothesis at the cellular level, we examined the activity of single neurons in the cerebellar dentate nucleus in monkeys performing the oculomotor version of the self-timing task. Animals were trained to report the passage of time of 400, 600, 1200, or 2400 ms following a visual cue by making self-initiated memory-guided saccades. We found a sizeable preparatory neuronal activity before self-timed saccades across delay intervals, while the time course of activity correlated with the trial-by-trial variation of saccade latency in different ways depending on the length of the delay intervals. For the shorter delay intervals, the ramping up of neuronal firing rate started just after the visual cue and the rate of rise of neuronal activity correlated with saccade timing. In contrast, for the longest delay (2400 ms), the preparatory activity started late during the delay period, and its onset time correlated with self-timed saccade latency. Because electrical microstimulation applied to the recording sites during saccade preparation advanced self-timed but not reactive saccades, regardless of their directions, the signals in the cerebellum may have a causal role in self-timing. We suggest that the cerebellum may regulate timing in both sub-second and supra-second ranges, although its relative contribution might be greater for sub-second than for supra-second time intervals.SIGNIFICANCE STATEMENT How we decide the timing of self-initiated movement is a fundamental question. According to the prevailing hypothesis, the cerebellum plays a role in monitoring sub-second timing, whereas the basal ganglia are important for supra-second timing. To verify this, we explored neuronal signals in the monkey cerebellum while animals reported the passage of time in the range 400-2400 ms by making eye movements. Contrary to our expectations, we found that neurons in the cerebellar dentate nucleus exhibited a similar preparatory activity for both sub-second and supra-second intervals, and that electrical simulation advanced self-timed saccades in both conditions. We suggest that the cerebellum plays a causal role in the fine adjustment of self-timing in a larger time range than previously thought.
  • Akiko Uematsu, Shogo Ohmae, Masaki Tanaka
    Neuroscience 346 190 - 196 0306-4522 2017/03/27 [Refereed][Not invited]
     
    The cerebellum is known to be involved in temporal information processing. However, the underlying neuronal mechanisms remain unclear. In our previous study, monkeys were trained to make a saccade in response to a single omission of periodically presented visual stimuli. To detect stimulus omission, animals had to predict the timing of each next stimulus. During this task, neurons in the cerebellar dentate nucleus exhibited a transient decrement of activity followed by a gradual increase in firing rate that peaked around the time of the next stimulus (Ohmae et al., 2013). In the present study, to address how these two components of neuronal activity contributed to omission detection, we applied electrical microstimulation to the recording site at different timing during the task. We found that electrical stimulation just before the stimulus omission shortened the latencies of both contraversive and ipsiversive saccades. Because the changes in saccade latency non-linearly depended on the timing of stimulation in each inter-stimulus interval, and electrical stimulation just before the early stimulus in the sequence failed to evoke saccades, the neuronal activity in the dentate nucleus might regulate temporal prediction rather than facilitating saccade execution. Our results support the hypothesis that the firing modulation in each inter-stimulus interval in the dentate nucleus represents neuronal code for the temporal prediction of next stimulus.
  • Jun Kunimatsu, Masaki Tanaka
    Neuroscience 337 131 - 142 0306-4522 2016/11/19 [Refereed][Not invited]
     
    The ability to adjust movement timing is essential in daily life. Explorations of the underlying neural mechanisms have reported a gradual increase or decrease in neuronal activity prior to self-timed movements within the cortico-basal ganglia loop. Previous studies in both humans and animals have shown that endogenous dopamine (DA) plays a modulatory role in self-timing. However, the specific site of dopaminergic regulation remains elusive because the systemic application of DA-related substances can directly alter both cortical and subcortical neuronal activities. To investigate the role of striatal DA in self-timing, we locally injected DA receptor agonists or antagonists into the striatum of two female monkeys (Macaca fuscata) while they performed two versions of the memory-guided saccade (MS) task. In the conventional, triggered MS task, animals made a saccade to the location of a previously flashed visual cue in response to the fixation point offset. In the self-timed MS task, monkeys were rewarded for making a self-initiated saccade within a predetermined time interval following the cue. Infusion of a small amount of a D1 or D2 antagonist led to early saccades in the self-timed, but not the triggered MS tasks, while infusion of DA agonists produced no consistent effect. We also found that local administration of nicotinic but not muscarinic acetylcholine receptor agonists and antagonists altered the timing of self-initiated saccades. Our data suggest that the timing of self-initiated movements may be regulated by the balance of signals in the direct and indirect basal ganglia pathways, as well as that between both hemispheres of the brain.
  • Tomoki W Suzuki, Jun Kunimatsu, Masaki Tanaka
    The Journal of neuroscience : the official journal of the Society for Neuroscience 36 (44) 11331 - 11337 0270-6474 2016/11/02 [Refereed][Not invited]
     
    Our daily experience of time is strongly influenced by internal states, such as arousal, attention, and mood. However, the underlying neuronal mechanism remains largely unknown. To investigate this, we recorded pupil diameter, which is closely linked to internal factors and neuromodulatory signaling, in monkeys performing the oculomotor version of the time production paradigm. In the self-timed saccade task, animals were required to make a memory-guided saccade during a predetermined time interval following a visual cue. We found that pupil diameter was negatively correlated with trial-by-trial latency of self-timed saccades. Because no significant correlation was found for visually guided saccades, correlation of self-timed saccades could not be explained solely by the facilitation of saccade execution. As the reward amount was manipulated, pupil diameter and saccade latency altered in opposite directions and the magnitudes of modulation correlated strongly across sessions, further supporting the close link between pupil diameter and the subjective passage of time. When the animals were trained to produce two different intervals depending on the instruction, the pupil size again correlated with the trial-by-trial variation of saccade latency in each condition; however, pupil diameter differed significantly for saccades with similar latencies generated under different conditions. Our results indicate that internal brain states indexed by pupil diameter, which parallel noradrenergic neuronal activity (Aston-Jones and Cohen, 2005), may bias trial-by-trial variation in the subjective passage of time. SIGNIFICANCE STATEMENT: Daily experience of time is strongly influenced by our internal state, but the underlying neuronal mechanism remains elusive. Here we demonstrate that pupil diameter is negatively correlated with subjective elapsed time in monkeys performing an oculomotor version of the time production task. When the animals reported two different intervals depending on the instruction, pupil size was correlated with reported timing in each condition but differed for similar timing under different conditions. Given the close correlation between pupil diameter and noradrenergic signaling reported previously, our data indicate that brain states probed by pupil diameter and noradrenergic neuronal activity might modulate subjective passage of time.
  • Jun Kunimatsu, Tomoki W Suzuki, Masaki Tanaka
    The Journal of neuroscience : the official journal of the Society for Neuroscience 36 (26) 7066 - 74 0270-6474 2016/06/29 [Refereed][Not invited]
     
    UNLABELLED: Although several lines of evidence establish the involvement of the medial and vestibular parts of the cerebellum in the adaptive control of eye movements, the role of the lateral hemisphere of the cerebellum in eye movements remains unclear. Ascending projections from the lateral cerebellum to the frontal and parietal association cortices via the thalamus are consistent with a role of these pathways in higher-order oculomotor control. In support of this, previous functional imaging studies and recent analyses in subjects with cerebellar lesions have indicated a role for the lateral cerebellum in volitional eye movements such as anti-saccades. To elucidate the underlying mechanisms, we recorded from single neurons in the dentate nucleus of the cerebellum in monkeys performing anti-saccade/pro-saccade tasks. We found that neurons in the posterior part of the dentate nucleus showed higher firing rates during the preparation of anti-saccades compared with pro-saccades. When the animals made erroneous saccades to the visual stimuli in the anti-saccade trials, the firing rate during the preparatory period decreased. Furthermore, local inactivation of the recording sites with muscimol moderately increased the proportion of error trials, while successful anti-saccades were more variable and often had shorter latency during inactivation. Thus, our results show that neuronal activity in the cerebellar dentate nucleus causally regulates anti-saccade performance. Neuronal signals from the lateral cerebellum to the frontal cortex might modulate the proactive control signals in the corticobasal ganglia circuitry that inhibit early reactive responses and possibly optimize the speed and accuracy of anti-saccades. SIGNIFICANCE STATEMENT: Although the lateral cerebellum is interconnected with the cortical eye fields via the thalamus and the pons, its role in eye movements remains unclear. We found that neurons in the caudal part of the lateral (dentate) nucleus of the cerebellum showed the increased firing rate during the preparation of anti-saccades. Inactivation of the recording sites modestly elevated the rate of erroneous saccades to the visual stimuli in the anti-saccade trials, while successful anti-saccades during inactivation tended to have a shorter latency. Our data indicate that neuronal signals in the lateral cerebellum may proactively regulate anti-saccade generation through the pathways to the frontal cortex, and may inhibit early reactive responses and regulate the accuracy of anti-saccades.
  • Atsushi Yoshida, Masaki Tanaka
    CEREBRAL CORTEX 26 (3) 1187 - 1199 1047-3211 2016/03 [Refereed][Not invited]
     
    The globus pallidus external segment (GPe) constitutes part of the indirect pathway of the basal ganglia. Because of inhibitory projections from the striatum, most GPe neurons are expected to reduce activity during movements. However, many GPe neurons in fact display increased activity. We previously found that both excitatory and inhibitory responses were modulated during antisaccades, when eyes were directed away from a visual stimulus. To elucidate the roles of these neurons during antisaccades, we examined neuronal activities as monkeys performed antisaccades, prosaccades, and NoGo tasks under 2 conditions. In the Deliberate condition, the task-rule was instructed by color of the fixation point, while in the Immediate condition, it was given by color of the target. Under both conditions, the increase-type neurons exhibited greater activity during antisaccades compared with the other tasks and neuronal activity negatively correlated with saccade latency. The decrease-type neurons also showed greater modulation during antisaccades but their activity was comparable between NoGo and antisaccade trials in the Immediate condition. These results suggest that the increase-type neurons might play a role in facilitating antisaccades, whereas the decrease-type neurons could mediate signals for reflexive saccade suppression. We propose that these GPe neurons are differently involved in basal ganglia pathways.
  • Shogo Ohmae, Masaki Tanaka
    Scientific reports 6 20615 - 20615 2045-2322 2016/02/05 [Refereed][Not invited]
     
    Although we can detect slight changes in musical rhythm, the underlying neural mechanism remains elusive. Here we show that two distinct mechanisms are automatically selected depending on the speed of the rhythm. When human subjects detected a single omission of isochronous repetitive auditory stimuli, reaction time strongly depended on the stimulus onset asynchrony (SOA) for shorter SOAs (<250 ms), but was almost constant for longer SOAs. For shorter SOAs, subjects were unable to detect stimulus omission when either monaural stimuli or those in different frequencies were randomly presented. In contrast, for longer SOAs, reaction time increased when different tempos were presented simultaneously to different ears. These results suggest that depending on the speed of rhythms, the brain may use either temporal grouping of discrete sounds or temporal prediction of upcoming stimuli to detect the absence of a regular stimulus. Because we also found a similar relationship between reaction time and SOA for both visual and tactile stimuli, dual detection strategies could be generalized to other sensory modalities.
  • Jun Kunimatsu, Naoki Miyamoto, Masayori Ishikawa, Hiroki Shirato, Masaki Tanaka
    Frontiers in Systems Neuroscience 9 67  1662-5137 2015/04/24 [Refereed][Not invited]
     
    Behavioral analysis of subjects with discrete brain lesions provides important information about the mechanisms of various brain functions. However, it is generally difficult to experimentally produce discrete lesions in deep brain structures. Here we show that a radiosurgical technique, which is used as an alternative treatment for brain tumors and vascular malformations, is applicable to create non-invasive lesions in experimental animals for the research in systems neuroscience. We delivered highly focused radiation (130–150 Gy at ISO center) to the frontal eye field (FEF) of macaque monkeys using a clinical linear accelerator (LINAC). The effects of irradiation were assessed by analyzing oculomotor performance along with magnetic resonance (MR) images before and up to 8 months following irradiation. In parallel with tissue edema indicated by MR images, deficits in saccadic and smooth pursuit eye movements were observed during several days following irradiation. Although initial signs of oculomotor deficits disappeared within a month, damage to the tissue and impaired eye movements gradually developed during the course of the subsequent 6 months. Postmortem histological examinations showed necrosis and hemorrhages within a large area of the white matter and, to a lesser extent, in the adjacent gray matter, which was centered at the irradiated target. These results indicated that the LINAC system was useful for making brain lesions in experimental animals, while the suitable radiation parameters to generate more focused lesions need to be further explored. We propose the use of a radiosurgical technique for establishing animal models of brain lesions, and discuss the possible uses of this technique for functional neurosurgical treatments in humans.
  • Ayano Matsushima, Masaki Tanaka
    JOURNAL OF NEUROSCIENCE 34 (30) 9963 - 9969 0270-6474 2014/07 [Refereed][Not invited]
     
    Human scan simultaneously track multiple moving objects with attention. The number of objects that can be tracked is known to be larger when visual stimuli are presented bilaterally rather than presented unilaterally. To elucidate the underlying neuronal mechanism, we trained monkeys to covertly track a single or multiple object(s). We found that neurons in the lateral prefrontal cortex exhibited greater activity for the target passing through the receptive field (RF) than for distractors. During multiple-object tracking, response enhancement for one target presented in the RF was stronger when the other target was located in the opposite than the same visual hemifield. Because the neuronal modulation did not differ depending on relative target locations with respect to upper and lower visual hemifields, the distance between the targets does not explain the results. We propose that inherent, anatomical separation of visual processing for contralateral and ipsilateral visual fields might constrain cognitive capacity.
  • Ayano Matsushima, Masaki Tanaka
    CEREBRAL CORTEX 24 (6) 1493 - 1501 1047-3211 2014/06 [Refereed][Not invited]
     
    For each saccade, we select an object to direct gaze and to specify the direction and amplitude of eye movement. Although these 2 processes are inevitably interdependent when visual stimuli are held stationary, several lines of evidence suggest that the neuronal signals in the frontal eye fields (FEF) that underlie the selection of visual objects are distinct from those underlying the selection of saccades. In the present study, we overtly dissociated these 2 processes spatially and temporally using the covert object-tracking paradigm, in which 4 identical objects moved randomly for 3 s before monkeys made a saccade to a previously selected target. To assess the causal role of the FEF in the 2 selection processes, we applied electrical microstimulation to the FEF at various times during the motion period. When stimulation was delivered at the motion onset, animals tended to choose an object that was initially presented at a particular location depending on the stimulation site. In contrast, the same stimulation delivered at the motion end failed to alter saccade end points. These results indicate that manipulation of FEF activity can change the selection of a visual object without affecting saccade goals, suggesting the existence of neurons solely regulating visual selection.
  • Ayano Matsushima, Masaki Tanaka
    JOURNAL OF NEUROSCIENCE 34 (16) 5621 - 5626 0270-6474 2014/04 [Refereed][Not invited]
     
    Spatial working memory is one of the most studied cognitive functions, serving as a model system to decipher computational principles of the brain. Although neuronal mechanisms for remembering a single location have been well elucidated, little is known about memory for multiple locations. Here, we examined the activities of prefrontal neurons during monkeys remembered positions of one or two visual cue(s). When the two cues were presented across the left and right visual fields, neurons exhibited a comparable response to the activity for the preferred cue presented alone. When the two cues were presented within the same hemifield, neurons exhibited an intermediate response between those to the individual cues. Subsequent computer simulations predicted a lower signal-to-noise ratio in the latter condition, which was further verified by behavioral experiments. Considering the separation of contralateral and ipsilateral visual processing, the lateral inhibition in local circuits might implicitly determine different neuronal computations and memory capacities for bilateral and unilateral displays.
  • Shogo Ohmae, Akiko Uematsu, Masaki Tanaka
    JOURNAL OF NEUROSCIENCE 33 (39) 15432 - 15441 0270-6474 2013/09 [Refereed][Not invited]
     
    The cerebellum is implicated in sensory prediction in the subsecond range. To explore how neurons in the cerebellum encode temporal information for the prediction of sensory events, we trained monkeys to make a saccade in response to either a single omission or deviation of isochronous repetitive stimuli. We found that neurons in the cerebellar dentate nucleus exhibited a gradual elevation of the baseline firing rate as the repetition progressed. Most neurons showed a transient suppression for each stimulus, and this firing modulation also increased gradually, opposed to the sensory adaptation. The magnitude of the enhanced sensory response positively correlated with interstimulus interval. Furthermore, when stimuli appeared unexpectedly earlier than the regular timing, the neuronal modulation became smaller, suggesting that the sensory response depended on the time elapsed since the previous stimulus. The enhancement of neuronal modulation was context dependent and was reduced or even absent when monkeys were unmotivated to detect stimulus omission. Asignificant negative correlation between neuronal activity at stimulus omission and saccade latency suggested that the timing of each stimulus was predicted by the amount of recovery from the transient response. Because inactivation of the recording sites delayed the detection of stimulus omission but only slightly altered the detection of stimulus deviation, these signals might be necessary for the prediction of stimulus timing but may not be involved only in the generation of saccades. Our results demonstrate a novel mechanism for temporal prediction of upcoming stimuli that accompanies the time-dependent modification of sensory gain in the cerebellum.
  • Ayano Matsushima, Masaki Tanaka
    NeuroReport 24 (2) 73 - 78 0959-4965 2013/01/23 [Refereed][Not invited]
     
    Neurons in the lateral prefrontal cortex show sustained activity during the maintenance of visual memory. Previous studies have also indicated that prefrontal neurons show predictive activity in anticipation of upcoming visual stimuli. Because these retrospective and prospective coding of visual stimuli have been examined in separate experiments, how these processes interact in individual neurons remains unknown. To examine this, we recorded from single prefrontal neurons while monkeys performed two behavioural tasks. In one task, the animals passively viewed a moving object during fixation, whereas in the other, they remembered the location of a briefly presented visual cue for subsequent saccades. We found that many neurons were reactive and responded only after the visual stimulus appeared in their receptive field, while some neurons were predictive and increased their activity even before the moving stimulus entered the receptive field. In the memory-guided saccade trials, the reactive neurons exhibited sustained activity during the delay period, whereas the predictive neurons did not. Delays of visual response to a moving stimulus did not correlate with visual latency for a stationary stimulus. Instead, it correlated with the magnitude of sustained activity during the delay period in the memory-guided saccade task. Our data show that retrospective and prospective coding of visual information are represented by distinct neuronal populations, and that their temporal preferences are stable across different task conditions. Reactive signals may reflect the amount of temporal integration in short-term memory, whereas predictive signals may solely represent future events in isolation from the maintenance of past information. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.
  • Masaki Tanaka, Jun Kunimatsu
    The Oxford Handbook of Eye Movements 2012/11/21 [Refereed][Not invited]
     
    The thalamus serves as the gateway to the cerebral cortex-all subcortical signals that ascend to the cortex are relayed by neurons in the thalamus. Different nuclei in the central thalamus receive inputs from the brainstem, the basal ganglia, and the cerebellum, and send outputs to the eye movement-related areas in the cortex, including the frontal eye field, the supplementary eye field, and the lateral prefrontal cortex. Consistent with the converging inputs, neurons in the central thalamus exhibit a variety of eye movement-related activities. Recent analyses of neural activity and eye movements in subjects with natural or experimentally-induced thalamic lesions suggest that signals in the central thalamus are essential for the online monitoring of self-motions and the generation of volitional saccades. In addition, the pathways through the central and the posterior thalamus appear to play a role in visuospatial attention that directly guides eye movements. We will describe recent findings and discuss the role for the thalamus in eye movements.
  • Jun Kunimatsu, Masaki Tanaka
    EUROPEAN JOURNAL OF NEUROSCIENCE 36 (9) 3258 - 3268 0953-816X 2012/11 [Refereed][Not invited]
     
    Although we can generate movements whenever we feel like doing so, the way in which neuronal signals regulate the timing of self-initiated movements remains elusive. There is evidence that the dorsomedial frontal cortex, including the supplementary eye field (SEF), is involved in the self-triggering of movements. Because the gradual evolution of cortical activity over the dorsomedial frontal cortex is known to reflect the temporal prediction of an upcoming event, we postulated that the timing of self-initiated movements is regulated by the time course of neuronal activity in the SEF. To test the causal role, we applied electrical microstimulation to the SEF when monkeys prepared for memory-guided saccades. Stimulation delayed the initiation of saccades when animals were required to make saccades 1200 +/- 300 ms following the cue (self-timed task), but not when they generated memory-guided saccades in response to the offset of the fixation point (conventional task). As well as the increment in median saccade latencies, stimulation at similar to 24% of sites also increased the occurrence of early erroneous saccades. Saccades facilitated by stimulation were always directed toward the cue, even when the cue was located away from the movement field. In contrast, stimulation to the frontal eye fields during saccade preparation exerted no effects in either task. These results suggest that the preparatory signals in the SEF may play a causal role in regulating the timing rather than the direction of self-initiated saccades.
  • Ayano Matsushima, Masaki Tanaka
    JOURNAL OF COGNITIVE NEUROSCIENCE 24 (10) 2043 - 2056 0898-929X 2012/10 [Refereed][Not invited]
     
    Resistance to distraction is a key component of executive functions and is strongly linked to the prefrontal cortex. Recent evidence suggests that neural mechanisms exist for selective suppression of task-irrelevant information. However, neuronal signals related to selective suppression have not yet been identified, whereas nonselective surround suppression, which results from attentional enhancement for relevant stimuli, has been well documented. This study examined single neuron activities in the lateral PFC when monkeys covertly tracked one of randomly moving objects. Although many neurons responded to the target, we also found a group of neurons that exhibited a selective response to the distractor that was visually identical to the target. Because most neurons were insensitive to an additional distractor that explicitly differed in color from the target, the brain seemed to monitor the distractor only when necessary to maintain internal object segregation. Our results suggest that the lateral PFC might provide at least two top-down signals during covert object tracking: one for enhancement of visual processing for the target and the other for selective suppression of visual processing for the distractor. These signals might work together to discriminate objects, thereby regulating both the sensitivity and specificity of target choice during covert object tracking.
  • Masaki Tanaka, Jun Kunimatsu
    EUROPEAN JOURNAL OF NEUROSCIENCE 33 (11) 2046 - 2057 0953-816X 2011/06 [Refereed][Not invited]
     
    Lesions in the motor thalamus can cause deficits in somatic movements. However, the involvement of the thalamus in the generation of eye movements has only recently been elucidated. In this article, we review recent advances into the role of the thalamus in eye movements. Anatomically, the anterior group of the intralaminar nuclei and paralaminar portion of the ventrolateral, ventroanterior and mediodorsal nuclei of the thalamus send massive projections to the frontal eye field and supplementary eye field. In addition, these parts of the thalamus, collectively known as the 'oculomotor thalamus', receive inputs from the cerebellum, the basal ganglia and virtually all stages of the saccade-generating pathways in the brainstem. In their pioneering work in the 1980s, Schlag and Schlag-Rey found a variety of eye movement-related neurons in the oculomotor thalamus, and proposed that this region might constitute a 'central controller' playing a role in monitoring eye movements and generating self-paced saccades. This hypothesis has been evaluated by recent experiments in non-human primates and by clinical observations of subjects with thalamic lesions. In addition, several recent studies have also addressed the involvement of the oculomotor thalamus in the generation of anti-saccades and the selection of targets for saccades. These studies have revealed the impact of subcortical signals on the higher-order cortical processing underlying saccades, and suggest the possibility of future studies using the oculomotor system as a model to explore the neural mechanisms of global cortico-subcortical loops and the neural basis of a local network between the thalamus and cortex.
  • Masaki Tanaka, Shogo Ohmae, Akiko Uematsu, B. Pharin
    Clinical Neurology 51 (11) 1121  0009-918X 2011 [Refereed][Not invited]
  • Jun Kunimatsu, Masaki Tanaka
    JOURNAL OF NEUROSCIENCE 30 (14) 5108 - 5117 0270-6474 2010/04 [Refereed][Not invited]
     
    In response to changes in our environment, we select from possible actions depending on the given situation. The underlying neural mechanisms for this flexible behavioral control have been examined using the antisaccade paradigm. In this task, subjects suppress saccades to the sudden appearance of visual stimuli (prosaccade) and make a saccade in the opposite direction. Because recent imaging studies showed enhanced activity in the thalamus and basal ganglia during antisaccades, we hypothesized that the corticobasal ganglia loop may be involved. To test this, we recorded from neurons in the paralaminar part of the ventroanterior (VA), ventrolateral (VL) and mediodorsal (MD) nuclei of the thalamus when 3 monkeys performed pro/antisaccade tasks. For many VL and some VA neurons, the firing rate was greater during anti-than prosaccades. In contrast, neurons in the MD thalamus showed much variety of responses. For the population as a whole, neuronal activity in the VA/VL thalamus was strongly enhanced during antisaccades compared with prosaccades, while activity in the MD nucleus was not. Inactivation of the VA/VL thalamus resulted in an increase in the number of error trials in the antisaccade tasks, indicating that signals in the motor thalamus play roles in the generation of antisaccades. Enhancement of firing modulation during antisaccades found in the thalamus and those reported previously in the supplementary eye field and the basal ganglia suggest a strong functional linkage between these structures. The neuronal processes through the thalamocortical pathways might be essential for the volitional control of saccades.
  • Atsushi Yoshida, Masaki Tanaka
    CEREBRAL CORTEX 19 (1) 206 - 217 1047-3211 2009/01 [Refereed][Not invited]
     
    The antisaccade task has been widely used to investigate the neural mechanisms underlying volitional movement control. In this task, subjects suppress reflexive saccades to the sudden appearance of peripheral visual stimuli (prosaccades) and generate a saccade in the opposite direction. Recent imaging studies suggest that the globus pallidus (GP) is involved in the generation of antisaccades. To understand the roles of the GP, we examined single neuron activity and the effects of local inactivation. Monkeys were trained to make either a pro- or antisaccade according to prior instruction provided by the color of the fixation point in each trial. Among 119 saccade-related neurons, 55% showed increased firing rates associated with saccades, whereas the remaining neurons showed decreased firing rates. For both populations of neurons, the activity modulation was enhanced during the preparation and execution of antisaccades, as compared with prosaccades. Inactivation of the recording sites in the external segment of the GP resulted in an increase in the number of error trials in the antisaccade tasks, suggesting that signals in the GP may play roles in suppressing inadequate prosaccades in the task. Signals in the GP might regulate eye movements through the nigro-collicular descending circuitry and through the basal ganglia-thalamocortical pathways.
  • Atsushi Yoshida, Masaki Tanaka
    NEUROREPORT 20 (2) 121 - 125 0959-4965 2009/01 [Refereed][Not invited]
     
    Although the roles of the basal ganglia in the control of saccadic eye movements have been extensively examined, little is known about their roles in smooth pursuit. Recent anatomical data suggest that, like somatic movements, smooth pursuit may also be regulated by signals through the basal ganglia thalamocortical pathways. To understand whether the basal ganglia, especially the globus pallidus (GP), could play roles in pursuit, we examined the firing of individual GP neurons when monkeys performed smooth pursuit. We found that a subset of neurons in both the external and the internal segments of the GP modulated firing during pursuit, suggesting that pathways through the GP might play roles in the control of smooth pursuit eye movements. NeuroReport 20:121-125 (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.
  • Masaki Tanaka
    JOURNAL OF NEUROSCIENCE 27 (44) 12109 - 12118 0270-6474 2007/10 [Refereed][Not invited]
     
    We often generate movements without any external event that immediately triggers them. How the brain decides the timing of self-initiated movements remains unclear. Previous studies suggest that the basal ganglia-thalamocortical pathways play this role, but the subcortical signals that determine movement timing have not been identified. The present study reports that a subset of thalamic neurons predicts the timing of self-initiated saccadic eye movements. When monkeys made a saccade in response to the fixation point ( FP) offset in the traditional memory saccade task, neurons in the ventrolateral and the ventroanterior nuclei of the thalamus exhibited a gradual buildup of activity that peaked around the most probable time of the FP offset; however, neither the timing nor the magnitude of neuronal activity correlated with saccade latencies, suggesting that the brain is unlikely to have used this information to decide the times of saccades in the traditional memory saccade task. In contrast, when monkeys were required to make a self-timed saccade within a fixed time interval after an external cue, the same neurons again exhibited a strong buildup of activity that preceded saccades by several hundred milliseconds, showing a close correlation between the times of neuronal activity and the times of self-initiated saccades. The results suggest that neurons in the motor thalamus carry subjective time information, which is used by cortical networks to determine the timing of self-initiated saccades.
  • Masaki Tanaka
    CEREBRAL CORTEX 17 (7) 1504 - 1515 1047-3211 2007/07 [Refereed][Not invited]
     
    Although both sensory and motor signals in multiple cortical areas are modulated by eye position, the origin of eye position signals for cortical neurons remains uncertain. One likely source is the central thalamus, which contains neurons sensitive to eye position. Because the central thalamus receives inputs from the brainstem, these neurons may transmit eye position signals arising from the neural integrator or from proprioceptive feedback. However, because the central thalamus also receives inputs from many cortical areas, eye position signals in the central thalamus could come from the cerebral cortex. To clarify these possibilities, spatial and temporal properties of eye position signals in the central thalamus were examined in trained monkeys. Data showed that eye position signals were decomposed into horizontal and vertical components, suggesting that the central thalamus lies within pathways that transmit brainstem eye position signals to the cortex. Further quantitative analyses suggested that 2 distinct groups of thalamic neurons mediate eye position signals from different subcortical origins, and that the signals are modified dynamically through ascending pathways. Eye position signals through the central thalamus may play essential roles in spatial transformation performed by cortical networks.
  • M Tanaka
    NATURE NEUROSCIENCE 9 (1) 20 - 22 1097-6256 2006/01 [Refereed][Not invited]
     
    The central thalamus transmits corollary discharge signals for eye movement control, but its role in eye movement generation remains uncertain. Inactivation of the paralaminar part of the ventrolateral thalamus delayed the initiation of contraversive saccades, particularly during a new memory-guided saccade task that required self-triggering of the movement. The results suggest that signals through the thalamus regulate the timing of self-initiated saccades.
  • M Tanaka
    NEUROREPORT 16 (12) 1261 - 1265 0959-4965 2005/08 [Refereed][Not invited]
     
    Neurons in the parietal cortex represent spatial memory of visual stimuli in an eye-centered coordinate frame. To preserve spatial stability across eye movements, spatial memory must be updated during each eye movement. Because eye movement signals in the parietal cortex are known to be modulated by eye position in the orbit, estimates of eye displacement on the basis of these signals could also be influenced by eye position. The present study examined the possible effect of eye position on the accuracy of memory-guided saccades in monkeys following saccades or smooth pursuit during the memory period. The results showed that eye position has a modest effect on saccade localization, suggesting that eye position signal plays a modulatory role in updating visuospatial working memory.
  • M Tanaka
    JOURNAL OF NEUROSCIENCE 25 (25) 5866 - 5876 0270-6474 2005/06 [Refereed][Not invited]
     
    During maintenance of smooth pursuit eye movements, the brain must keep track of pursuit velocity to reconstruct target velocity from motion of retinal images. Although a recent study showed that corollary discharge signals through the thalamus to the cortex are used for internal monitoring of saccades, it remains unknown whether signals in the thalamus also contribute to monitoring and on-line regulation of smooth pursuit. The present study sought possible roles of the thalamocortical pathways in pursuit by recording activities of single thalamic neurons and by analyzing the effects of local inactivation. Data showed that many neurons in the ventrolateral thalamus exhibited directional modulation during pursuit. Most neurons discharged before or during initiation of pursuit, and the firing rate was proportional to the speed of target motion in a preferred direction. When the tracking target was extinguished briefly during maintenance of pursuit, these neurons continued firing, indicating that they carried extra-retinal, eye movement signals. The majority of neurons showed no change in activity around the time of small catch-up saccades during pursuit but responded transiently to large (16 degrees) memory-guided saccades in the preferred pursuit direction. Local inactivation of the recording sites did not alter pursuit latency but reduced eye velocity modestly during initiation and maintenance of ipsiversive pursuit. The results suggest that the central thalamus lies within pathways that regulate and monitor smooth pursuit eye movements.
  • M Tanaka
    JOURNAL OF NEUROPHYSIOLOGY 90 (3) 2080 - 2086 0022-3077 2003/09 [Refereed][Not invited]
     
    Information about ongoing behavior is necessary for stable perception and subsequent motor planning. Although many recurrent networks are known in the motor systems, the pathways that transmit the signals for internal monitoring of behavior are not specified. The present study reports that the pathways originating from sites downstream of cerebellar adaptation provide internal signals that are used for subsequent eye-movement programming. When monkeys made two successive saccades toward the locations of previously flashed targets or initial fixation, the second saccade compensated for the adaptive changes in the primary saccade. The use of signals downstream from adaptation for saccade programming contrasts with recent findings that signals upstream from adaptation control the perceptual localization of visual stimuli presented around the time of saccade, suggesting that separate recurrent networks provide behavioral information for perception versus movement programming.
  • M Tanaka, SG Lisberger
    JOURNAL OF NEUROPHYSIOLOGY 87 (6) 2684 - 2699 0022-3077 2002/06 [Refereed][Not invited]
     
    Anatomical and physiological studies have shown that the "frontal pursuit area" (FPA) in the arcuate cortex of monkeys is involved in the control of smooth pursuit eye movements. To further analyze the signals carried by the FPA, we examined the activity of pursuit-related neurons recorded from a discrete region near the arcuate spur during a variety of oculomotor tasks. Pursuit neurons showed direction tuning with a wide range of preferred directions and a mean full width at half-maximum of 129degrees. Analysis of latency using the "receiver operating characteristic" to compare responses to target motion in opposite directions showed that the directional response of 58% of FPA neurons led the initiation of pursuit, while 19% led by 25 ms or more. Analysis of neuronal responses during pursuit of a range of target velocities revealed that the sensitivity to eye velocity was larger during the initiation of pursuit than during the maintenance of pursuit, consistent with two components of firing related to image motion and eye motion. FPA neurons showed correlates of two behavioral features of pursuit documented in prior reports. 1) Eye acceleration at the initiation of pursuit declines as a function of the eccentricity of the moving target. FPA neurons show decreased firing at the initiation of pursuit in parallel with the decline in eye acceleration. This finding is consistent with prior suggestions that the FPA plays a role in modulating the gain of visual-motor transmission for pursuit. 2) A stationary eccentric cue evokes a smooth eye movement opposite in direction to the cue and enhances the pursuit evoked by subsequent target motions. Many pursuit neurons in the FPA showed weak, phasic visual responses for stationary targets and were tuned for the positions about 4degrees eccentric on the side opposite to the preferred pursuit direction. However, few neurons (12%) responded during the preparation or execution of saccades. The responses to the stationary target could account for the behavioral effects of stationary, eccentric cues. Further analysis of the relationship between firing rate and retinal position error during pursuit in the preferred and opposite directions failed to provide evidence for a large contribution of image position to the firing of FPA neurons. We conclude that FPA processes information in terms of image and eye velocity and that it is functionally separate from the saccadic frontal eye fields, which processes information in terms of retinal image position.
  • M Tanaka, SG Lisberger
    JOURNAL OF NEUROPHYSIOLOGY 87 (6) 2700 - 2714 0022-3077 2002/06 [Refereed][Not invited]
     
    When monkeys view two targets moving in different directions and are given no cues about which to track, the initiation of smooth pursuit is a vector average of the response evoked by each target singly. In the present experiments, double-target stimuli consisted of two identical targets moving in opposite directions along the preferred axis of pursuit for the neuron under study for 200 ms, followed by the continued motion for 800 ms of one target chosen randomly. Among the neurons that showed directional modulation during pursuit, recordings revealed three groups. The majority (32/60) showed responses that were intermediate to, and statistically different from, the responses to either target presented alone. Another large group (22/60) showed activity that was statistically indistinguishable from the response to the target moving in the preferred (n = 15) or opposite (n = 7) direction of the neuron under study. The minority (6/60) showed statistically higher firing during averaging pursuit than for either target presented singly. We conclude that many pursuit-related neurons in the frontal pursuit area (FPA) carry signals related to the motor output during averaging pursuit, while others encode the motion of one target or the other. Microstimulation with 200-ms trains of pulses at 50 muA while monkeys performed the same double-target tasks biased the averaging eye velocity in the direction of evoked eye movements during fixation. The effect of stimulation was compared with the predictions of three different models that placed the site of vector averaging upstream from, at, or downstream from the sites where the FPA regulates the gain of pursuit. The data were most consistent with a site for pursuit averaging downstream from the gain control, both for double-target stimuli that presented motion in opposite directions and in orthogonal directions. Thus the recording and stimulation data suggest that the FPA is both downstream and upstream from the sites of vector averaging. We resolve this paradox by suggesting that the site of averaging is really downstream from the site of gain control, while feedback of the eye velocity command from the brain stem and/or cerebellum is responsible for the firing of FPA neurons in relation to the averaged eye velocity. We suggest that eye velocity feedback allows FPA neurons to continue firing during accurate tracking, when image motion is small, and that the persistent output from the FPA is necessary to keep the internal gain of pursuit high and permit accurate pursuit.
  • M Tanaka, SG Lisberger
    JOURNAL OF NEUROPHYSIOLOGY 87 (2) 802 - 818 0022-3077 2002/02 [Refereed][Not invited]
     
    Periarcuate frontal cortex is involved in the control of smooth pursuit eye movements, but its role remains unclear. To better understand the control of pursuit by the "frontal pursuit area" (FPA), we applied electrical microstimulation when the monkeys were performing a variety of oculomotor tasks. In agreement with previous studies, electrical stimulation consisting of a train of 50-muA pulses at 333 Hz during fixation of a stationary target elicited smooth eye movements with a short latency (similar to26 ms). The size of the elicited smooth eye movements was enhanced when the stimulation pulses were delivered during the maintenance of pursuit. The enhancement increased as a function of ongoing pursuit speed and was greater during pursuit in the same versus opposite direction of the eye movements evoked at a site. If stimulation was delivered during pursuit in eight different directions, the elicited eye velocity was fit best by a model incorporating two stimulation effects: a directional signal that drives eye velocity and an increase in the gain of ongoing pursuit eye speed in all directions. Separate experiments tested the effect of stimulation on the response to specific image motions. Stimulation consisted of a train of pulses at 100 or 200 Hz delivered during fixation so that only small smooth eye movements were elicited. If the stationary target was perturbed briefly during microstimulation, normally weak eye movement responses showed strong enhancement. If delivered at the initiation of pursuit, the same microstimulation caused enhancement of the presaccadic initiation of pursuit for steps of target velocity that moved the target either away from the position of fixation or in the direction of the eye movement caused by stimulation at the site. Stimulation in the FPA increased the latency of saccades to stationary or moving targets. Our results show that the FPA has two kinds of effects on the pursuit system. One drives smooth eye velocity in a fixed direction and is subject to on-line gain control by ongoing pursuit. The other causes enhancement of both the speed of ongoing pursuit and the responses to visual motion in a way that is not strongly selective for the direction of pursuit. Enhancement may operate either at a single site or at multiple sites. We conclude that the FPA plays an important role in on-line gain control for pursuit as well as possibly delivering commands for the direction and speed of smooth eye motion.
  • M Tanaka, SG Lisberger
    NATURE 409 (6817) 191 - 194 0028-0836 2001/01 [Refereed][Not invited]
     
    In studies of the neural mechanisms giving rise to behaviour, changes in the neural and behavioural responses produced by a given stimulus have been widely reported. This `gain control' can boost the responses to sensory inputs that are particularly relevant(1-4), select among reflexes for execution by motoneurons(5,6) or emphasize specific movement targets(7). Gain control is also an integral part of the smooth-pursuit eye movement system(8-13). One signature of gain control is that a brief perturbation of a stationary target during fixation causes tiny eye movements, whereas the same perturbation of a moving target during the active state of accurate pursuit causes large responses(9). Here we show that electrical stimulation of the smooth-pursuit eye movement region in the arcuate sulcus of the frontal lobe (`the frontal pursuit area', FPA) mimics the active state of pursuit. Such stimulation enhances the response to a brief perturbation of target motion, regardless of the direction of motion. We postulate that the FPA sets the gain of pursuit, thereby participating in target selection for pursuit.
  • M Tanaka, SG Lisberger
    JOURNAL OF NEUROPHYSIOLOGY 84 (4) 1748 - 1762 0022-3077 2000/10 [Refereed][Not invited]
     
    The appearance of a stationary but irrelevant cue triggers a smooth eye movement away from the position of the cue in monkeys that have been trained extensively to smoothly track the motion of moving targets while not making saccades to the stationary cue. We have analyzed the parameters that regulate the size of the cue-evoked smooth eye movement and examined whether presentation of the cue changes the initiation of pursuit for subsequent steps of target velocity. Cues evoked smooth eye movements in blocks of target motions that required smooth pursuit to moving targets, but evoked much smaller smooth eye movements in blocks that required saccades to stationary targets. The direction of the cue-evoked eye movement was always opposite to the position of the cue and did not depend on whether subsequent target motion was toward or away from the position of fixation. The latency of the cue-evoked smooth eye movement was near 100 ms and was slightly longer than the latency of pursuit for target motion away from the position of fixation. The size of the cue-evoked smooth eye movement was as large as 10 degrees/s and decreased as functions of the eccentricity of the cue and the illumination of the experimental room. To study the initiation of pursuit in the wake of the cues, we used bilateral cues at equal eccentricities to the right and left of the position of fixation. These evoked smaller eye velocities that were consistent with vector averaging of the responses to each cue. In the wake of bilateral cues, the initiation of pursuit was enhanced for target motion away from the position of fixation, but not for target motion toward the position of fixation. We suggest that the cue-evoked smooth eye movement is related to a previously postulated on-line gain control for pursuit, and that it is a side-effect of sudden activation of the gain-controlling element.
  • M Tanaka, T Yoshida, K Fukushima
    EXPERIMENTAL BRAIN RESEARCH 121 (1) 92 - 98 0014-4819 1998/07 [Refereed][Not invited]
     
    To examine the effects of smooth-pursuit eye movements on the initiation of saccades, their latency was measured when subjects initially fixated or pursued a target. In half of the block of trials, the fixation or pursuit target was extinguished 200 ms before the saccade tar-eel was illuminated (gap trials). Reduction of the mean saccade latency in the gap trials (the "gap effect") was evident even when the subjects were pursuing a moving target. consistent with previous observations. The effect of pm-suit direction on saccade latency was also examined. Saccades in the same direction as the preceding pursuit (forward saccades) had shorter latencies than those in the opposite direction (backward saccades). This asymmetry was observed in both the gap and nongap trials. Although the forward-backward asymmetry was much smaller than the "gap effect", it was statistically significant in six of eight cases. These results suggest that the preparation of saccades is affected by smooth-pursuit eye movements.
  • M Tanaka, K Fukushima
    JOURNAL OF NEUROPHYSIOLOGY 80 (1) 28 - 47 0022-3077 1998/07 [Refereed][Not invited]
     
    To examine how the periarcuate area is involved in the control of smooth pursuit eye movements, we recorded 177 single neurons while monkeys pursued a moving target in the dark. The majority (52%, 92/177) of task-related neurons responded to pursuit but had little or no response to saccades. Histological reconstructions showed that these neurons were located mainly in the posterior bank of the arcuate sulcus near the sulcal spur. Twenty-seven percent (48/ 177) changed their activity at the onset of saccades. Of these, 36 (75%) showed presaccadic burst activity with strong preference for contraversive saccades. Eighteen (10%, 18/177) were classified as eye-position-related neurons, and 11% (19/177) were related to other aspects of the stimuli or response. Among the 92 neurons that responded to pursuit, 85 (92%) were strongly directional with uniformly distributed preferred directions. Further analyses were performed in these directionally sensitive pursuit-related neurons. For 59 neurons that showed distinct changes in activity around the initiation of pursuit, the median latency from target motion was 96 ms and that preceding pursuit was -12 ms, indicating that these neuron can influence the initiation of pursuit. We tested some neurons how briefly extinguishing the tracking tar et (n = 39) or controlling its movement with the eye position signal (n = 24). The distribution of the change in pursuit-related activity was similar to previous data for the dorsomedial part of the medial superior temporal neurons (Newsome et al. 1988), indicating that pursuit-related neurons in the periarcuate area also carry extraretinal signals. For 22 neurons, we examined the responses when the animals reversed pursuit direction to distinguish the effects of eye acceleration in the preferred direction from oppositely directed eye velocity. Almost all neurons discharged before eye velocity reached zero, however, only nine neurons discharged before the eyes were accelerated in the preferred direction. The delay in neuronal responses relative to the onset of eye acceleration in these trials might be caused by suppression from oppositely directed pursuit velocity. The results suggest that the periarcuate neurons do not participate in the earliest stage of eye acceleration during the change in pursuit direction, although most of them may participate in the early stages of pursuit initiation in the ordinary step-ramp pursuit trials. Some neurons changed their activity when the animals fixated a stationary target, and this activity could be distinguished easily from the strong pursuit-related responses. Our results suggest that the periarcuate pursuit area carries extraretinal signals and affects the premotor circuitry for smooth pursuit.
  • M Tanaka, K Fukushima
    NEUROSCIENCE RESEARCH 29 (1) 93 - 98 0168-0102 1997/09 [Refereed][Not invited]
     
    We examined the influence of a peripheral visual stimulus on eye movement while monkeys performed a horizontal step-ramp pursuit task. When an irrelevant visual stimulus was presented before the onset of the target motion, slow eye movement away from the stimulus was observed. When the stimulus appeared during a temporal gap between the offset of the fixation point and the onset of target motion, the velocity of the slow eye movement increased. The onset of the movement was time-locked to the onset of the extraneous visual stimulus and its latency was comparable to the latency of smooth pursuit in trials without a peripheral stimulus. The results demonstrate a new form of smooth eye movement, suggesting that the eye movement may be contained in the initial stages of smooth pursuit observed in step-ramp paradigms. (C) 1997 Elsevier Science Ireland Ltd.
  • K Fukushima, M Tanaka, Y Suzuki, J Fukushima, T Yoshida
    NEUROSCIENCE RESEARCH 25 (4) 391 - 398 0168-0102 1996/08 [Refereed][Not invited]
     
    Adaptive changes in initial eye velocity of pursuit eye movement were examined in nine normal subjects using a target that moved in a multiple ramp fashion. Significant changes in initial eye velocity occurred rapidly after training in six of the subjects. The magnitude and direction of the induced changes were a function of the training conditions. Adaptive changes started 100-200 ms after onset of pursuit eye movement (usually 140 ms), suggesting that the late (but not early) component of initial eye velocity was under adaptive control by our training paradigms.
  • K Fukushima, S Chin, J Fukushima, M Tanaka
    NEUROSCIENCE RESEARCH 24 (3) 275 - 289 0168-0102 1996/02 [Refereed][Not invited]
     
    To understand how the cerebellar flocculus is involved in the processing of semicircular canal signals in the vertical vestibule-ocular reflex (VOR), we analyzed the simple-spike activity of floccular Purkinje (P) cells that was modulated by sinusoidal pitch rotation, and then analyzed their activity during presentation of sinusoidal vertical optokinetic stimuli in alert, head-fixed cats. The great majority of P cells also responded to optokinetic stimuli with peak discharge near peak stimulus velocity. Eighty percent of P cells that responded to both pitch and optokinetic stimuli showed increased activity when the directions of the resultant eye movements were the same. During rapid modification of the VOR induced by visual pattern movement, modulation amplitudes of the cells tested increased together with the eye velocity increase. Maximal activation directions of these cells studied during vertical rotation in many planes were near the vertical canal planes, similar to those in our previous studies. The remaining 20% of P cells showed increased discharge for the same direction of stimulus movement. These results suggest that the activity of the majority of pitch-responding P cells contains, at least partly, a vertical eye velocity component during presentation of vestibular or optokinetic stimuli in addition to canal inputs during pitch rotation.
  • Fukushima, K, Chin, S, Fukushima, J, Tanaka, M, Kurkin, S, Norita, M, B, o, T, Stein, BE
    Extrageniculostriate Mechanisms Underlying Visually-Guided Orientation Behavior 112 1996

MISC

  • 澤頭 亮, 田中 真樹  BRAIN and NERVE: 神経研究の進歩  76-  (6)  0709  -0714  2024/06  
    ＜文献概要＞視覚探索の効率を上げるためには,一度見たものを記憶し,再び注意が向かないようにする必要がある。多数の物体の中から標的を探し出す採餌課題中の二度見行動に着目し,短期記憶の容量,忘却率,利用率を定量化する方法を考案した。サルの採餌行動の成績はケタミン投与で低下し,ニコチン投与で向上したが,いずれも短期記憶の利用率の変化を伴っていた。複雑な教示を必要としない本課題を用いれば,さまざまな被験者で作業記憶を定量化できる。
  • 【神経疾患における時間認知障害】時間知覚と予測の神経機構
    田中 真樹, 岡田 研一, 亀田 将史  脳神経内科  100-  (6)  563  -571  2024/06
  • 【時間の神経科学-時を生み出すこころと脳の仕組み】時間の心理学と神経科学 同期運動とリズム知覚の神経機構
    田中 真樹, 岡田 研一, 亀田 将史  Clinical Neuroscience  41-  (8)  1044  -1047  2023/08
  • 田中 真樹  北海道医学雑誌  93-  94  2018  [Not refereed]
  • 北澤 茂, 田中 真樹, 河村 満  BRAIN and NERVE  69-  (11)  1177  -1185  2017/11/01
  • Masaki Tanaka, Tomoki W. Suzuki, Masashi Kameda, Ryuji Takeya  Brain and Nerve  69-  (11)  1213  -1222  2017/11/01  [Not refereed][Not invited]
     
    When waiting for a traffic light or dancing to a musical beat, we unconsciously keep track of elapsed time and precisely predict the timing of forthcoming sensory events. Temporal monitoring and prediction are integral to our daily life, and are regulated by neuronal processes through multiple global networks involving the frontoparietal cortices, the basal ganglia and the cerebellum. These processes are also known to be influenced by a variety of internal state and neuromodulators. Here, we review recent advance of research in the field.
  • 竹谷隆司, 田中真樹  Clinical Neuroscience  35-  (8)  938‐940  2017/08/01  [Not refereed][Not invited]
  • 松嶋 藻乃, 田中 真樹  北海道醫學雜誌 = Acta medica Hokkaidonensia  88-  (4)  143  -143  2013/09/01
  • 田中真樹, 國松淳, 大前彰吾  Brain Nerve  65-  (8)  941  -948  2013/08/01  [Not refereed][Not invited]
  • 松嶋 藻乃, 田中 真樹  2012/12  [Refereed][Invited]
  • 松嶋 藻乃, 田中 真樹  北海道醫學雜誌 = Acta medica Hokkaidonensia  87-  (6)  282  -282  2012/11/01
  • 國松 淳, 田中 真樹  北海道醫學雜誌 = Acta medica Hokkaidonensia  87-  (6)  283  -283  2012/11/01  [Not refereed][Not invited]
  • 國松淳, 田中真樹  比較生理生化学  29-  (4)  2012
  • Jun Kunimatsu, Masaki Tanaka  Brain and Nerve  63-  (8)  871  -877  2011/08/01  [Not refereed][Not invited]
     
    Although the roles of the thalamocortical pathways in somatic movements are well documented, their roles in eye movements have only recently been examined. The oculomotor-related areas in the frontal cortex receive inputs from the basal ganglia and the cerebellum via the thalamus. Consistent with this, neurons in the paralaminar part of the ventrolateral (VL), ventroanterior (VA), and mediodorsal (MD) nuclei and those in the intralaminar nuclei exhibit a variety of eye movement-related responses. To date, the thalamocortical pathways are known to play at least 2 roles in eye movements. First, they are involved in the generation of volitional, but not reactive, saccades. Thalamic neurons discharge during anti-saccades, which are known to be impaired in several neurological and psychiatric disorders, such as Parkinson's disease, attention deficit/hyperactivity disorder, and schizophrenia. In addition, neurons in the thalamus also exhibit a gradual increase in firing rate that predicts the timing of self-initiated saccades. Recent inactivation experiments have established the causal roles of these thalamic signals in the generation of volitional saccades. Second, the thalamocortical pathways transmit the efference copy signals for eye movements. During inactivation of the MD thalamus, which relays signals from the superior colliculus to the frontal eye field (FEF), the accuracy of the saccade is reduced in tasks requiring efference copy signals. In addition, inactivation of the same pathways reduces the predictive visual response associated with saccades in neurons in the FEF. Moreover the VL thalamus has been reported to play a role in monitoring smooth pursuit. While the functional analysis of thalamocortical pathways in eye movements is just a beginning, the anatomical data suggest their important roles. Analysis of eye movement control may shed light on the functions of the thalamocortical pathways in general, and may reveal the neural mechanisms of cerebro-cerebellar, cerebro-basal ganglia, and cerebro-thalamic interactions.
  • 田中 真樹  日本生理学雜誌  73-  (3)  54  -55  2011/03/01
  • 田中 真樹  日本生理学雜誌  70-  (2)  2008/02/01  [Not refereed][Not invited]

Books etc

Association Memberships

  • 北米神経科学学会   PHYSIOLOGICAL SOCIETY OF JAPAN   THE JAPAN NEUROSCIENCE SOCIETY   日本小脳学会   

Research Projects

  • 日本学術振興会：科学研究費助成事業
    Date (from‐to) : 2024/04 -2029/03 
    Author : 田中 真樹
  • 科学技術振興機構：戦略的な研究開発の推進 戦略的創造研究推進事業 CREST
    Date (from‐to) : 2023 -2028 
    Author : 田中 真樹
     
    周期的な感覚刺激は、リズム知覚を生じさせ、運動を引き込み、注意や視知覚を変化させ、脳の可塑性を誘導します。本研究では、周期的な刺激が知覚、運動、脳波を引き込む機序を解明し、これを利用したリハビリテーション治療法や日常生活における知覚や注意の操作法を開発します。また、周期的な錯視から脳波を推定する技術を開発し、スマホに実装することで脳波と関連づけたビッグデータを構築し、新たな疫学研究につなげます。
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (A)
    Date (from‐to) : 2021/04 -2025/03 
    Author : 田中 真樹
     
    「慎重を要する状況における行動の制御に外側小脳と前頭葉皮質の機能連関が関与する」との作業仮説を検証する。突然現れる視覚刺激と反対方向に眼球運動を行うアンチサッカード課題をサルに訓練し、その次の試行で視覚刺激に向かうプロサッカードの潜時が延長することを行動抑制の指標として一連の実験を行う。実験は、所属機関が設置する動物実験委員会の事前の審査と承認を受けて行う。
    当初の予定どおり、現在までに、アンチサッカード課題を訓練した1頭のサルの小脳歯状核から記録を行うとともに、補足眼野に多点電極を刺入して局所場電位（LFP）記録を行っている。これまでに、眼球運動の方向や種類、エラー試行、あるいは反応時間によって活動を変化させる小脳核ニューロンを少数ながら記録している。また、エラーに関連した大脳LFP成分を抽出することに成功している。ただし、前試行の行動への影響は小さく、引き続きより適切な課題パラメータを探索するとともに、LFPデータのさらに詳細な解析が必要と考えている。また、これまでニューロン記録は小脳核の背側を中心に行っており、今後、大脳連合野との関連が強いより腹側も探索する。令和4年度は、新たな個体を訓練し、2頭からのデータを蓄積することを第一の目標とする。小脳歯状核の電気刺激を行い、大脳LFPの応答性を調べる。行動の成否に加え、反応時間との神経相関を詳しく調べるとともに、今年度中に多点電極による小脳核の単一ニューロン記録を試みる。また、小脳皮質に興奮性オプシンを発現させるための諸条件を共同研究者とともに調査する。インタクトな個体に種々の条件でベクター接種を行い、小脳核終末での光刺激に対する応答変化と小脳Purkinje細胞のオプシンの発現を確認することを予定している。
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2022/06 -2024/03 
    Author : 田中 真樹
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
    Date (from‐to) : 2018/06 -2023/03 
    Author : 田中 真樹, 村上 郁也, 寺尾 安生, 天野 薫
     
    本計画研究では、時間情報の脳内機構を多面的に調べている。二年目の今年度は、これまでの研究を継続しつつ、新たな実験課題に着手した。 研究代表者の田中（神経生理学）らは、サル用の大型ケージを整備して研究の効率化を図るとともに、新たに大脳皮質をターゲットとした実験を開始した。また、リズム知覚に関連した線条体・小脳核の神経活動や眼球運動を用いた時間学習について論文を発表した。 研究分担者の村上（実験心理学）らは、秒未満の時間知覚について、オンセット時刻、持続時間、明滅テンポの知覚の観点から心理物理実験を行い、これらの心理量と他の認知機能との関係を調べた。特に、高精度で知覚時刻を実測する方法を開発し、錯視を用いて注意の移動に伴う時間知覚の変容を定量化した。その結果、復帰抑制によって標的への反応が遅れる効果が、標的のオンセットの知覚の遅れによって説明できることがわかった。 寺尾（病態生理学）らは、パーキンソニズムを呈する神経疾患患者で時間生成・再生課題・二分課題を行い、秒単位の記憶を伴う課題の成績が症状の進行とともに低下することを見出した。また、健常者で時間幅を実際と違う時間長として学習する誤学習課題を行い、学習保持の時間経過を調べた。学習前に４連発パターン磁気刺激で右一次運動野、前頭前野、側頭頭頂接合部を刺激すると前頭前野の刺激時のみ誤学習保持の時間が延長することを発見した。 天野（先端脳計測）らは、時間的に近接して呈示される二つのターゲット刺激（例えば数字）を検出する課題において、二つ目のターゲットを見落としやすくなる注意の瞬きと呼ばれる現象を用いて、視知覚のリズムについて検討した。その結果、二つ目のターゲット刺激の検出成績が、ターゲット刺激間の時間差に応じて周期的に変動し、その変動周波数は課題に関係のない妨害刺激（例えば文字）の有無によって変化することを見出した。
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)
    Date (from‐to) : 2017/04 -2020/03 
    Author : TANAKA MASAKI
     
    The basal ganglia are essential for adjusting the size and speed of movements along with selecting actions for given situations. During preparation of self-timed eye movements, we found that the time course of neuronal activity in the striatum differed from that in the cerebellar nucleus; the former was scaled by the length of time to be measured, while the latter correlated with trial-by-trial latency variation. We also found that the low-frequency components of local field potentials and visual evoked responses recorded from the striatum dynamically changed according to the length of time to be measured. On the other hand, the striatal evoked response to electrical stimulation of the cortex was too small to investigate the effects of behavioral conditions, so future studies should consider the use of optogenetic manipulation.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
    Date (from‐to) : 2018/04 -2019/03 
    Author : 田中 真樹
     
    リズム知覚のような周期的な時間情報を処理する神経機構を調べる目的で研究を行った。一定間隔であらわれる視覚刺激の欠落を検出するようにサルを訓練し（欠落オドボール課題）、これまでの研究で小脳核と尾状核から記録してきた繰り返し刺激に対して振幅を漸増させる周期活動について、新たな行動課題を用いてその特性を調べた。これまでに、小脳は感覚刺激の方向、線条体は運動の方向によって周期活動の振幅を変化させることを見出している。これらの実験は現在も継続中であり、平成30年7月に採択された新学術領域研究「時間生成学」の中で、計画研究「知覚や講堂に伴う心的時間の脳内機構とその操作」の一部としてさらに発展させる予定である。また、時間の情報処理に関連して、単一時間長を測定する際の線条体と小脳のニューロン活動を調べ、論文として発表した。同課題中に、本新学術領域（オシロロジー領域）と関連の深い線条体の集合電位の周期活動を発見し、現在論文を投稿している。さらに、今年度は周期的に呈示される視覚刺激に同期して眼球運動をおこなわせ、その詳細な行動解析を行うとともに小脳核からの神経活動記録を行い、本領域の班会議で報告した。以上の研究成果の一部は6月と7月にそれぞれ日本生体医工学会と日本神経科学学会でも発表した。
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2013/06 -2018/03 
    Author : KITAZAWA Shigeru, TANAKA Masaki, KAWAMURA Mitsuru, OTSU Yukio, IKEGAYA Yuji, NAKANO Tamami, NISHIYAMA Yuji, MURAKAMI Ikuya, HIRATA Satoshi, YOTSUMOTO Yuko
     
    We refer to the awareness of time, over the past, present and future, as the “mental time”. The mental time is a cognitive function that has been evolved in humans in particular. In this research project, we aimed at constructing a new research area “the science of the mental time”, through active collaborations across neuroscientists, psychologists, clinical neurologists, linguists, philosophers, and comparative ethologists. The five-year collaborative project across seven programmed and 58 proposed research teams produced more than 380 research papers, and achieved three major goals. (1) We drew the map of the mental time on the medial surface of the cerebral cortex that extended over the cingulate cortex, precuneus, retrosplenial cortex, and the hippocampus. (2) We developed a method for manipulating the mental time using lab animals, and initiated clinical applications. (3) We revealed the process of evolution and development of the episodic-like memory.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
    Date (from‐to) : 2013/06 -2018/03 
    Author : Tanaka Masaki, KUNIMATU JUN, TAKEYA RYUJI, OHMAE SHOGO, YOSHIDA ATSUSHI, MATSUSHIMA AYANO, UEMATSU AKIKO, MATSUYAMA KEI, SUZUKI TOMOKI, KAMEDA MASASHI
     
    Temporal monitoring and prediction of event timing are essential for behavioral control in daily life. In this study, we examined neuronal activity in the striatum and the cerebellar dentate nucleus in monkeys performing a variety of timing tasks. We also conducted behavioral experiments exploring the relationship between pupil diameter and subjective passage of time, neural mechanism of rhythm perception, and the capability of synchronized movements in nonhuman primates. Through these studies in the field of neuroscience, we could contribute to the advancement of The Science of Mental Time.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Research Activity Start-up
    Date (from‐to) : 2015/08 -2017/03 
    Author : Takeya Ryuji, TANAKA Masaki
     
    The objective of the present study is to uncover neural mechanisms of deployment of spatio-temporal attention by single cell recording from monkeys. To achieve the task, it is necessary to develop cognitive task for monkeys and identify neural mechanisms of internal time estimation. The applicant trained monkeys synchronized saccade task in which they synchronize their eye movement with isochronously and alternatively presented left or right side targets. As results, monkeys learned the task. Moreover, the applicant recorded from cerebellum where have been considered as a part of neural mechanisms of synchronized movement, and found neural activation for adjustment of movement interval for synchronized movement.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research
    Date (from‐to) : 2014/04 -2017/03 
    Author : Tanaka Masaki, KUNIMATU JUN, TAKEYA RYUJI, ISHIKAWA MASAYORI, MIYAMOTO NAOKI
     
    Experimental technique to produce focal brain lesions may provide opportunities for future research exploring mechanisms of brain function and recovery from injury. As a candidate method, we evaluated the radiosurgical technique. We also tried to develop behavioral and electrophysiological techniques to examine subcortical brain functions, and explored new methods to generate focal brain lesions. We evaluated the oculomotor behavior in monkeys up to 8 months following irradiation to the frontal eye field. In addition, we have developed several behavioral tasks and a method to record cortical potentials through epi-dural electrodes, both of which are usable to detect subcortical dysfunction. Further, we performed a feasible study of chemogenetic application to monkeys by injecting a viral vector into the cerebellum. Through these studies, we could obtain valuable information for future studies.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2012/04 -2015/03 
    Author : KURKIN SERGEY, TANAKA Masaki, SASAKI Hidenao, YABE Ichiro, UEMATSU Akiko, MATSUYAMA Kei, YOSHIDA Atsushi, ITOH Sayaka, MATSUSHIMA Ayano
     
    The cerebellum is interconnected with the association areas in the frontal and parietal cortices, and therefore is thought to play roles in non-motor cognitive functions such as time perception and prediction. We devised a variety of psychophysical tests to evaluate cerebellar cognitive functions and examined the performance of patients with spinocerebellar degeneration (type 6). We found that some behavioral parameters differed significantly between patents and matched controls, and correlated with the volume of lateral cerebellum (Crus I and II). Furthermore, we trained monkeys in similar behavioral paradigms for future physiological studies.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)
    Date (from‐to) : 2011/04 -2015/03 
    Author : TANAKA Masaki, KUNIMATSU Jun, OHMAE Shogo, UEMATSU Akiko, MATSUYAMA Kei
     
    Both the basal ganglia and cerebellum play roles in time perception and temporal control of movements. We trained monkeys to report the time interval by making eye movements, and compared neuronal activity in the striatum and the cerebellar nucleus. The time course of neuronal activity in the striatum strongly depended on the time interval to be reported, while that in the cerebellum did not. Effects of local application of neuroactive agents to the recording sites were also examined. Neuronal activity related to temporal prediction was also recorded in monkeys that attempted to detect single omission of repetitive audiovisual stimuli.
  • 日本学術振興会：科学研究費助成事業 新学術領域研究(研究領域提案型)
    Date (from‐to) : 2012/04 -2014/03 
    Author : 田中 真樹
     
    外界の出来事を予測し、適切なタイミングで意思決定を行うためには、時間の情報が不可欠である。本研究では、主にサルを用いて時間情報処理に関わる脳内機構を２種類の行動課題で調べた。 第一の研究では、一定の時間間隔で現れる視聴覚刺激の不意の欠落を検出させる（欠落オドボール課題）。これには試行ごとに異なる刺激間隔を学習し、次に現れる刺激のタイミングを予測し、欠落に対して予測誤差の信号を生成する必要がある。これまでに、小脳歯状核に刺激提示の時間間隔をコードするニューロン群を見いだしており、H25年度はこれをJ Neurosci誌に発表した。さらに本研究では運動性視床の神経活動を解析し、一定の成果をあげることができた。視床ニューロンの一部が繰り返し刺激に対する応答を興奮性から抑制性にスイッチすることを発見し、反応性から予測性の情報変換がこのレベルで行われていると考えられた。これらの成果は学会で報告するとともに、論文作成に向けて研究を継続している。 また、第二の課題では、手がかり刺激の提示後、一定の時間経過の後に自発的に眼球運動を行わせた。この課題の際に、漸増する準備活動を基底核（線条体）および小脳核（歯状核）で探索し、両部位の神経活動を比較検討した。前者は再現時間によって活動の上昇率が変化し、目標とするタイミングまでの相対的な時間経過をコードしているのに対し、後者では再現時間に関わらず、運動に一定時間先行して活動を上昇させ、運動タイミングの微調整に関与していることが示唆された。これらの研究成果も共同研究者の助教および学生が複数の学会で報告している。 申請者はこれらの成果をさらに大きく発展させるため、H25年度に新たに発足した新学術領域「こころの時間学」に計画班員として参加することとなった。重複制限のため、本公募課題はやむなく廃止することとしたが、研究は発展的に継続する。
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research
    Date (from‐to) : 2012/04 -2014/03 
    Author : TANAKA Masaki, ISHIKAWA Masayori, KUNIMATU Jun, MIYAMOTO Naoki
     
    We developed a research technique to create animal model of brain lesions using the therapeutic linear accelerator. A total of four irradiations (130-150 Gy) were performed on the right frontal eye field of three Japanese monkeys. During a few weeks following irradiation, brain edema was evident in MRI and the performance of oculomotor tasks was declined; however, it recovered thereafter. For one monkey that was followed up about 8 months, the behavioral deficits reappeared in the 4th month and gradually progressed. Postmortem histological examination in two animals revealed large necrosis in the white matter and surrounding hemorrhage, but the cortical gray matter retained layers. This technique can be applied to deep brain structures in the future study. We now plan to use lower doses and will follow up longer interval.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)
    Date (from‐to) : 2008 -2010 
    Author : TANAKA Masaki
     
    We select from multiple actions depending on a given situation. Analysis of the underlying neural mechanisms may shed light on the understanding of the pathophysiology in a variety of neurological and psychiatric disorders which accompany behavioral deficits. We examined neuronal activity in the basal ganglia and the thalamus in monkeys performing eye movement tasks, and found that neuronal activity was enhanced as the animals were required to suppress impulsive behavior. Inactivation of the recording sites resulted in the increment of impulsive behavior, suggesting that the basal ganglia?thalamocortical pathways may play a causal role in the organization of purposeful behavior.
  • 日本学術振興会：科学研究費助成事業 特定領域研究
    Date (from‐to) : 2008 -2009 
    Author : 田中 真樹
     
    空間的注意のトップダウン制御の神経機構を調べるため、注意の移動が必要となる行動課題(Covert tracking課題)をサルに訓練し、前頭眼野を含む外側前頭前野からニューロン記録をおこなってきた。今年度はこれらに加え、課題中の微小電気刺激を試みた。予備的な実験では、前頭眼野の電気刺激でmovement fieldを決め、そこに提示した視覚刺激を選択する頻度が、閾値以下の電気刺激で増加するかどうかを調べたが、一貫した傾向が認められなかった。そこで、眼球運動が誘発されない刺激部位での影響を調べることにした。色の変化によるターゲットの手がかりを与えずに4つの視覚刺激を3秒間動かしてその中のひとつを任意に選ばせた。動き始めから0,500,2000ミリ秒のいずれかで前頭眼野周囲の微小電気刺激を行った。刺激は同部位に視覚応答性のニューロンが存在することを確認してから行った。動きの方向によるバイアスを除外するため、視覚刺激はいずれも固視点から遠ざかる方向に動き始めるようにした。それぞれのタイミングでターゲット位置の平均を求め、電気刺激の有無でそれらを比較したところ、電気刺激の影響は、ターゲットが動き出すのと同時に与えたときにのみ認められることが分かった。同様の実験を眼球運動が誘発される部位で行った結果、電気刺激による明らかな影響はみられなかった。これは、眼球運動そのものではなく、視覚応答を示すニューロン群によって、空間的注意が制御されていることを示唆する。
  • 科学技術振興機構：戦略的な研究開発の推進 戦略的創造研究推進事業 さきがけ
    Date (from‐to) : 2006 -2009 
    Author : 田中 真樹
     
    次に起こる出来事を予測することは、生活する上でなくてはならない能力です。これに必要となる時間情報の処理機構には、大脳皮質-基底核ループによるものと小脳が関与するものの二つがあると考えられています。本研究では、主に小脳が関与すると期待される、数百ミリ秒間隔の「リズム」の生成に関係した神経機構を調べます。神経活動や行動データをもとに、脳が採用しているタイミングの予測アルゴリズムを理解することを目指します。
  • 日本学術振興会：科学研究費助成事業 特定領域研究
    Date (from‐to) : 2006 -2007 
    Author : 田中 真樹
     
    われわれは視野内の複数の場所にむかって次々に、あるいは移動する物体に伴って連続的に、随意的に注意をむけることができる。こうした空間的注意のトップダウン制御には、前頭および頭頂葉の眼球運動関連領野が密接に関与すると考えられている。本研究では独自に考案した注意の移動を要する行動課題(Covert tracking課題)をサルに訓練し、その神経機構を単一ニューロンのレベルで調べた。この課題では視野内を動き回る複数の視覚刺激のうち1つを選択し、眼を動かさないでそれを内的に追跡する必要がある。前頭眼野およびその数ミリメートル前方の外側前頭前野領域からデータを収集し、解析をおこなった。 前頭眼野ニューロンの多くは、受容野内にtargetが入ったときにdistractorが入ったときと比べて視覚応答が増強した。ところがさらに前方の前頭前野からはこれらとは異なった興味深い神経活動が記録された。一部のニューロンでは受容野内にdistractorが提示されたときに活動が上昇し、また、別のニューロンではtargetが受容野内にあるだけではなく、同時にdistractorが受容野外め特定の場所にあると発火し、"conditional modulation"の様相を示した。これらのニューロンが混在していることから、こうした神経活動を統一的に説明できる神経機構が存在することが示唆された。 今後は、本研究で見出された神経活動の定量的な解析と、電気刺激実験などを組み合わせることで研究の大きな進展が見込まれる。また、大脳皮質の情報処理には視床を介した皮質下からの情報が必須であることから、視床や大脳基底核などの神経活動との関連も視野にいれて研究を進める必要がある。
  • 日本学術振興会：科学研究費助成事業 若手研究(B)
    Date (from‐to) : 2005 -2006 
    Author : 田中 真樹
     
    眼球運動系において基底核と小脳はいずれもフィードフォワード経路を構成し、大脳から脳幹に至る運動信号を修飾・調節していると考えられている。しかし一方、基底核と小脳(とくに外側部)は視床を介して大脳皮質に信号を送っており、体性運動系ではこの上行性経路が運動の企画や意思決定に関与していることが症例研究や機能画像研究によって示されている。中でも運動のタイミングの調節にこれらの上行性の信号が重要であることがよく知られており、皮質下病変における自発運動の開始異常の神経基盤として注目されている。本研究では眼球運動をモデルとして、運動の計画段階における皮質下信号の役割をサルを用いて調べた。 これまでの研究で、運動性視床の不活化により、反対側にむかう記憶誘導性サッカードの潜時が延長することを見いだし、平成17年度にNature Neuroscience誌に発表した。本年度はこの実験の前後に得られた神経活動を詳細に解析した。サッカードに先行したburst activityの大きさは視覚刺激に応じて運動をおこなったときと自発的におこなったときで多くの場合違いがなく、その一方で遅延期間中にみられたbuildup activityの潜時はinternally triggered課題でのサッカードの潜時によく相関した。このことから運動性視床は運動信号そのものというよりも、自発運動のタイミングを決定するための時間情報を大脳皮質に供給していることが示唆される。また、運動性視床から記録された眼球位置信号、smooth pursuit信号について定量的な解析を行った。これらの研究成果は平成18年度に開催された国内外のシンポジウム・研究会で発表し、またその一部は専門誌上にて発表した。平成17年度から2年間にわたる本研究課題で得られた成果は、今後新たな研究課題の中でさらに発展させることができると期待される。
  • 日本学術振興会：科学研究費助成事業 特定領域研究
    Date (from‐to) : 2005 -2005 
    Author : 田中 真樹
     
    眼球運動系において基底核と小脳はいずれもフィードフォワード経路を構成し、大脳から脳幹に至る運動信号を修飾・調節していると考えられている。しかし一方、基底核と小脳外側部は視床を介して大脳皮質に信号を送っており、体性運動系ではこの上行経路が運動の企画や意思決定に関与していることが症例研究や機能画像研究によって示されている。中でも運動のタイミングの調節にこれらの経路が重要であることがよく知られており、皮質下病変における自発運動の開始異常の神経基盤として注目されている。本研究では眼球運動の計画段階における皮質下信号の役割をサルを用いて調べた。 これまでの研究で、運動性視床の不活化により、反対側にむかう記憶誘導性サッカードの潜時が延長することを見いだした。とくに、固視点を消すことによって運動を開始させる従来の課題よりも、手がかり刺激が提示された後、一定時間の後に自発的に記憶誘導性サッカードをおこなわせるinternally triggered課題で障害効果が大きかった。このことは視床を経由する信号が自発性眼球運動の発現、特にその時間的調節に関与する可能性を示唆する。本年度はこの現象の再現性を確認した上で専門誌に発表し、さらには不活化実験の前後に得られた神経活動を詳細に解析した。サッカードに先行したburst activityの大きさは視覚刺激に応じて運動をおこなったときと自発的におこなったときで多くの場合違いがなく、その一方で遅延期間中にみられたbuildup activityの潜時はinternally triggered課題でのサッカードの潜時によく相関した。このことから運動性視床は運動信号そのものというよりも、自発運動のタイミングを決定するための時間情報を大脳皮質に供給していることが示唆される。
  • 日本学術振興会：科学研究費助成事業 特定領域研究
    Date (from‐to) : 2004 -2004 
    Author : 田中 真樹
     
    運動性視床は皮質下の運動情報を大脳皮質につたえる上行性経路として重要であり、その信号は自身の行動をモニターすることに利用され、また、体性運動系においては随意運動の発現にも関与することが知られている。これまで、眼球運動系の研究では大脳皮質から直接、あるいは大脳基底核を経由して間接的に脳幹・小脳にいたる下行性の経路がよく調べられてきた。しかし、解剖学的には運動性視床の多くのニューロンが眼球運動関連領野に投射することが知られており、また、髄板内核群周辺からは眼球運動に関連したニューロンが記録される。本課題ではこれらの神経活動を解析するとともに、記録部位に微量のムシモールを注入し、眼球運動系における上行性信号の役割を調べた。 2種類の眼球運動について検討した。(1)滑動性眼球運動の最中に活動を変化させるニューロンの約8割には方向選択性があり、多くは同側に至適方向をもっていた。運動性視床を不活化すると滑動性眼球運動のゲインがわずかながら低下し、その効果は同側にむかう運動で大きかった。多くの場合、障害は運動の開始後数十ミリ秒であらわれ、このことは運動性視床が同眼球運動系の内在性の正の帰還経路の一部であることを示唆する。(2)視床の障害によって反対側にむかう記憶誘導性サッカードの潜時が延長した。とくに、固視点を消すことによって運動を開始させる従来のexternally triggered課題よりも、手がかり刺激が提示された後、一定時間の後に自発的に記憶誘導性サッカードをおこなわせるinternally triggered課題で障害効果が大きかった。このことは上行性信号が自発性眼球運動の発現、特にその時間的調節に関与する可能性を示唆する。この障害効果を裏付ける神経活動として、遅延期間中にみられたbuildup activityが有力であると考えられる。
  • 日本学術振興会：科学研究費助成事業 特定領域研究
    Date (from‐to) : 2003 -2003 
    Author : 田中 真樹
     
    運動系の各段階における情報処理の結果は帰還性経路を経てより上位の中枢につたえられ、運動計画の更新や感覚入力の解釈に利用される。視床-大脳経路は脳幹、小脳、大脳基底核などの皮質下運動中枢から発した信号を上行性につたえ、その特性を知ることは運動の制御機構を理解する上で重要である。本課題では行動中のサルの運動性視床から単一ニューロン活動を記録した。髄板内核群の周辺領域からサッカードあるいは眼球位置に関連した細胞を多数記録した。いずれも約半数が眼球運動にわずかに先行して活動を変化させた。サッカードに先行してバーストするものの多くは方向選択性をもち、その至適方向は視野のあらゆる方向に分布していた。これに対し、眼球位置に対応するものは水平あるいは垂直方向に至適方向をもち、あきらかなmovement fieldをもたなかった。また、サッカードに関連したものの中には視覚誘導性サッカード課題よりも記憶誘導性課題で活動が増強するものが見いだされた。これらの結果から視床におけるサッカード信号と眼球位置信号はそれぞれ眼球運動系の異なった段階から供給されていることが示唆された。具体的にはサッカード信号は基底核あるいは上丘からもたらされ、眼球位置信号は基本的には脳幹にある神経積分器からの信号をうけていると考えられる。しかし、眼球位置に関連したものの多くはヒステリシスをもっており、忠実に眼球位置をコードしているわけではなく、視床内あるいは視床に至るまでに何らかの修飾をうけていると予想される。さらに、これら記憶誘導性サッカード、遅延期間、あるいは眼球位置に関連した細胞の一部は滑動性眼球運動の最中にも活動を変化させた。これらのことから大脳皮質は、視床を介した経路により、皮質下運動中枢の複数の段階における情報処理の結果をモニターしていることが明らかになった。
  • 日本学術振興会：科学研究費助成事業 若手研究(B)
    Date (from‐to) : 2002 -2003 
    Author : 田中 真樹
     
    運動系の各段階における情報処理の結果は帰還性経路を経てより上位の中枢につたえられ、運動計画の更新や感覚入力の解釈に利用される。視床-大脳経路は脳幹、小脳、大脳基底核などの皮質下運動中枢から発した信号を上行性につたえ、その特性を知ることは運動の制御機構を理解する上で重要である。本課題では行動中のサルの運動性視床から単一ニューロン活動を記録した。髄板内核群の周辺領域からサッカードあるいは眼球位置に関連した細胞を多数記録した。いずれも約半数が眼球運動にわずかに先行して活動を変化させた。サッカードに先行してバーストするものの多くは方向選択性をもち、その至適方向は視野のあらゆる方向に分布していた。これに対し、眼球位置に対応するものは水平あるいは垂直方向に至適方向をもち、あきらかなmovement fieldをもたなかった。また、サッカードに関連したものの中には視覚誘導性サッカード課題よりも記憶誘導性課題で活動が増強するものが見いだされた。これらの結果から視床におけるサッカード信号と眼球位置信号はそれぞれ眼球運動系の異なった段階から供給されていることが示唆された。具体的にはサッカード信号は基底核あるいは上丘からもたらされ、眼球位置信号は基本的には脳幹にある神経積分器からの信号をうけていると考えられる。しかし、眼球位置に関連したものの多くはヒステリシスをもっており、忠実に眼球位置をコードしているわけではなく、視床内あるいは視床に至るまでに何らかの修飾をうけていると予想される。さらに、これら記憶誘導性サッカード、遅延期間、あるいは眼球位置に関連した細胞の一部は滑動性眼球運動の最中にも活動を変化させた。これらのことから大脳皮質は、視床を介した経路により、皮質下運動中枢の複数の段階における情報処理の結果をモニターしていることが明らかになった。
  • 日本学術振興会：科学研究費助成事業 特定領域研究
    Date (from‐to) : 2002 -2002 
    Author : 田中 真樹
     
    交付を受けた研究助成金により、サルの慢性実験用のシステムを構築して2頭のサルを訓練し、行動解析および運動性視床からの単一神経細胞外記録をおこなった。訓練と並行して行った行動実験では、行動のモニターに運動系のどのレベルの信号が用いられるのか、眼球運動系における小脳学習課題によって調べた。この実験ではふたつの視標を短時間提示し、サルはこれらが消えた後にそれぞれの位置向かって順にサッカードをするように要求された。このとき、ひとつ目のサッカードのベクトルは視標の網膜座標に一致するが、ふたつ目のサッカードは視標の網膜位置から直前の眼球運動を引き算して計算される。ひとつ目のサッカードを学習課題によって変化させたところ、ふたつ目のサッカードの振幅が変化した。この結果から、小脳より下流から発し、運動性視床を介して大脳皮質に至る上行性の経路が随意性眼球運動の制御に重要であることが示された。この成果は現在投稿中てある。また、これらのサルの運動性視床から眼球運動に関連した神経活動を記録し、サッカード、眼球位置、遅延期間などに特異的に応答するニューロン群を見いだした。サッカードに関連するものの多くは運動に遅れて活動を変化させ、眼球位置に関連するものはその方向選択性が水平または垂直方向にほぼ限られていた。このことは視床が運動の発現よりもその評価に関係している可能性を示唆し、その信号は脳幹からの上行性の投射によってもたらされていると考えられる。また、遅延期間に応答するニューロンの一部は滑動性眼球運動の際にも活動を変化させた。今後はこれらの神経活動の定量的な解析をおこない、その信号が運動の制御にどのように用いられるのかを調べていく必要がある。

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