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Interhemispheric cortical connections and time perception: A case study with agenesis of the corpus callosum
Brain and Cognition 117 (2017) 12–16
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Brain and Cognition journal homepage: www.elsevier.com/locate/b&c
Interhemispheric cortical connections and time perception: A case study with agenesis of the corpus callosum Miku Okajimaa, Akinori Futamurab, Motoyasu Honmab, Mitsuru Kawamurab, Yuko Yotsumotoa, a b
MARK ⁎
Department of Life Sciences, The University of Tokyo, 3-8-1, Komaba, Meguro-ku, Tokyo 153-8092, Japan Department of Neurology, Showa University School of Medicine, 1-5-8, Hatanodai, Shinagawa-ku, Tokyo 142-8666, Japan
A R T I C L E I N F O
A B S T R A C T
Keywords: Time perception Split-brain Agenesis of corpus callosum (ACC) Subcortical structures Interhemispheric communication
In daily life, we sometimes select temporal cues of one sort while suppressing others. This study investigated the mechanism of suppression by examining a split-brain patient’s perception of target intervals while ignoring distractor intervals. A patient with agenesis of corpus callosum and five age- and sex-matched control subjects participated in reproduction of target intervals while ignoring distractors displayed in the visual field either ipsilateral or contralateral to target. In the patient, the distractor interfered with reproduction performance more strongly when contralateral rather than ipsilateral. Our results suggest that the corpus callosum plays an inhibitory role in interhemispheric interference and that temporal interval information can be transferred via subcortical structures when there are no direct interhemispheric pathways.
1. Introduction Time perception is an essential life skill. Although it remains unclear exactly how we perceive interval duration, subcortical structures are known to play a critical role for interval encoding (Buhusi & Meck, 2005; Ivry, 1996; Matell & Meck, 2000). The cerebellum and basal ganglia in particular are involved in interval perception: a structural MRI study revealed correlation of interval precision and gray matter volume in cerebellum (Hayashi, Kantele, Walsh, Carlson, & Kanai, 2014), a transcranial magnetic stimulation (TMS) study demonstrated repetitive TMS on cerebellum interferes with interval processing (Koch et al., 2007), positron emission tomography (PET) studies found blood flow increases in cerebellum during interval tasks (Jueptner et al., 1995; Maquet et al., 1996), electrophysiological studies demonstrated striatal activity correlates with behavior in temporal tasks (Hattori & Sakata, 2014; Matell, Meck, & Nicolelis, 2003), functional MRI found activation of basal ganglia during interval processing (Ferrandez et al., 2003; Pouthas et al., 2005), and a recent study with Parkinson’s Disease (PD) patients showed correlation between striatal dopamine transporter deficit and error rate in interval production (Honma, Kuroda, Futamura, Shiromaru, & Kawamura, 2016). Handy, Gazzaniga, and Ivry (2003) have also investigated subcortical involvement in interval representation. In their study, a splitbrain patient participated in interval discrimination tasks, in which standard intervals were displayed in both visual fields and target intervals in one or other visual field. For example, when the target
⁎
Corresponding author at: 3-8-1, Komaba, Meguro-ku, Tokyo 153-8092, Japan. E-mail address: [email protected] (Y. Yotsumoto).
http://dx.doi.org/10.1016/j.bandc.2017.07.005 Received 27 December 2016; Received in revised form 29 June 2017; Accepted 4 July 2017 0278-2626/ © 2017 Published by Elsevier Inc.
interval was displayed in the left visual field and the patient made a response with his right hand, his left hemisphere was involved in controlling his right hand but had no direct access to target interval information because of the lack of callosal connections. Therefore, if temporal representations were lateralized, the accuracy of the task performance would depend on target position and responding hand, and a hand would be observed by visual field interaction. However, they failed to observe such interaction, suggesting that temporal representations are bilateral. Since there is no callosal route, the interval information is accessed by both hemispheres via subcortical routing. Although their experiment was designed to assess all intervals, in daily life we need to select given intervals while ignoring others. In this study, we focused on selective suppression by examining a split-brain patient’s perception of target interval while ignoring distractor intervals. Interval perception is susceptible to task-irrelevant stimuli. For example, stable target intervals are perceived longer after adaptation to a flickering stimulus (Droit-volet & Wearden, 2002; Ortega, GuzmanMartinez, Grabowecky, & Suzuki, 2012), 10-Hz flickering intervals are perceived as shorter after adaptation to a flickering stimulus (Johnston, Arnold, & Nishida, 2006; Johnston et al., 2008), and intervals are perceived as longer when an oddball is simultaneously displayed (New & Scholl, 2009). Our previous study has also demonstrated that a stable target stimulus was perceived as longer when a flickering distractor stimulus was simultaneously displayed, and that the effect of the distractor was larger when ipsilateral rather than contralateral to the
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Y.M. had normal grades and graduated from college. She exhibited no neurological deficits in everyday life and had no signs of classical disconnection syndrome, such as tachistoscopic unilateral alexia, or deficits in ability to draw, construct, name objects, and write with either hand. The results of neuropsychological examinations and single photon emission computed tomography (SPECT) are described in Supplementary Material. A detailed report of Y.M. can be found in Midorikawa, Kawamura, and Takaya (2006). Five subjects participated in the experiment as age- and sex-matched controls. All were right-handed females with normal or correctedto-normal vision. The age range of the controls was from 46 to 52, with a mean age of 49.8 (standard deviation of 2.4). All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the institutional review boards of the University of Tokyo and Showa University Hospital.
target (Okajima & Yotsumoto, 2016). This result indicates that an intrahemispheric distractor has a larger effect on target perception than an interhemispheric distractor. Considering the fact that the corpus callosum is absent in split-brain patients, the interhemispheric distractor effect would be smaller, if the corpus callosum plays an excitatory role. On the other hand, the interhemispheric distractor effect would be greater, if the corpus callosum plays an inhibitory role. There is disagreement as to whether the corpus callosum plays an excitatory or inhibitory role on interhemispheric communication (Bloom & Hynd, 2005; van der Knaap & van der Ham, 2011). In evidence supporting inhibition, Clarke, Lufkin, and Zaidel (1993) showed negative correlation between corpus callosum size and accuracy in dichotic listening, suggesting that corpus callosum size is associated with degree of interhemispheric inhibition. On the other hand, Yazgan, Wexler, Kinsbourne, Peterson, and Leckman (1995) found that corpus callosum size negatively correlated with behavioral laterality as measured by several tasks, suggesting interhemispheric asymmetry decreases as corpus callosum size increases. Although ambiguous, the available research primarily supports the idea that the corpus callosum is excitatory (Bloom & Hynd, 2005; Paul et al., 2007). Brown, Jeeves, Dietrich, and Burnison (1999) also provide evidence supporting excitation. In their study, electroencephalogram (EEG) was measured during subject observation of visual stimuli displayed in either visual field. While normal subjects exhibited evoked potentials on the ipsilateral hemisphere to visual stimuli, such evoked potentials were absent in patients with agenesis of corpus callosum (ACC). This study suggests that patients with ACC lack interhemispheric transfer of visual stimuli. In this study, we examined the role of corpus callosum on interhemispheric transfer of temporal interval information using target and distractor stimuli. Since we used visual stimuli, it is possible that visual distractor information would not be transferred interhemispherically, thus supporting corpus callosum excitation. On the other hand, in view of subcortical contribution to time perception, it is also possible that distractor information is transferred interhemispherically, thereby supporting the theory of corpus callosum inhibition.
2.2. Apparatus The experiment for controls was conducted in a darkroom in the University of Tokyo, and that for Y.M. was conducted in a dimly lit room in Showa University. In both cases, subjects sat in front of a 23inch LCD monitor at a distance of 57.3 cm, with their heads on a chin rest. The monitor was a screen unit of Tobii TX300 Eye Tracker (Tobii Technology AB, Stockholm, Sweden) with 1920 × 1080 pixel resolution at a refresh rate of 60 Hz. Eye movement was measured using the Tobii TX300 Eye Tracker. The stimuli presentation and the key response recording was conducted with Matlab 2014b (The MathWorks Inc., Natick, MA, USA) using Psychophysics Toolbox extensions (Brainard, 1997; Pelli, 1997). Eye movement was recorded with Matlab 2014b using a Tobii Analytics Software Development Kit. 2.3. Stimuli A white fixation cross was presented in the center of the display against a black background (0.3 cd/m2). Two stimuli—target and distractor—were used in the experiment (Fig. 2). The target stimulus was a white disk with a radius of 3°. Its center was 7° right of, and 7° above, the fixation cross. The luminance of the white disk was 51 cd/m2 for controls and 119 cd/m2 for Y.M. We determined the luminance for subjects to observe the stimuli comfortably. While controls participated in the darkroom, Y.M. participated in a dimly lit room because a physician needed to watch over her during the experiment. When the stimulus luminance for Y.M. was the same as that for controls, its perceived contrast to background was too low to perform the task. So, the
2. Methods 2.1. Subjects Subject Y.M. was a 51 years old female with ACC. She was ambidextrous, and wrote with her right hand. She had corrected-to-normal vision. Structural magnetic resonance images (MRI) reveled ACC. No other problem was observed (Fig. 1).
Fig. 1. Structural magnetic resonance images (MRI) of subject Y.M. Left, coronal section. Right, sagittal section. “R” indicates the right-hand side of the patient’s head. MRI revealed agenesis of corpus callosum (ACC). There were no other malformations and the anterior commissure was intact.
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Fig. 2. Stimulus configurations. The target was the white disk and appeared in the upper right of the display. The distractor was a green disk. Left, the ipsilateral distractor appeared in the same visual hemifield as the target. Right, the contralateral distractor appeared in the different visual hemifield. The distance between target and distractor was constant regardless of whether the distractor was ipsilateral or contralateral.
luminance for Y.M. was set relatively high, so that its perceived contrast to background was subjectively the same as that for controls. Although the luminance difference might affect interval perception, this effect would be constant among conditions. So, the differences between conditions, which was our main interest, would be little affected by luminance difference. The distractor stimulus was a green disk equiluminant to the target. It had a radius of 3°, and was displayed either ipsilateral or contralateral to the target. The center of the ipsilateral distractor was positioned 14° below the center of the target. The center of the contralateral distractor was positioned 14° left of target. The distance between target and distractor was 8° from edge to edge. This distance was constant regardless of whether the distractor was ipsilateral or contralateral. The stimuli were either stable or flickering at 10 Hz. In some conditions, the target was flickering and the distractor was stable to make it easy for subjects to pay attention to the target stimuli. In other conditions, the target was stable and the distractor was flickering so that the distractor captured more attention by increasing relative saliency. Since our main interest was in the difference between ipsilateral and contralateral distractors, not in the difference between hemispheres, the target stimuli were always presented in the upper right visual field to simplify the condition and lighten the burden imposed on subjects. We determined the target position based on a previous study of Y.M. indicating better performance in the temporal task with the right hand rather than the left (Midorikawa et al., 2006).
Fig. 4. Schematics of the experimental conditions. SSi condition: Stable target and Stable distractor ipsilateral. SSc condition: Stable target and Stable distractor contralateral. FSi condition: Flickering target and Stable distractor ipsilateral. FSc condition: Flickering target and Stable distractor contralateral. SFi condition: Stable target and Flickering distractor ipsilateral. SFc condition: Stable target and Flickering distractor contralateral.
the target duration by pressing the space key on the keyboard. No feedback was provided during or after reproduction. When the space key was released, the trial ended. The inter trial interval (ITI) was 250–500 ms. Six conditions were included in the experiment, and named on the basis of whether the target and the distractor were stable or flickering and whether the distractor was ipsilateral or contralateral (Fig. 4): SSi condition, Stable target and Stable distractor ipsilateral; SSc condition, Stable target and Stable distractor contralateral; FSi condition, Flickering target and Stable distractor ipsilateral; FSc condition, Flickering target and Stable distractor contralateral; SFi condition, Stable target and Flickering distractor ipsilateral; SFc condition, Stable target and Flickering distractor contralateral. Each condition had 30 trials and 8 catch trials, resulting in a total of 228 trials. Trials were divided into 4 sessions and each consisted of 5 blocks. Subjects could take a rest between blocks. For the details of the eye tracking procedure, see Supplementary Material. 2.5. Analysis
2.4. Procedure
We compared Y.M’s results with those of controls using the nonparametric bootstrapping test. Each control subject’s reproduced durations were resampled for each condition, the mean and variance of each resampled data set was calculated, and then the mean and variance differences between contralateral distractor and ipsilateral distractor conditions were calculated. By iterating the resampling and difference calculation 3000 times, the distributions of mean difference and variance differences were obtained for each condition. The mean and variance differences of Y.M. were also calculated and plotted on the distributions of control subjects’ differences. P values were obtained by dividing the number of resampled differences more extreme than Y.M.’s by iteration number.
The distractor appeared at the beginning of the trial, and then the target appeared 2000–2500 ms afterwards (Fig. 3). The distractor remained during and after target presentation. The target interval duration was 650 ms, while it was jittered from 350 to 950 ms in catch trials. The distractor disappeared 1000–1500 ms after target offset. The fixation cross then turned red and subjects were required to reproduce
3. Results Trials in which subjects moved their eyes more than 4° from fixation point, in which the reaction time was beyond the median ± 3 SDs, or in which the reproduced duration was beyond ± 3 SDs were excluded from further analysis. Subject Y.M. reproduced the target duration longer in the contralateral distractor conditions (SSc, FSc, SFc) than in the ipsilateral distractor durations (SSi, FSi, FSi) (Fig. 5). The mean, variance and standard deviation of reproduced duration for each condition is shown
Fig. 3. Time course of a trial. The distractor appeared at the beginning of a trial, followed by the target stimulus for 650 ms. After the distractor disappeared, the fixation cross turned red and subjects were required to reproduce target duration. No feedback was provided during or after reproduction. The trial ended when the button was released. After the intertrial interval (ITI), the next trial started.
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Fig. 5. Box plots of Y.M.’s reproduced duration for each condition. She had a tendency to reproduce target duration longer in the contralateral distractor conditions (SSc, FSc, SFc) as opposed to ipsilateral distractor durations (SSi, FSi, FSi).
Fig. 7. The difference of variance in reproduced duration. Positive value indicates that the variance of reproduced duration was greater for contralateral distractor durations (SSc, FSc, or SFc) than ipsilateral distractor conditions (SSi, FSi, or SFi), and vice versa for negative value. *p < 0.05, ***p < 0.001. Error bars indicate SEs.
Table 1 Mean, variance and standard deviation of the duration reproduced by subject Y.M. for each condition.
SSi SSc FSi FSc SFi SFc
Mean (ms)
Variance (ms2)
SD (ms)
471 667 568 752 442 775
34,259 42,816 121,272 93,630 18,692 69,466
185 207 348 306 137 264
larger than controls, except for FS conditions (p = 0.03 in SSc vs SSi, p = 0.16 in FSc vs FSi, p < 0.001 in SFc vs SFi). In addition, the patient reported difficulty during the experiment, saying that it was easier to respond when the green disk was displayed in the right visual field (ipsilateral conditions) as opposed to the left visual field (contralateral conditions). She was not sure why this was the case. 4. Discussions
in Table 1. Aside from the FSi and FSc conditions, the variance and SD were larger in the contralateral distractor conditions (SSc, SFc) than in the ipsilateral distractor conditions (SSi, SFi). We calculated differences of mean and variance between contralateral and ipsilateral distractor conditions, and compared those of subject Y.M. with controls (Figs. 6, 7). The nonparametric bootstrapping test revealed that Y.M.’s mean differences for reproduced durations between contralateral and ipsilateral distractors were significantly larger than controls (uncorrected p < 0.001 in the three comparisons). Y.M.’s variance differences for reproduced durations between contralateral and ipsilateral distractors were also significantly
In patient Y.M. with ACC, the reproduced duration of target interval was longer in contralateral distractor conditions (SSc, FSc and SFc) compared to ipsilateral distractor conditions (SSi, FSi and SFi). Precision of reproduction was lower in SSc and SFc as opposed to SSi and SFi. These differences were not observed in control subjects. In addition, Y.M. verbally reported difficulty with contralateral conditions during the experiment. These results demonstrate that the interhemispheric distractor effect was larger than the intrahemispheric distractor effect for the patient. Reproduction precision impairment by the contralateral distractor was not observed in FSc condition. This is probably because saliency of targets was larger than that of distractors in FSc and FSi conditions. In SSc, SSi, SFc and SFi conditions, the distractor had the same or greater saliency than the target. Greater saliency would attract more attention and increase the distractor effect, making precision difference prominent. In this study, we examined the role of the corpus callosum on interhemispheric transfer of temporal information. Because patient Y.M. lacks direct interhemispheric connections, the contralateral distractor would not interfere with target interval duration perception if the corpus callosum played an interhemispheric excitatory role. On the other hand, the distractor would interfere with perception of target duration if the corpus callosum played an inhibitory role. Our results thus support the notion that the corpus callosum inhibits interhemispheric transfer of distracting interval information. Since there is no corpus callosum, interval information of contralateral distractors is transferred via subcortical structures, suggested as playing a critical role in time perception (Buhusi & Meck, 2005; Merchant, Harrington, & Meck, 2013). Furthermore, a previous study with a split-brain patient showed subcortical interhemispheric transfer of temporal information (Handy et al., 2003). Although our study is not designed to identify the subcortical structures involved in temporal processing, previous studies show that different neural networks are
Fig. 6. The mean difference of reproduced duration. Positive value indicates that the mean of reproduced duration was greater in contralateral distractor conditions (SSc, FSc, or SFc) than in ipsilateral distractor conditions (SSi, FSi, or SFi), and vice versa for negative value. ***p < 0.001. Error bars indicate SEs.
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recruited for hundreds of milliseconds and a few seconds of perception (Lewis & Miall, 2003; Murai & Yotsumoto, 2016; Wiener, Turkeltaub, & Coslett, 2010). The cerebellum and basal ganglia are possibly involved for hundreds of milliseconds and a few seconds perception, respectively (Buhusi & Meck, 2005; Hinton & Meck, 2004; Lewis & Miall, 2006). Thus, the cerebellum may be involved in interhemispheric transfer in our experiment in which target interval duration was within the hundreds of milliseconds range. Since the distractor interval duration was within a few seconds, however, we cannot exclude involvement of basal ganglia. A further neuroimaging study is needed to identify the subcortical interhemispheric pathway. While Handy et al. (2003) established the contribution of the corpus callosum to interval perception, our study shows the inhibitory role of the corpus callosum in interhemispheric interference in interval perception. Although some studies show that the corpus callosum plays an inhibitory role on interhemispheric transfer (Clarke et al., 1993; Dennis, 1976), however, there is further evidence to support corpus callosum excitation (Bloom & Hynd, 2005; Dorion et al., 2000; Hopkins & Rilling, 2000; Yazgan et al., 1995). The inconsistency of our study with previous work may be due to task specificity. As discussed above, subcortical structures are known to be important for temporal interval processing. It is possible that the role of the corpus callosum depends on whether subcortical structures are involved or not. Further studies with various tasks are necessary to test this hypothesis. Our results also highlight our ability to focus on the duration of a given event. Since the ipsilateral distractor had a smaller effect than the contralateral distractor in patient Y.M., we can say that the interference of the ipsilateral distractor was inhibited. Taking into account the fact that contralateral distractor interference was not inhibited, corticocortical connections may be necessary for inhibition of temporal interference. Further investigation of interference inhibition is necessary. Interference induced by the interhemispheric distractor may sound counterintuitive, when contrasted with canonical textbook explanations that assumed divided consciousness for each split hemisphere. Recently, Pinto et al. (2017) has shown that split-brain patients exhibit full awareness of presence as well as some levels of recognition for the interhemispherically presented visual items. Our results are consistent with their finding, and further suggest interhemispheric interferences. The idea that consciousness of the split-brain patients is not completely split and sometimes interference from the opposite visual field exists, would be worth considered in future clinical practice. In conclusion, we have demonstrated that the interhemispheric distractor interfered with target interval perception more than the intrahemispheric distractor. This suggests an inhibitory role for the corpus callosum in interhemispheric transfer of distracting interval information, and supports the notion that subcortical structures are involved in interval perception. Acknowledgements This study was supported by Grants-in-Aid for Scientific Research for YY (KAKENHI-25119003, 16H03749) and for MK (KAKENHI25119006). Appendix A. Supplementary material Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.bandc.2017.07.005. References Bloom, J. S., & Hynd, G. W. (2005). The role of the corpus callosum in interhemispheric transfer of information: Excitation or inhibition? Neuropsychology Review, 15(2), 59–71. Brainard, D. H. (1997). The psychophysics toolbox. Spatial Vision, 10(4), 433–436. Brown, W. S., Jeeves, M. A., Dietrich, R., & Burnison, D. S. (1999). Bilateral field advantage and evoked potential interhemispheric transmission in commissurotomy and
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Brain and Cognition journal homepage: www.elsevier.com/locate/b&c
Interhemispheric cortical connections and time perception: A case study with agenesis of the corpus callosum Miku Okajimaa, Akinori Futamurab, Motoyasu Honmab, Mitsuru Kawamurab, Yuko Yotsumotoa, a b
MARK ⁎
Department of Life Sciences, The University of Tokyo, 3-8-1, Komaba, Meguro-ku, Tokyo 153-8092, Japan Department of Neurology, Showa University School of Medicine, 1-5-8, Hatanodai, Shinagawa-ku, Tokyo 142-8666, Japan
A R T I C L E I N F O
A B S T R A C T
Keywords: Time perception Split-brain Agenesis of corpus callosum (ACC) Subcortical structures Interhemispheric communication
In daily life, we sometimes select temporal cues of one sort while suppressing others. This study investigated the mechanism of suppression by examining a split-brain patient’s perception of target intervals while ignoring distractor intervals. A patient with agenesis of corpus callosum and five age- and sex-matched control subjects participated in reproduction of target intervals while ignoring distractors displayed in the visual field either ipsilateral or contralateral to target. In the patient, the distractor interfered with reproduction performance more strongly when contralateral rather than ipsilateral. Our results suggest that the corpus callosum plays an inhibitory role in interhemispheric interference and that temporal interval information can be transferred via subcortical structures when there are no direct interhemispheric pathways.
1. Introduction Time perception is an essential life skill. Although it remains unclear exactly how we perceive interval duration, subcortical structures are known to play a critical role for interval encoding (Buhusi & Meck, 2005; Ivry, 1996; Matell & Meck, 2000). The cerebellum and basal ganglia in particular are involved in interval perception: a structural MRI study revealed correlation of interval precision and gray matter volume in cerebellum (Hayashi, Kantele, Walsh, Carlson, & Kanai, 2014), a transcranial magnetic stimulation (TMS) study demonstrated repetitive TMS on cerebellum interferes with interval processing (Koch et al., 2007), positron emission tomography (PET) studies found blood flow increases in cerebellum during interval tasks (Jueptner et al., 1995; Maquet et al., 1996), electrophysiological studies demonstrated striatal activity correlates with behavior in temporal tasks (Hattori & Sakata, 2014; Matell, Meck, & Nicolelis, 2003), functional MRI found activation of basal ganglia during interval processing (Ferrandez et al., 2003; Pouthas et al., 2005), and a recent study with Parkinson’s Disease (PD) patients showed correlation between striatal dopamine transporter deficit and error rate in interval production (Honma, Kuroda, Futamura, Shiromaru, & Kawamura, 2016). Handy, Gazzaniga, and Ivry (2003) have also investigated subcortical involvement in interval representation. In their study, a splitbrain patient participated in interval discrimination tasks, in which standard intervals were displayed in both visual fields and target intervals in one or other visual field. For example, when the target
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Corresponding author at: 3-8-1, Komaba, Meguro-ku, Tokyo 153-8092, Japan. E-mail address: [email protected] (Y. Yotsumoto).
http://dx.doi.org/10.1016/j.bandc.2017.07.005 Received 27 December 2016; Received in revised form 29 June 2017; Accepted 4 July 2017 0278-2626/ © 2017 Published by Elsevier Inc.
interval was displayed in the left visual field and the patient made a response with his right hand, his left hemisphere was involved in controlling his right hand but had no direct access to target interval information because of the lack of callosal connections. Therefore, if temporal representations were lateralized, the accuracy of the task performance would depend on target position and responding hand, and a hand would be observed by visual field interaction. However, they failed to observe such interaction, suggesting that temporal representations are bilateral. Since there is no callosal route, the interval information is accessed by both hemispheres via subcortical routing. Although their experiment was designed to assess all intervals, in daily life we need to select given intervals while ignoring others. In this study, we focused on selective suppression by examining a split-brain patient’s perception of target interval while ignoring distractor intervals. Interval perception is susceptible to task-irrelevant stimuli. For example, stable target intervals are perceived longer after adaptation to a flickering stimulus (Droit-volet & Wearden, 2002; Ortega, GuzmanMartinez, Grabowecky, & Suzuki, 2012), 10-Hz flickering intervals are perceived as shorter after adaptation to a flickering stimulus (Johnston, Arnold, & Nishida, 2006; Johnston et al., 2008), and intervals are perceived as longer when an oddball is simultaneously displayed (New & Scholl, 2009). Our previous study has also demonstrated that a stable target stimulus was perceived as longer when a flickering distractor stimulus was simultaneously displayed, and that the effect of the distractor was larger when ipsilateral rather than contralateral to the
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Y.M. had normal grades and graduated from college. She exhibited no neurological deficits in everyday life and had no signs of classical disconnection syndrome, such as tachistoscopic unilateral alexia, or deficits in ability to draw, construct, name objects, and write with either hand. The results of neuropsychological examinations and single photon emission computed tomography (SPECT) are described in Supplementary Material. A detailed report of Y.M. can be found in Midorikawa, Kawamura, and Takaya (2006). Five subjects participated in the experiment as age- and sex-matched controls. All were right-handed females with normal or correctedto-normal vision. The age range of the controls was from 46 to 52, with a mean age of 49.8 (standard deviation of 2.4). All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the institutional review boards of the University of Tokyo and Showa University Hospital.
target (Okajima & Yotsumoto, 2016). This result indicates that an intrahemispheric distractor has a larger effect on target perception than an interhemispheric distractor. Considering the fact that the corpus callosum is absent in split-brain patients, the interhemispheric distractor effect would be smaller, if the corpus callosum plays an excitatory role. On the other hand, the interhemispheric distractor effect would be greater, if the corpus callosum plays an inhibitory role. There is disagreement as to whether the corpus callosum plays an excitatory or inhibitory role on interhemispheric communication (Bloom & Hynd, 2005; van der Knaap & van der Ham, 2011). In evidence supporting inhibition, Clarke, Lufkin, and Zaidel (1993) showed negative correlation between corpus callosum size and accuracy in dichotic listening, suggesting that corpus callosum size is associated with degree of interhemispheric inhibition. On the other hand, Yazgan, Wexler, Kinsbourne, Peterson, and Leckman (1995) found that corpus callosum size negatively correlated with behavioral laterality as measured by several tasks, suggesting interhemispheric asymmetry decreases as corpus callosum size increases. Although ambiguous, the available research primarily supports the idea that the corpus callosum is excitatory (Bloom & Hynd, 2005; Paul et al., 2007). Brown, Jeeves, Dietrich, and Burnison (1999) also provide evidence supporting excitation. In their study, electroencephalogram (EEG) was measured during subject observation of visual stimuli displayed in either visual field. While normal subjects exhibited evoked potentials on the ipsilateral hemisphere to visual stimuli, such evoked potentials were absent in patients with agenesis of corpus callosum (ACC). This study suggests that patients with ACC lack interhemispheric transfer of visual stimuli. In this study, we examined the role of corpus callosum on interhemispheric transfer of temporal interval information using target and distractor stimuli. Since we used visual stimuli, it is possible that visual distractor information would not be transferred interhemispherically, thus supporting corpus callosum excitation. On the other hand, in view of subcortical contribution to time perception, it is also possible that distractor information is transferred interhemispherically, thereby supporting the theory of corpus callosum inhibition.
2.2. Apparatus The experiment for controls was conducted in a darkroom in the University of Tokyo, and that for Y.M. was conducted in a dimly lit room in Showa University. In both cases, subjects sat in front of a 23inch LCD monitor at a distance of 57.3 cm, with their heads on a chin rest. The monitor was a screen unit of Tobii TX300 Eye Tracker (Tobii Technology AB, Stockholm, Sweden) with 1920 × 1080 pixel resolution at a refresh rate of 60 Hz. Eye movement was measured using the Tobii TX300 Eye Tracker. The stimuli presentation and the key response recording was conducted with Matlab 2014b (The MathWorks Inc., Natick, MA, USA) using Psychophysics Toolbox extensions (Brainard, 1997; Pelli, 1997). Eye movement was recorded with Matlab 2014b using a Tobii Analytics Software Development Kit. 2.3. Stimuli A white fixation cross was presented in the center of the display against a black background (0.3 cd/m2). Two stimuli—target and distractor—were used in the experiment (Fig. 2). The target stimulus was a white disk with a radius of 3°. Its center was 7° right of, and 7° above, the fixation cross. The luminance of the white disk was 51 cd/m2 for controls and 119 cd/m2 for Y.M. We determined the luminance for subjects to observe the stimuli comfortably. While controls participated in the darkroom, Y.M. participated in a dimly lit room because a physician needed to watch over her during the experiment. When the stimulus luminance for Y.M. was the same as that for controls, its perceived contrast to background was too low to perform the task. So, the
2. Methods 2.1. Subjects Subject Y.M. was a 51 years old female with ACC. She was ambidextrous, and wrote with her right hand. She had corrected-to-normal vision. Structural magnetic resonance images (MRI) reveled ACC. No other problem was observed (Fig. 1).
Fig. 1. Structural magnetic resonance images (MRI) of subject Y.M. Left, coronal section. Right, sagittal section. “R” indicates the right-hand side of the patient’s head. MRI revealed agenesis of corpus callosum (ACC). There were no other malformations and the anterior commissure was intact.
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Fig. 2. Stimulus configurations. The target was the white disk and appeared in the upper right of the display. The distractor was a green disk. Left, the ipsilateral distractor appeared in the same visual hemifield as the target. Right, the contralateral distractor appeared in the different visual hemifield. The distance between target and distractor was constant regardless of whether the distractor was ipsilateral or contralateral.
luminance for Y.M. was set relatively high, so that its perceived contrast to background was subjectively the same as that for controls. Although the luminance difference might affect interval perception, this effect would be constant among conditions. So, the differences between conditions, which was our main interest, would be little affected by luminance difference. The distractor stimulus was a green disk equiluminant to the target. It had a radius of 3°, and was displayed either ipsilateral or contralateral to the target. The center of the ipsilateral distractor was positioned 14° below the center of the target. The center of the contralateral distractor was positioned 14° left of target. The distance between target and distractor was 8° from edge to edge. This distance was constant regardless of whether the distractor was ipsilateral or contralateral. The stimuli were either stable or flickering at 10 Hz. In some conditions, the target was flickering and the distractor was stable to make it easy for subjects to pay attention to the target stimuli. In other conditions, the target was stable and the distractor was flickering so that the distractor captured more attention by increasing relative saliency. Since our main interest was in the difference between ipsilateral and contralateral distractors, not in the difference between hemispheres, the target stimuli were always presented in the upper right visual field to simplify the condition and lighten the burden imposed on subjects. We determined the target position based on a previous study of Y.M. indicating better performance in the temporal task with the right hand rather than the left (Midorikawa et al., 2006).
Fig. 4. Schematics of the experimental conditions. SSi condition: Stable target and Stable distractor ipsilateral. SSc condition: Stable target and Stable distractor contralateral. FSi condition: Flickering target and Stable distractor ipsilateral. FSc condition: Flickering target and Stable distractor contralateral. SFi condition: Stable target and Flickering distractor ipsilateral. SFc condition: Stable target and Flickering distractor contralateral.
the target duration by pressing the space key on the keyboard. No feedback was provided during or after reproduction. When the space key was released, the trial ended. The inter trial interval (ITI) was 250–500 ms. Six conditions were included in the experiment, and named on the basis of whether the target and the distractor were stable or flickering and whether the distractor was ipsilateral or contralateral (Fig. 4): SSi condition, Stable target and Stable distractor ipsilateral; SSc condition, Stable target and Stable distractor contralateral; FSi condition, Flickering target and Stable distractor ipsilateral; FSc condition, Flickering target and Stable distractor contralateral; SFi condition, Stable target and Flickering distractor ipsilateral; SFc condition, Stable target and Flickering distractor contralateral. Each condition had 30 trials and 8 catch trials, resulting in a total of 228 trials. Trials were divided into 4 sessions and each consisted of 5 blocks. Subjects could take a rest between blocks. For the details of the eye tracking procedure, see Supplementary Material. 2.5. Analysis
2.4. Procedure
We compared Y.M’s results with those of controls using the nonparametric bootstrapping test. Each control subject’s reproduced durations were resampled for each condition, the mean and variance of each resampled data set was calculated, and then the mean and variance differences between contralateral distractor and ipsilateral distractor conditions were calculated. By iterating the resampling and difference calculation 3000 times, the distributions of mean difference and variance differences were obtained for each condition. The mean and variance differences of Y.M. were also calculated and plotted on the distributions of control subjects’ differences. P values were obtained by dividing the number of resampled differences more extreme than Y.M.’s by iteration number.
The distractor appeared at the beginning of the trial, and then the target appeared 2000–2500 ms afterwards (Fig. 3). The distractor remained during and after target presentation. The target interval duration was 650 ms, while it was jittered from 350 to 950 ms in catch trials. The distractor disappeared 1000–1500 ms after target offset. The fixation cross then turned red and subjects were required to reproduce
3. Results Trials in which subjects moved their eyes more than 4° from fixation point, in which the reaction time was beyond the median ± 3 SDs, or in which the reproduced duration was beyond ± 3 SDs were excluded from further analysis. Subject Y.M. reproduced the target duration longer in the contralateral distractor conditions (SSc, FSc, SFc) than in the ipsilateral distractor durations (SSi, FSi, FSi) (Fig. 5). The mean, variance and standard deviation of reproduced duration for each condition is shown
Fig. 3. Time course of a trial. The distractor appeared at the beginning of a trial, followed by the target stimulus for 650 ms. After the distractor disappeared, the fixation cross turned red and subjects were required to reproduce target duration. No feedback was provided during or after reproduction. The trial ended when the button was released. After the intertrial interval (ITI), the next trial started.
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Fig. 5. Box plots of Y.M.’s reproduced duration for each condition. She had a tendency to reproduce target duration longer in the contralateral distractor conditions (SSc, FSc, SFc) as opposed to ipsilateral distractor durations (SSi, FSi, FSi).
Fig. 7. The difference of variance in reproduced duration. Positive value indicates that the variance of reproduced duration was greater for contralateral distractor durations (SSc, FSc, or SFc) than ipsilateral distractor conditions (SSi, FSi, or SFi), and vice versa for negative value. *p < 0.05, ***p < 0.001. Error bars indicate SEs.
Table 1 Mean, variance and standard deviation of the duration reproduced by subject Y.M. for each condition.
SSi SSc FSi FSc SFi SFc
Mean (ms)
Variance (ms2)
SD (ms)
471 667 568 752 442 775
34,259 42,816 121,272 93,630 18,692 69,466
185 207 348 306 137 264
larger than controls, except for FS conditions (p = 0.03 in SSc vs SSi, p = 0.16 in FSc vs FSi, p < 0.001 in SFc vs SFi). In addition, the patient reported difficulty during the experiment, saying that it was easier to respond when the green disk was displayed in the right visual field (ipsilateral conditions) as opposed to the left visual field (contralateral conditions). She was not sure why this was the case. 4. Discussions
in Table 1. Aside from the FSi and FSc conditions, the variance and SD were larger in the contralateral distractor conditions (SSc, SFc) than in the ipsilateral distractor conditions (SSi, SFi). We calculated differences of mean and variance between contralateral and ipsilateral distractor conditions, and compared those of subject Y.M. with controls (Figs. 6, 7). The nonparametric bootstrapping test revealed that Y.M.’s mean differences for reproduced durations between contralateral and ipsilateral distractors were significantly larger than controls (uncorrected p < 0.001 in the three comparisons). Y.M.’s variance differences for reproduced durations between contralateral and ipsilateral distractors were also significantly
In patient Y.M. with ACC, the reproduced duration of target interval was longer in contralateral distractor conditions (SSc, FSc and SFc) compared to ipsilateral distractor conditions (SSi, FSi and SFi). Precision of reproduction was lower in SSc and SFc as opposed to SSi and SFi. These differences were not observed in control subjects. In addition, Y.M. verbally reported difficulty with contralateral conditions during the experiment. These results demonstrate that the interhemispheric distractor effect was larger than the intrahemispheric distractor effect for the patient. Reproduction precision impairment by the contralateral distractor was not observed in FSc condition. This is probably because saliency of targets was larger than that of distractors in FSc and FSi conditions. In SSc, SSi, SFc and SFi conditions, the distractor had the same or greater saliency than the target. Greater saliency would attract more attention and increase the distractor effect, making precision difference prominent. In this study, we examined the role of the corpus callosum on interhemispheric transfer of temporal information. Because patient Y.M. lacks direct interhemispheric connections, the contralateral distractor would not interfere with target interval duration perception if the corpus callosum played an interhemispheric excitatory role. On the other hand, the distractor would interfere with perception of target duration if the corpus callosum played an inhibitory role. Our results thus support the notion that the corpus callosum inhibits interhemispheric transfer of distracting interval information. Since there is no corpus callosum, interval information of contralateral distractors is transferred via subcortical structures, suggested as playing a critical role in time perception (Buhusi & Meck, 2005; Merchant, Harrington, & Meck, 2013). Furthermore, a previous study with a split-brain patient showed subcortical interhemispheric transfer of temporal information (Handy et al., 2003). Although our study is not designed to identify the subcortical structures involved in temporal processing, previous studies show that different neural networks are
Fig. 6. The mean difference of reproduced duration. Positive value indicates that the mean of reproduced duration was greater in contralateral distractor conditions (SSc, FSc, or SFc) than in ipsilateral distractor conditions (SSi, FSi, or SFi), and vice versa for negative value. ***p < 0.001. Error bars indicate SEs.
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Neural network involved in time perception: An fMRI study comparing long and short interval estimation. Human Brain Mapping, 25(4), 433–441. van der Knaap, L. J., & van der Ham, I. J. M. (2011). How does the corpus callosum mediate interhemispheric transfer? A review. Behavioural Brain Research, 223(1), 211–221. Wiener, M., Turkeltaub, P., & Coslett, H. B. (2010). The image of time: A voxel-wise metaanalysis. NeuroImage, 49(2), 1728–1740. Yazgan, M. Y., Wexler, B. E., Kinsbourne, M., Peterson, B., & Leckman, J. F. (1995). Functional significance of individual variations in callosal area. Neuropsychologia, 33(6), 769–779.
recruited for hundreds of milliseconds and a few seconds of perception (Lewis & Miall, 2003; Murai & Yotsumoto, 2016; Wiener, Turkeltaub, & Coslett, 2010). The cerebellum and basal ganglia are possibly involved for hundreds of milliseconds and a few seconds perception, respectively (Buhusi & Meck, 2005; Hinton & Meck, 2004; Lewis & Miall, 2006). Thus, the cerebellum may be involved in interhemispheric transfer in our experiment in which target interval duration was within the hundreds of milliseconds range. Since the distractor interval duration was within a few seconds, however, we cannot exclude involvement of basal ganglia. A further neuroimaging study is needed to identify the subcortical interhemispheric pathway. While Handy et al. (2003) established the contribution of the corpus callosum to interval perception, our study shows the inhibitory role of the corpus callosum in interhemispheric interference in interval perception. Although some studies show that the corpus callosum plays an inhibitory role on interhemispheric transfer (Clarke et al., 1993; Dennis, 1976), however, there is further evidence to support corpus callosum excitation (Bloom & Hynd, 2005; Dorion et al., 2000; Hopkins & Rilling, 2000; Yazgan et al., 1995). The inconsistency of our study with previous work may be due to task specificity. As discussed above, subcortical structures are known to be important for temporal interval processing. It is possible that the role of the corpus callosum depends on whether subcortical structures are involved or not. Further studies with various tasks are necessary to test this hypothesis. Our results also highlight our ability to focus on the duration of a given event. Since the ipsilateral distractor had a smaller effect than the contralateral distractor in patient Y.M., we can say that the interference of the ipsilateral distractor was inhibited. Taking into account the fact that contralateral distractor interference was not inhibited, corticocortical connections may be necessary for inhibition of temporal interference. Further investigation of interference inhibition is necessary. Interference induced by the interhemispheric distractor may sound counterintuitive, when contrasted with canonical textbook explanations that assumed divided consciousness for each split hemisphere. Recently, Pinto et al. (2017) has shown that split-brain patients exhibit full awareness of presence as well as some levels of recognition for the interhemispherically presented visual items. Our results are consistent with their finding, and further suggest interhemispheric interferences. The idea that consciousness of the split-brain patients is not completely split and sometimes interference from the opposite visual field exists, would be worth considered in future clinical practice. In conclusion, we have demonstrated that the interhemispheric distractor interfered with target interval perception more than the intrahemispheric distractor. This suggests an inhibitory role for the corpus callosum in interhemispheric transfer of distracting interval information, and supports the notion that subcortical structures are involved in interval perception. Acknowledgements This study was supported by Grants-in-Aid for Scientific Research for YY (KAKENHI-25119003, 16H03749) and for MK (KAKENHI25119006). Appendix A. Supplementary material Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.bandc.2017.07.005. References Bloom, J. S., & Hynd, G. W. (2005). The role of the corpus callosum in interhemispheric transfer of information: Excitation or inhibition? Neuropsychology Review, 15(2), 59–71. Brainard, D. H. (1997). The psychophysics toolbox. Spatial Vision, 10(4), 433–436. Brown, W. S., Jeeves, M. A., Dietrich, R., & Burnison, D. S. (1999). Bilateral field advantage and evoked potential interhemispheric transmission in commissurotomy and
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