臺灣博碩士論文加值系統

中文摘要：
從睡眠中醒來到完全清醒，睡眠遲惰現象是一個不斷變化的動態過程，伴隨著主觀困倦感與客觀認知表現下降。為了衡量睡眠遲惰期間的認知表現，研究者通常選用與警覺作業相關的行為範式。關於其神經生理機制，近期雖有研究表明該現象與早期清醒狀態的大腦自發性動態重組有關， 但未曾與認知功能下降建立直接聯繫。因此本實驗採用腦電波融合功能性磁振造影(EEG-fMRI)的測量，並通過對16位受試睡前醒後多次的心理動作警覺任務（PVT）與靜息態影像的掃描（共四次：睡前一次，醒後三次），旨在進一步揭示睡眠遲惰現象的潛在神經基礎並幫助我們理解醒後大腦功能重組對於認知行為表現之意義。我們的行為結果表明，相較於初始的清醒狀態，醒後50分鐘後受試的反應速度之標準差有顯著增加。進一步的交互效應分析顯示，相較於平均反應速度，在50分鐘後最快20%的PVT反應速度有顯著變快趨勢。在腦活動的變化上，時間維度的主效應存在於右側額下回，頂葉下回以及雙側的丘腦。值得關注的是，在任務和靜息兩種模態下前扣帶迴網路下的丘腦區域都受到睡眠遲惰效應的影響。在早期清醒時段，丘腦在任務下的微弱激活強度顯著與受試的反應速度正相關。並且，丘腦區域激活強度在醒後的逐漸回復伴隨著靜息狀態下腦連結和低頻振蕩指標的同時上升，儘管這些靜息態指標不能直接反映PVT下的激活強度。綜上所述，我們的研究表明在睡眠遲惰期間，前扣帶迴網路下丘腦區域的激活不足，但是卻能顯著地決定著當下的行為表現，而其他相關區域似乎也受到睡眠遲惰的影響而無法正常工作。這一現象可能代表著睡眠遲惰效應所導致的任務狀態下短期認知功能受損的潛在神經生理機制。

Abstract:
Sleep inertia (SI) depicts a transition phase from initial awakening to well-functioned wakefulness, as noted for its objective performance decline with the persistence of subjective drowsiness. The cognitive impairments in the SI period were conventionally measured by alertness-related behavioral tasks. To reveal its neural mechanisms, recent studies demonstrated the altered spontaneous reorganizations of neural networks along early wakefulness. However, the linkage between the resting-state network organizations and the cognitive impairments remains missing. In this study, using four-time EEG-fMRI acquisitions of both Psychomotor vigilance task (PVT) and resting sessions (before sleep and three times after awakening) on sixteen subjects at midnight, we aim to uncover the neural substrates of sleep inertia via alertness tasks and meanwhile to interpret the role of resting reorganization in PVT performances. Our results indicated that in the initial wakefulness after a nocturnal nap, the standard deviation of response speed decreased as compared to the latest wakefulness at around 50 mins after awakening. The performance impairment of fastest trials (top 20%) was observed on initial wakefulness, evidenced by a significant interaction with mean speed performance. In brain activity, the right-side inferior frontal gyrus, superior parietal cortex and the bilateral thalamus showed the time effect in repeated-measure Friedman test. Importantly, within Cingulo-Opercular Network (CON), thalamus showed the most prominent SI effect after awakening, observed from both resting and task modalities. During early post-sleep wakefulness, the insufficient thalamus activations in PVT contributed to mean response speed during the SI period. The rebound of the thalamus activation was parallel to its fluctuation in multiple resting indices, such as functional connectivity to CON and the ALFF, whereas the resting-state indices did not show correlation with PVT activation. Under vigilance task demand, our findings suggest that the weak activation of CO network, especially in thalamus, was in charge of the alertness maintenance in the SI period while other alertness-related nodes were unable to function normally during this period, which could be served as the neural signatures underlying the alertness impairments during sleep inertia.

Table of Contents
中文摘要 ............................................................................................- I -
Abstract........................................................................................... - II -
List of Tables................................................................................... - V -
List of Figures.................................................................................. - V -
Introduction ..................................................................................... - 1 -
Method............................................................................................ - 4 -
6.1 Participants ............................................................................... - 4 -
6.2 Experiment Design and Inclusion Criteria .................................. - 5 -
6.3 Simultaneous EEG/fMRI recordings ........................................... - 6 -
6.4 Behavioral Analysis of PVT ........................................................ - 7 -
6.5 EEG Data Preprocessing and Sleep Scoring............................... - 8 -
6.6 MRI Data Preprocessing ............................................................ - 8 -
6.7 Brain Activation of PVT and Spontaneous Activity in Resting State ........................................................................................................ - 9 -
6.8 Region of Interest (ROI) Analysis and Correlations .................. - 10 -
Result ............................................................................................. - 11 -
7.1 Behavioral Performance of PVT ................................................ - 11 -
7.2 Dynamic Change of PVT Activation in CON............................... - 11 -
7.3 Deactivation in DMN and the Correlation with fSPD ................. - 12 -
7.4 Dynamic Change of Resting Signatures in CON ....................... - 13 -
Conclusion and Discussion ............................................................ - 14 -
8.1 Maintained PVT Performance After the Nocturnal Nap............. - 15 -
8.2 Nocturnal Nap Restored the Positive Task Engagement of CON ....................................................................................................... - 15 -
8.3 The Alertness-related Dynamics through SI, within CON ........ - 16 -
8.4 The Alertness-related Dynamics through SI, beyond CON....... - 17 -
8.5 Failed detection of SI effect on DMN’s negative task engagement ...................................................................................................... - 19 -
8.6 Parallel Change of Thalamus’s Resting Indices in The Inertia
Group............................................................................................ - 20 -
Limitation and Future Works ......................................................... - 22 -
Table and Figures.......................................................................... - 23 -
Reference ..................................................................................... - 43 -
Appendix ...................................................................................... - 48 -

1. Tassi, P. & Muzet, A. Sleep inertia. Sleep Med. Rev. 4, 341–353 (2000).
2. Trotti, L. M. Waking up is the hardest thing I do all day: Sleep inertia and sleep
drunkenness. Sleep Med. Rev. 35, 76–84 (2017).
3. Ohayon, M. M., Priest, R. G., Zulley, J. & Smirne, S. The place of confusional arousals in
sleep and mental disorders: findings in a general population sample of 13,057 subjects. J.
Nerv. Ment. Dis. 188, 340–8 (2000).
4. Kanady, J. C. & Harvey, A. G. Development and Validation of the Sleep Inertia
Questionnaire (SIQ) and Assessment of Sleep Inertia in Analogue and Clinical
Depression. Cognit. Ther. Res. 39, 601–612 (2015).
5. Billiard, M. & Sonka, K. Idiopathic hypersomnia. Sleep Med. Rev. 29, 23–33 (2016).
6. Burke, T. M. et al. Sleep inertia, sleep homeostatic and circadian influences on higher-
order cognitive functions. J. Sleep Res. 24, n/a-n/a (2015).
7. Ferrara, M. et al. The electroencephalographic substratum of the awakening. Behav. Brain
Res. 167, 237–244 (2006).
8. Marzano, C., Ferrara, M., Moroni, F. & De Gennaro, L. Electroencephalographic sleep
inertia of the awakening brain. Neuroscience 176, 308–317 (2011).
9. Gorgoni, M. et al. EEG topography during sleep inertia upon awakening after a period of
increased homeostatic sleep pressure. Sleep Med. 16, 883–890 (2015).
10. Balkin, T. J. The process of awakening: a PET study of regional brain activity patterns
mediating the re-establishment of alertness and consciousness. Brain 125, 2308–2319
(2002).
11. Vallat, R., Meunier, D., Nicolas, A. & Ruby, P. Hard to wake up? The cerebral correlates
of sleep inertia assessed using combined behavioral, EEG and fMRI measures.
Neuroimage 184, 266–278 (2019).
12. Tassi, P. et al. EEG spectral power and cognitive performance during sleep inertia: The
effect of normal sleep duration and partial sleep deprivation. Physiol. Behav. 87, 177–184
(2006).
13. Salamé, P. et al. Effects of sleep inertia on cognitive performance following a 1-hour nap.
Work Stress 9, 528–539 (1995).
14. Sadaghiani, S. & Kleinschmidt, A. Brain Networks and α-Oscillations: Structural and
Functional Foundations of Cognitive Control. Trends Cogn. Sci. 20, 805–817 (2016).
15. Basner, M. et al. Repeated administration effects on psychomotor vigilance test
performance. Sleep 41, (2018).
16. Basner, M. & Dinges, D. F. Maximizing sensitivity of the psychomotor vigilance test
(PVT) to sleep loss. Sleep 34, 581–91 (2011).
17. Hilditch, C. J., Centofanti, S. A., Dorrian, J. & Banks, S. A 30-Minute, but Not a 10-
Minute Nighttime Nap is Associated with Sleep Inertia. Sleep 39, 675–685 (2016).
18. Rupp, T. L., Wesensten, N. J. & Balkin, T. J. Trait-like vulnerability to total and partial
sleep loss. Sleep 35, 1163–72 (2012).
19. Coste, C. P. & Kleinschmidt, A. Cingulo-opercular network activity maintains alertness.
Neuroimage (2016). doi:10.1016/j.neuroimage.2016.01.026
20. Sturm, W. & Willmes, K. On the Functional Neuroanatomy of Intrinsic and Phasic
Alertness. Neuroimage 14, S76–S84 (2001).
21. Clemens, B. et al. Revealing the Functional Neuroanatomy of Intrinsic Alertness Using fMRI: Methodological Peculiarities. PLoS One 6, e25453 (2011).
22. Sadaghiani, S. & D’Esposito, M. Functional Characterization of the Cingulo-Opercular
Network in the Maintenance of Tonic Alertness. Cereb. Cortex 25, 2763–73 (2015).
23. Sadaghiani, S. et al. Intrinsic connectivity networks, alpha oscillations, and tonic
alertness: a simultaneous electroencephalography/functional magnetic resonance imaging
study. J. Neurosci. (2010). doi:10.1523/JNEUROSCI.1004-10.2010
24. Boly, M. et al. Baseline brain activity fluctuations predict somatosensory perception in
humans. Proc. Natl. Acad. Sci. 104, 12187–12192 (2007).
25. Sadaghiani, S., Hesselmann, G. & Kleinschmidt, A. Distributed and antagonistic
contributions of ongoing activity fluctuations to auditory stimulus detection. J. Neurosci.
29, 13410–7 (2009).
26. Sturm, W. et al. Functional anatomy of intrinsic alertness: Evidence for a fronto-parietal-
thalamic-brainstem network in the right hemisphere. Neuropsychologia (1999).
doi:10.1016/S0028-3932(98)00141-9
27. Lim, J. et al. Imaging brain fatigue from sustained mental workload: An ASL perfusion
study of the time-on-task effect. Neuroimage (2010).
doi:10.1016/j.neuroimage.2009.11.020
28. Weissman, D. H., Roberts, K. C., Visscher, K. M. & Woldorff, M. G. The neural bases of
momentary lapses in attention. Nat. Neurosci. 9, 971–978 (2006).
29. Coull, J. T., Frith, C. D., Frackowiak, R. S. J. & Grasby, P. M. A fronto-parietal network for rapid visual information processing: A PET study of sustained attention and working
memory. Neuropsychologia (1996). doi:10.1016/0028-3932(96)00029-2
30. Sturm, W. et al. Network for auditory intrinsic alertness: A PET study. Neuropsychologia
(2004). doi:10.1016/j.neuropsychologia.2003.11.004
31. Drummond, S. P. A. et al. The neural basis of the psychomotor vigilance task. Sleep 28,
1059–68 (2005).
32. Hayden, B. Y., Smith, D. V. & Platt, M. L. Electrophysiological correlates of default-
mode processing in macaque posterior cingulate cortex. Proc. Natl. Acad. Sci. U. S. A.
106, 5948–53 (2009).
33. Anticevic, A. et al. The role of default network deactivation in cognition and disease.
Trends Cogn. Sci. 16, 584–92 (2012).
34. Dosenbach, N. U. F. et al. A Core System for the Implementation of Task Sets. Neuron
(2006). doi:10.1016/j.neuron.2006.04.031
35. Singh, K. D. & Fawcett, I. P. Transient and linearly graded deactivation of the human
default-mode network by a visual detection task. Neuroimage 41, 100–12 (2008).
36. Iber, C., Ancoli-Israel, S., Chesson, A. & Quan, S. F. The AASM Manual for the Scoring
of Sleep and Associated Events: Rules, Terminology and Technical Specification. Journal
of Clinical Sleep Medicine (2007). doi:10.1017/CBO9781107415324.004
37. Power, J. D. et al. Functional Network Organization of the Human Brain. Neuron (2011).
doi:10.1016/j.neuron.2011.09.006
38. Hilditch, C. J., Dorrian, J., Centofanti, S. A., Van Dongen, H. P. & Banks, S. Sleep inertia
associated with a 10-min nap before the commute home following a night shift: A
laboratory simulation study. Accid. Anal. Prev. 99, 411–415 (2017).
39. Hofer-Tinguely, G. et al. Sleep inertia: Performance changes after sleep, rest and active
waking. Cogn. Brain Res. 22, 323–331 (2005).
40. Miccoli, L., Versace, F., Koterle, S. & Cavallero, C. Comparing sleep-loss sleepiness and sleep inertia: Lapses make the difference. Chronobiol. Int. (2008).
doi:10.1080/07420520802397228
41. Kubo, T. et al. How do the timing and length of a night-shift nap affect sleep inertia?
Chronobiol. Int. (2010). doi:10.3109/07420528.2010.489502
42. Signal, T. L., Van Den Berg, M. J., Mulrine, H. M. & Gander, P. H. Duration of sleep
inertia after napping during simulated night work and in extended operations. Chronobiol.
Int. (2012). doi:10.3109/07420528.2012.686547
43. Tietzel, A. J. & Lack, L. C. The short-term benefits of brief and long naps following
nocturnal sleep restriction. Sleep (2001). doi:10.1093/sleep/24.3.293
44. Hilditch, C. J., Dorrian, J. & Banks, S. A review of short naps and sleep inertia: do naps of
30 min or less really avoid sleep inertia and slow-wave sleep? Sleep Med. 32, 176–190
(2017).
45. Silva, E. J. & Duffy, J. F. Sleep Inertia Varies With Circadian Phase and Sleep Stage in
Older Adults. Behav. Neurosci. (2008). doi:10.1037/0735-7044.122.4.928
46. Scheer, F. A. J. L., Shea, T. J., Hilton, M. F. & Shea, S. A. An endogenous circadian
rhythm in sleep inertia results in greatest cognitive impairment upon awakening during the
biological night. J. Biol. Rhythms (2008). doi:10.1177/0748730408318081
47. Lovato, N., Lack, L., Ferguson, S. & Tremaine, R. The effects of a 30-min nap during
night shift following a prophylactic sleep in the afternoon. Sleep Biol. Rhythms (2009).
doi:10.1111/j.1479-8425.2009.00382.x
48. Nakajima, M. & Halassa, M. M. Thalamic control of functional cortical connectivity.
Current Opinion in Neurobiology 44, 127–131 (2017).
49. Hwang, K., Bertolero, M. A., Liu, W. B., Mark, X. & Esposito, D. ’. The Human
Thalamus Is an Integrative Hub for Functional Brain Networks. (2017).
doi:10.1523/JNEUROSCI.0067-17.2017
50. Magnin, M. et al. Thalamic deactivation at sleep onset precedes that of the cerebral cortex
in humans. Proc. Natl. Acad. Sci. 107, 3829–3833 (2010).
51. Baker, R. et al. Altered Activity in the Central Medial Thalamus Precedes Changes in the
Neocortex during Transitions into Both Sleep and Propofol Anesthesia. J. Neurosci. 34,
13326–13335 (2014).
52. Ren, S. et al. The paraventricular thalamus is a critical thalamic area for wakefulness.
Science (80-. ). 362, 429–434 (2018).
53. Honjoh, S. et al. Regulation of cortical activity and arousal by the matrix cells of the
ventromedial thalamic nucleus. Nat. Commun. 9, 2100 (2018).
54. Poudel, G. R., Innes, C. R. H., Bones, P. J., Watts, R. & Jones, R. D. Losing the struggle
to stay awake: Divergent thalamic and cortical activity during microsleeps. Hum. Brain
Mapp. 35, 257–269 (2014).
55. Poudel, G. R., Innes, C. R. H. & Jones, R. D. Temporal evolution of neural activity and
connectivity during microsleeps when rested and following sleep restriction. Neuroimage
174, 263–273 (2018).
56. Wu, J. C. et al. The Effect of Sleep Deprivation on Cerebral Glucose Metabolic Rate in
Normal Humans Assessed with Positron Emission Tomography. Sleep 14, 109–115
(1991).
57. Thomas, M. L. et al. Neural basis of alertness and cognitive performance impairments
during sleepiness I. Effects of 24 of sleep deprivation on waking human regional brain activity. J. Sleep Res. (2000). doi:10.1016/S1472-9288(03)00020-7
58. Thomas, M. Neural basis of alertness and cognitive performance impairments during sleepiness II. Effects of 48 and 72 h of sleep deprivation on waking human regional brain activity. Thalamus Relat. Syst. 2, 199–229 (2003).
59. Ong, J. L. et al. Co-activated yet disconnected—Neural correlates of eye closures when trying to stay awake. Neuroimage 118, 553–562 (2015).
60. Chang, C. et al. Tracking brain arousal fluctuations with fMRI. Proc. Natl. Acad. Sci. U. S. A. 113, 4518–23 (2016).
61. Olbrich, S. et al. EEG-vigilance and BOLD effect during simultaneous EEG/fMRI measurement. Neuroimage 45, 319–332 (2009).
62. Liu, X. et al. Subcortical evidence for a contribution of arousal to fMRI studies of brain activity. Nat. Commun. 9, 395 (2018).
63. Chand, T. et al. Predicting Vigilance State from the Mean Voxels Signals of Arousal Network. in OHBM (2018).
64. Paus, T. et al. Time-related changes in neural systems underlying attention and arousal during the performance of an auditory vigilance task. J. Cogn. Neurosci. (1997). doi:10.1162/jocn.1997.9.3.392
65. Yanaka, H. T., Saito, D. N., Uchiyama, Y. & Sadato, N. Neural substrates of phasic alertness: A functional magnetic resonance imaging study. Neurosci. Res. 68, 51–58 (2010).
66. Chee, M. W. L. & Tan, J. C. Lapsing when sleep deprived: Neural activation characteristics of resistant and vulnerable individuals. Neuroimage (2010). doi:10.1016/j.neuroimage.2010.02.031
67. Portas, C. M. et al. A Specific Role for the Thalamus in Mediating the Interaction of Attention and Arousal in Humans. J. Neurosci. 18, 8979–8989 (1998).
68. Schmidt, C. et al. Homeostatic sleep pressure and responses to sustained attention in the suprachiasmatic area. Science (80-. ). 324, 516–519 (2009).
69. Poudel, G. R., Innes, C. R. H. & Jones, R. D. Distinct neural correlates of time-on-task and transient errors during a visuomotor tracking task after sleep restriction. Neuroimage (2013). doi:10.1016/j.neuroimage.2013.03.054
70. Chee, M. W. et al. Lapsing during sleep deprivation is associated with distributed changes in brain activation. J Neurosci 28, 5519–5528 (2008).
71. Tomasi, D. et al. Impairment of attentional networks after 1 night of sleep deprivation. Cereb. Cortex (2009). doi:10.1093/cercor/bhn073
72. Drummond, S. P. A. et al. Altered brain response to verbal learning following sleep deprivation. Nature (2000). doi:10.1038/35001068
73. Drummond, S. P. A., Gillin, J. C. & Brown, G. G. Increased cerebral response during a divided attention task following sleep deprivation. J. Sleep Res. (2001). doi:10.1046/j.1365-2869.2001.00245.x
74. Drummond, S. P. A., Brown, G. G., Salamat, J. S. & Gillin, J. C. Increasing task difficulty facilitates the cerebral compensatory response to total sleep deprivation. Sleep (2004).
75. Drummond, S. P. A., Meloy, M. J., Yanagi, M. A., Orff, H. J. & Brown, G. G. Compensatory recruitment after sleep deprivation and the relationship with performance. Psychiatry Res. - Neuroimaging (2005). doi:10.1016/j.pscychresns.2005.06.007
76. Czisch, M. et al. On the Need of Objective Vigilance Monitoring: Effects of Sleep Loss on Target Detection and Task-Negative Activity Using Combined EEG/fMRI. Front. Neurol. 3, 67 (2012).
77. Jakab, A., Molnár, P. P., Bogner, P., Béres, M. & Berényi, E. L. Connectivity-based parcellation reveals interhemispheric differences in the insula. Brain Topogr. (2012). doi:10.1007/s10548-011-0205-y
78. Seeley, W. W. et al. Dissociable Intrinsic Connectivity Networks for Salience Processing and Executive Control. J. Neurosci. (2007). doi:10.1523/JNEUROSCI.5587-06.2007
79. Magnuson, M. E. et al. Errors on interrupter tasks presented during spatial and verbal
working memory performance are linearly linked to large-scale functional network connectivity in high temporal resolution resting state fMRI. Brain Imaging Behav. (2015). doi:10.1007/s11682-014-9347-3
80. Thompson, G. J. et al. Short-time windows of correlation between large-scale functional brain networks predict vigilance intraindividually and interindividually. Hum. Brain Mapp. (2013). doi:10.1002/hbm.22140
81. Clare Kelly, A. M., Uddin, L. Q., Biswal, B. B., Castellanos, F. X. & Milham, M. P. Competition between functional brain networks mediates behavioral variability. Neuroimage (2008). doi:10.1016/j.neuroimage.2007.08.008
82. Tomasi, D., Wang, R., Wang, G. J. & Volkow, N. D. Functional connectivity and brain activation: A synergistic approach. Cereb. Cortex 24, 2619–2629 (2014).
83. Tomasi, D. & Volkow, N. D. Association Between Brain Activation and Functional Connectivity. Cereb. Cortex 29, 1984–1996 (2019).
84. Kalcher, K. et al. RESCALE: Voxel-specific task-fMRI scaling using resting state fluctuation amplitude. Neuroimage 70, 80–88 (2013).
85. Kannurpatti, S. S., Rypma, B. & Biswal, B. B. Prediction of Task-Related BOLD fMRI with Amplitude Signatures of Resting-State fMRI. Front. Syst. Neurosci. 6, 7 (2012).
86. Dai, R. et al. Interplay between Heightened Temporal Variability of Spontaneous Brain Activity and Task-Evoked Hyperactivation in the Blind. Front. Hum. Neurosci. 10, 632 (2016).
87. Yuan, R. et al. Regional homogeneity of resting-state fMRI contributes to both neurovascular and task activation variations. Magn. Reson. Imaging 31, 1492–1500 (2013).
88. Fransson, P. How default is the default mode of brain function? Neuropsychologia 44, 2836–2845 (2006).
89. Cole, M. W., Ito, T., Bassett, D. S. & Schultz, D. H. Activity flow over resting-state networks shapes cognitive task activations. Nat. Neurosci. 19, 1718–1726 (2016).
90. Haag, L. M. et al. Resting BOLD fluctuations in the primary somatosensory cortex correlate with tactile acuity. Cortex 64, 20–28 (2015).