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Motor memory consolidation potentiated by exposition to a conditioned stimulus in stage 2 sleep
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Abstracts / Sleep Medicine 14S (2013) e165–e238
<5 h sleep. There was significant CONDITION*SLEEP interaction, p = .016. Post-hoc tests indicated that the nap group performed better in the <5 h sleep group (p < .05) but not in the other three groups (ps > .05). For negative memory, a significant main effect of CONDITION was found with better performance in the Nap group (p = .004). No main effect of SLEEP but significant CONDITION*SLEEP interaction was found (p=.045). Post-hoc tests indicated that better performance in the Nap group was found among those with <5 h, 5–6.5 h and >6.5–8 h sleep (ps < .05), but not those with >8 h sleep (ps > .05). For positive memory, no main or interaction effects were found. Conclusion: Our results showed that a nap strengthened memory of neutral valence in only the most sleep-restricted group, but the napping effects on memory of negative valence were present in groups of all sleep duration, except for the most sleep-satiated. This study provided the first evidence on the interaction between habitual sleep duration and a daytime nap on emotional memory. Acknowledgement: This work was supported by HKU Seed Funding Program for Basic Research. http://dx.doi.org/10.1016/j.sleep.2013.11.416
Tasimelteon treatment entrains the circadian clock and demonstrates significant benefit on sleep and wake parameters in totally blind individuals with non-24 hour circadian rhythms S. Lockley 1, M. Dressman 2, R. Torres 2, C. Lavedan 2, L. Licamele 2, M. Polymeropoulos 2 1 Division of Sleep Medicine, Harvard Medical School, MA, United States 2 Vanda Pharmaceuticals, United States
Introduction: The majority of totally blind individuals exhibit non24-h circadian rhythms due to light signals not reaching the suprachiasmatic nucleus, resulting in Non-24-h Sleep–Wake Disorder (Non-24), a serious circadian rhythm disorder with no approved treatment. Tasimelteon is a novel circadian regulator in development for Non-24 with selective agonist activity for melatonin MT1 and MT2 receptors. Materials and methods: Two phase III placebo-controlled studies in blind Non-24 patients assessed safety, efficacy and maintenance of effect of tasimelteon treatment (20 mg/day). Circadian period was assessed from urinary 6-sulfatoxymelatonin (aMT6s) and cortisol. Clinical assessments included a Non-24 Clinical Response Scale (N24CRS), nighttime sleep, daytime naps and Clinical Global Impression of Change (CGIC). Results: Entrainment Study (SET) (n = 84): Tasimelteon entrained the circadian clock (aMT6s: 20.0% vs. 2.6%; cortisol: 17.5% vs. 2.6%), had more clinical responders on the N24CRS (23.7 vs. 0%), improved CGIC (2.6% vs. 3.4), increased sleep in the worst quartile of nights (LQ-nTST) (57% vs. 17 min), and decreased nap duration in the worst quartile of days (UQ-dTSD) (46% vs. 18 min), compared to placebo (p < 0.05). Maintenance Study (RESET) (n = 20): Tasimelteonentrained patients were randomized to continued treatment or placebo. Tasimelteon maintained entrainment compared to placebo (aMT6s: 90% vs. 20%; cortisol: 80% vs. 20%). In treated patients, nighttime sleep (LQ-nTST) increased, and daytime sleep (UQ-dTSD) decreased, by 67 and 59 min/day, respectively (p < 0.05). During the run-in phase of the study, the rate of entrainment among tasimelteon treated patients ranged from 55% to 75% in subpopulation sensitivity analysis. Tasimelteon was safe and well-tolerated in both studies. Conclusion: Tasimelteon entrained the circadian pacemaker in blind patients with Non-24, and caused significant clinical improvement in multiple measures of sleep, wake and global functioning. Discontinuation of tasimelteon abolished circadian entrainment,
resulting in an hour less sleep each night and an hour more sleep each day. These studies demonstrate that tasimelteon is an effective circadian regulator, and that continued treatment is required to maintain entrainment and the resulting clinical benefits. Acknowledgements: Support for the study was provided by Vanda Pharmaceuticals Inc. (ClinicalTrials.gov NCT01163032 and NCT01430754). Statistical and Analytical Support was provided by Dennis Fisher at ’’P Less Than’’ company. http://dx.doi.org/10.1016/j.sleep.2013.11.417
Motor memory consolidation potentiated by exposition to a conditioned stimulus in stage 2 sleep S. Laventure, S. Fogel, G. Albouy, P. Sévigny-Dupont, J. Carrier, J. Doyon Université de Montréal, Canada
Introduction: Motor sequence learning refers to the process by which simple, stereotyped movement elements come to be performed effortlessly as a unitary sequence through multiple sessions of practice. Numerous studies have convincingly demonstrated that sleep (at night and daytime) plays a critical role in the consolidation of motor sequence learning. Yet there is no consensus regarding the sleep stages implicated in the consolidation of various motor skills. Mounting evidence indicates that stage 2 sleep and spindle activity in particular, are critical for motor memory consolidation to occur, but most of those studies are only correlational in nature. In this study, we probed a possible causal role of stage 2 sleep in motor memory consolidation using an olfactory stimulation/motor sequence learning (MSL) conditioning protocol. Materials and methods: We conditioned a first group of participants (n = 26) with a rose-like odor during learning of a sequence of finger movements, and re-exposed them to the odor during stage 2 sleep (ST2). A second group (n = 26) was conditioned with the same odor while doing the MSL task and was re-exposed during REM sleep (REM). Finally, a third group (n = 22) was not conditioned with the odor during the MSL task, but was exposed to it during stage 2 sleep (CTL). All subjects were re-tested in the morning 2 h after waking up. Performance was assessed by comparing the mean time to complete the four first blocs of retest to the four last blocs of training. Results: Analysis of gains in performance revealed a significant interaction between the experimental manipulation and participant’s gender ((F(2,68) = 5.10, p = .01). Gains were significantly higher for men than women in the ST2 group (p = .01). Also, results demonstrated that men in the ST2 group showed greater gains in performance than those in the CTL (p = .01), but not the REM group (p = .73). Men’s performance in REM group showed no significant difference to CTL group (p = .20). Conclusion: These findings not only show that it is possible to potentiate the consolidation of a motor memory trace during sleep but also strongly support the proposal that the association between stage 2 sleep and motor memory consolidation is critical. However, in regards to our results we can’t designate that effect to be specific to stage 2 sleep. Gender differences could be cause by several factors as (1) familiarity to the odor, (2) hormonal fluctuations (Genzel, 2012) or (3) differences in sleep and its characteristics during cuing. Acknowledgements: Ovidiu Lungu, Bradley King, Arnaud Boré. http://dx.doi.org/10.1016/j.sleep.2013.11.418
Abstracts / Sleep Medicine 14S (2013) e165–e238
<5 h sleep. There was significant CONDITION*SLEEP interaction, p = .016. Post-hoc tests indicated that the nap group performed better in the <5 h sleep group (p < .05) but not in the other three groups (ps > .05). For negative memory, a significant main effect of CONDITION was found with better performance in the Nap group (p = .004). No main effect of SLEEP but significant CONDITION*SLEEP interaction was found (p=.045). Post-hoc tests indicated that better performance in the Nap group was found among those with <5 h, 5–6.5 h and >6.5–8 h sleep (ps < .05), but not those with >8 h sleep (ps > .05). For positive memory, no main or interaction effects were found. Conclusion: Our results showed that a nap strengthened memory of neutral valence in only the most sleep-restricted group, but the napping effects on memory of negative valence were present in groups of all sleep duration, except for the most sleep-satiated. This study provided the first evidence on the interaction between habitual sleep duration and a daytime nap on emotional memory. Acknowledgement: This work was supported by HKU Seed Funding Program for Basic Research. http://dx.doi.org/10.1016/j.sleep.2013.11.416
Tasimelteon treatment entrains the circadian clock and demonstrates significant benefit on sleep and wake parameters in totally blind individuals with non-24 hour circadian rhythms S. Lockley 1, M. Dressman 2, R. Torres 2, C. Lavedan 2, L. Licamele 2, M. Polymeropoulos 2 1 Division of Sleep Medicine, Harvard Medical School, MA, United States 2 Vanda Pharmaceuticals, United States
Introduction: The majority of totally blind individuals exhibit non24-h circadian rhythms due to light signals not reaching the suprachiasmatic nucleus, resulting in Non-24-h Sleep–Wake Disorder (Non-24), a serious circadian rhythm disorder with no approved treatment. Tasimelteon is a novel circadian regulator in development for Non-24 with selective agonist activity for melatonin MT1 and MT2 receptors. Materials and methods: Two phase III placebo-controlled studies in blind Non-24 patients assessed safety, efficacy and maintenance of effect of tasimelteon treatment (20 mg/day). Circadian period was assessed from urinary 6-sulfatoxymelatonin (aMT6s) and cortisol. Clinical assessments included a Non-24 Clinical Response Scale (N24CRS), nighttime sleep, daytime naps and Clinical Global Impression of Change (CGIC). Results: Entrainment Study (SET) (n = 84): Tasimelteon entrained the circadian clock (aMT6s: 20.0% vs. 2.6%; cortisol: 17.5% vs. 2.6%), had more clinical responders on the N24CRS (23.7 vs. 0%), improved CGIC (2.6% vs. 3.4), increased sleep in the worst quartile of nights (LQ-nTST) (57% vs. 17 min), and decreased nap duration in the worst quartile of days (UQ-dTSD) (46% vs. 18 min), compared to placebo (p < 0.05). Maintenance Study (RESET) (n = 20): Tasimelteonentrained patients were randomized to continued treatment or placebo. Tasimelteon maintained entrainment compared to placebo (aMT6s: 90% vs. 20%; cortisol: 80% vs. 20%). In treated patients, nighttime sleep (LQ-nTST) increased, and daytime sleep (UQ-dTSD) decreased, by 67 and 59 min/day, respectively (p < 0.05). During the run-in phase of the study, the rate of entrainment among tasimelteon treated patients ranged from 55% to 75% in subpopulation sensitivity analysis. Tasimelteon was safe and well-tolerated in both studies. Conclusion: Tasimelteon entrained the circadian pacemaker in blind patients with Non-24, and caused significant clinical improvement in multiple measures of sleep, wake and global functioning. Discontinuation of tasimelteon abolished circadian entrainment,
resulting in an hour less sleep each night and an hour more sleep each day. These studies demonstrate that tasimelteon is an effective circadian regulator, and that continued treatment is required to maintain entrainment and the resulting clinical benefits. Acknowledgements: Support for the study was provided by Vanda Pharmaceuticals Inc. (ClinicalTrials.gov NCT01163032 and NCT01430754). Statistical and Analytical Support was provided by Dennis Fisher at ’’P Less Than’’ company. http://dx.doi.org/10.1016/j.sleep.2013.11.417
Motor memory consolidation potentiated by exposition to a conditioned stimulus in stage 2 sleep S. Laventure, S. Fogel, G. Albouy, P. Sévigny-Dupont, J. Carrier, J. Doyon Université de Montréal, Canada
Introduction: Motor sequence learning refers to the process by which simple, stereotyped movement elements come to be performed effortlessly as a unitary sequence through multiple sessions of practice. Numerous studies have convincingly demonstrated that sleep (at night and daytime) plays a critical role in the consolidation of motor sequence learning. Yet there is no consensus regarding the sleep stages implicated in the consolidation of various motor skills. Mounting evidence indicates that stage 2 sleep and spindle activity in particular, are critical for motor memory consolidation to occur, but most of those studies are only correlational in nature. In this study, we probed a possible causal role of stage 2 sleep in motor memory consolidation using an olfactory stimulation/motor sequence learning (MSL) conditioning protocol. Materials and methods: We conditioned a first group of participants (n = 26) with a rose-like odor during learning of a sequence of finger movements, and re-exposed them to the odor during stage 2 sleep (ST2). A second group (n = 26) was conditioned with the same odor while doing the MSL task and was re-exposed during REM sleep (REM). Finally, a third group (n = 22) was not conditioned with the odor during the MSL task, but was exposed to it during stage 2 sleep (CTL). All subjects were re-tested in the morning 2 h after waking up. Performance was assessed by comparing the mean time to complete the four first blocs of retest to the four last blocs of training. Results: Analysis of gains in performance revealed a significant interaction between the experimental manipulation and participant’s gender ((F(2,68) = 5.10, p = .01). Gains were significantly higher for men than women in the ST2 group (p = .01). Also, results demonstrated that men in the ST2 group showed greater gains in performance than those in the CTL (p = .01), but not the REM group (p = .73). Men’s performance in REM group showed no significant difference to CTL group (p = .20). Conclusion: These findings not only show that it is possible to potentiate the consolidation of a motor memory trace during sleep but also strongly support the proposal that the association between stage 2 sleep and motor memory consolidation is critical. However, in regards to our results we can’t designate that effect to be specific to stage 2 sleep. Gender differences could be cause by several factors as (1) familiarity to the odor, (2) hormonal fluctuations (Genzel, 2012) or (3) differences in sleep and its characteristics during cuing. Acknowledgements: Ovidiu Lungu, Bradley King, Arnaud Boré. http://dx.doi.org/10.1016/j.sleep.2013.11.418