Evidence for the re-enactment of a recently learned behavior during sleepwalking

Animal studies have shown that sequenced patterns of neuronal activity may be replayed during sleep. However, the existence of such replay in humans has not yet been directly demonstrated. Here we studied patients who exhibit overt behaviors during sleep to test whether sequences of movements trained during the day may be spontaneously reenacted by the patients during sleep. We recruited 19 sleepwalkers (who displayed complex and purposeful behaviors emerging from non REM sleep), 20 patients with REM sleep behavior disorder (who enacted their dreams in REM sleep) and 18 healthy controls. Continuous video sleep recordings were performed during sleep following intensive training on a sequence of large movements (learned during a variant of the serial reaction time task). Both patient groups showed learning of the intensively trained motor sequence after sleep. We report the re-enactment of a fragment of the recently trained motor behavior during one sleepwalking episode. This study provides, to our knowledge, the first evidence of a temporally-structured replay of a learned behavior during sleep in humans. Our observation also suggests that the study of such sleep disorders may provide unique and critical information about cognitive functions operating during sleep.     

Daytime Sleep Enhances Consolidation of the Spatial but Not Motoric Representation of Motor Sequence Memory

Motor sequence learning is known to rely on more than a single process. As the skill develops with practice, two different representations of the sequence are formed: a goal representation built under spatial allocentric coordinates and a movement representation mediated through egocentric motor coordinates. This study aimed to explore the influence of daytime sleep (nap) on consolidation of these two representations. Through the manipulation of an explicit finger sequence learning task and a transfer protocol, we show that both allocentric (spatial) and egocentric (motor) representations of the sequence can be isolated after initial training. Our results also demonstrate that nap favors the emergence of offline gains in performance for the allocentric, but not the egocentric representation, even after accounting for fatigue effects. Furthermore, sleep-dependent gains in performance observed for the allocentric representation are correlated with spindle density during non-rapid eye movement (NREM) sleep of the post-training nap. In contrast, performance on the egocentric representation is only maintained, but not improved, regardless of the sleep/wake condition. These results suggest that motor sequence memory acquisition and consolidation involve distinct mechanisms that rely on sleep (and specifically, spindle) or simple passage of time, depending respectively on whether the sequence is performed under allocentric or egocentric coordinates.     

Awareness modifies the skill-learning benefits of sleep

Behind every skilled movement lies months of practice. However, practice alone is not responsible for the acquisition of all skill; performance can improve between, not just within, practice sessions. An important principle shaping these offline improvements may be an individual's awareness of learning a new skill. New skills, such as a sequence of finger movements, can be learned unintentionally (with little awareness for the sequence, implicit learning) or intentionally (explicit learning). We measured skill in an implicit and explicit sequence-learning task before and after a 12 hr interval. This interval either did (8 p.m. to 8 a.m.) or did not (8 a.m. to 8 p.m.) include a period of sleep. Following explicit sequence learning, offline skill improvements were only observed when the 12 hr interval included sleep. This overnight improvement was correlated with the amount of NREM sleep. The same improvement could also be observed in the evening (with an interval from 8 p.m. to 8 p.m.), so it was not coupled to retesting at a particular time of day and cannot therefore be attributed to circadian factors. In contrast, in the implicit learning task, offline learning was observed regardless of whether the 12 hr interval did or did not contain a period of sleep. However, these improvements were not observed with only a 15 min interval between sessions. Therefore, the practice available within each session cannot account for these skill improvements. Instead, sufficient time is necessary for offline learning to occur. These results show a behavioral dissociation, based upon an individual's awareness for having learned a sequence of finger movements. Offline learning is sleep dependent for explicit skills but time dependent for implicit skills.     

Are spatial memories strengthened in the human hippocampus during slow wave sleep?

In rats, the firing sequences observed in hippocampal ensembles during spatial learning are replayed during subsequent sleep, suggesting a role for posttraining sleep periods in the offline processing of spatial memories. Here, using regional cerebral blood flow measurements, we show that, in humans, hippocampal areas that are activated during route learning in a virtual town are likewise activated during subsequent slow wave sleep. Most importantly, we found that the amount of hippocampal activity expressed during slow wave sleep positively correlates with the improvement of performance in route retrieval on the next day. These findings suggest that learning-dependent modulation in hippocampal activity during human sleep reflects the offline processing of recent episodic and spatial memory traces, which eventually leads to the plastic changes underlying the subsequent improvement in performance.     

Hippocampal Sharp Wave/Ripples during Sleep for Consolidation of Associative Memory

The beneficial effect of sleep on memory has been well-established by extensive research on humans, but the neurophysiological mechanisms remain a matter of speculation. This study addresses the hypothesis that the fast oscillations known as ripples recorded in the CA1 region of the hippocampus during slow wave sleep (SWS) may provide a physiological substrate for long term memory consolidation. We trained rats in a spatial discrimination task to retrieve palatable reward in three fixed locations. Hippocampal local field potentials and cortical EEG were recorded for 2 h after each daily training session. There was an increase in ripple density during SWS after early training sessions, in both trained rats and in rats randomly rewarded for exploring the maze. In rats learning the place -reward association, there was a striking further significant increase in ripple density correlated with subsequent improvements in behavioral performance as the rat learned the spatial discrimination aspect of the task. The results corroborate others showing an experience-dependent increase in ripple activity and associated ensemble replay after exploratory activity, but in addition, for the first time, reveal a clear further increase in ripple activity related to associative learning based on spatial discrimination.     

Dynamics of population code for working memory in the prefrontal cortex

Some neurons (delay cells) in the prefrontal cortex elevate their activities throughout the time period during which the animal is required to remember past events and prepare future behavior, suggesting that working memory is mediated by continuous neural activity. It is unknown, however, how working memory is represented within a population of prefrontal cortical neurons. We recorded from neuronal ensembles in the prefrontal cortex as rats learned a new delayed alternation task. Ensemble activities changed in parallel with behavioral learning so that they increasingly allowed correct decoding of previous and future goal choices. In well-trained rats, considerable decoding was possible based on only a few neurons and after removing continuously active delay cells. These results show that neural activity in the prefrontal cortex changes dynamically during new task learning so that working memory is robustly represented and that working memory can be mediated by sequential activation of different neural populations.     

Interaction between Hippocampal and Striatal Systems Predicts Subsequent Consolidation of Motor Sequence Memory

The development of fast and reproducible motor behavior is a crucial human capacity. The aim of the present study was to address the relationship between the implementation of consistent behavior during initial training on a sequential motor task (the Finger Tapping Task) and subsequent sleep-dependent motor sequence memory consolidation, using functional magnetic resonance imaging (fMRI) and total sleep deprivation protocol. Our behavioral results indicated significant offline gains in performance speed after sleep whereas performance was only stabilized, but not enhanced, after sleep deprivation. At the cerebral level, we previously showed that responses in the caudate nucleus increase, in parallel to a decrease in its functional connectivity with frontal areas, as performance became more consistent. Here, the strength of the competitive interaction, assessed through functional connectivity analyses, between the caudate nucleus and hippocampo-frontal areas during initial training, predicted delayed gains in performance at retest in sleepers but not in sleep-deprived subjects. Moreover, during retest, responses increased in the hippocampus and medial prefrontal cortex in sleepers whereas in sleep-deprived subjects, responses increased in the putamen and cingulate cortex. Our results suggest that the strength of the competitive interplay between the striatum and the hippocampus, participating in the implementation of consistent motor behavior during initial training, conditions subsequent motor sequence memory consolidation. The latter process appears to be supported by a reorganisation of cerebral activity in hippocampo-neocortical networks after sleep.     

NREM2 and Sleep Spindles Are Instrumental to the Consolidation of Motor Sequence Memories

Although numerous studies have convincingly demonstrated that sleep plays a critical role in motor sequence learning (MSL) consolidation, the specific contribution of the different sleep stages in this type of memory consolidation is still contentious. To probe the role of stage 2 non-REM sleep (NREM2) in this process, we used a conditioning protocol in three different groups of participants who either received an odor during initial training on a motor sequence learning task and were re-exposed to this odor during different sleep stages of the post-training night (i.e., NREM2 sleep [Cond-NREM2], REM sleep [Cond-REM], or were not conditioned during learning but exposed to the odor during NREM2 [NoCond]). Results show that the Cond-NREM2 group had significantly higher gains in performance at retest than both the Cond-REM and NoCond groups. Also, only the Cond-NREM2 group yielded significant changes in sleep spindle characteristics during cueing. Finally, we found that a change in frequency of sleep spindles during cued-memory reactivation mediated the relationship between the experimental groups and gains in performance the next day. These findings strongly suggest that cued-memory reactivation during NREM2 sleep triggers an increase in sleep spindle activity that is then related to the consolidation of motor sequence memories.     

Odor fear conditioning modifies piriform cortex local field potentials both during conditioning and during post-conditioning sleep

Background

Sleep plays an active role in memory consolidation. Sleep structure (REM/Slow wave activity [SWS]) can be modified after learning, and in some cortical circuits, sleep is associated with replay of the learned experience. While the majority of this work has focused on neocortical and hippocampal circuits, the olfactory system may offer unique advantages as a model system for exploring sleep and memory, given the short, non-thalamic pathway from nose to primary olfactory (piriform cortex), and rapid cortex-dependent odor learning.

Methodology/Principal Findings

We examined piriform cortical odor responses using local field potentials (LFPs) from freely behaving Long-Evans hooded rats over the sleep-wake cycle, and the neuronal modifications that occurred within the piriform cortex both during and after odor-fear conditioning. We also recorded LFPs from naïve animals to characterize sleep activity in the piriform cortex and to analyze transient odor-evoked cortical responses during different sleep stages. Naïve rats in their home cages spent 40% of their time in SWS, during which the piriform cortex was significantly hypo-responsive to odor stimulation compared to awake and REM sleep states. Rats trained in the paired odor-shock conditioning paradigm developed enhanced conditioned odor evoked gamma frequency activity in the piriform cortex over the course of training compared to pseudo-conditioned rats. Furthermore, conditioned rats spent significantly more time in SWS immediately post-training both compared to pre-training days and compared to pseudo-conditioned rats. The increase in SWS immediately after training significantly correlated with the duration of odor-evoked freezing the following day.

Conclusions/Significance

The rat piriform cortex is hypo-responsive to odors during SWS which accounts for nearly 40% of each 24 hour period. The duration of slow-wave activity in the piriform cortex is enhanced immediately post-conditioning, and this increase is significantly correlated with subsequent memory performance. Together, these results suggest the piriform cortex may go offline during SWS to facilitate consolidation of learned odors with reduced external interference.     

Offline persistence of memory-related cerebral activity during active wakefulness

Much remains to be discovered about the fate of recent memories in the human brain. Several studies have reported the reactivation of learning-related cerebral activity during post-training sleep, suggesting that sleep plays a role in the offline processing and consolidation of memory. However, little is known about how new information is maintained and processed during post-training wakefulness before sleep, while the brain is actively engaged in other cognitive activities. We show, using functional magnetic resonance imaging, that brain activity elicited during a new learning episode modulates brain responses to an unrelated cognitive task, during the waking period following the end of training. This post-training activity evolves in learning-related cerebral structures, in which functional connections with other brain regions are gradually established or reinforced. It also correlates with behavioral performance. These processes follow a different time course for hippocampus-dependent and hippocampus-independent memories. Our experimental approach allowed the characterization of the offline evolution of the cerebral correlates of recent memories, without the confounding effect of concurrent practice of the learned material. Results indicate that the human brain has already extensively processed recent memories during the first hours of post-training wakefulness, even when simultaneously coping with unrelated cognitive demands.     

Neural correlates of internal-model loading

Skilled object manipulation requires knowledge, or internal models, of object dynamics relating applied force to motion , and our ability to handle myriad objects indicates that the brain maintains multiple models . Recent behavioral studies have shown that once learned, an internal model of an object with novel dynamics can be rapidly recruited and derecruited as the object is grasped and released . We used event-related fMRI to investigate neural activity linked to grasping an object with recently learned dynamics in preparation for moving it after a delay. Subjects also performed two control tasks in which they either moved without the object in hand or applied isometric forces to the object. In all trials, subjects received a cue indicating which task to perform in response to a go signal delivered 5-10 s later. We examined BOLD responses during the interval between the cue and go and assessed the conjunction of the two contrasts formed by comparing the primary task to each control. The analysis revealed significant activity in the ipsilateral cerebellum and the contralateral and supplementary motor areas. We propose that these regions are involved in internal-model recruitment in preparation for movement execution.     

Redundant information encoding in primary motor cortex during natural and prosthetic motor control

Redundant encoding of information facilitates reliable distributed information processing. To explore this hypothesis in the motor system, we applied concepts from information theory to quantify the redundancy of movement-related information encoded in the macaque primary motor cortex (M1) during natural and neuroprosthetic control. Two macaque monkeys were trained to perform a delay center-out reaching task controlling a computer cursor under natural arm movement (manual control, ‘MC’), and using a brain-machine interface (BMI) via volitional control of neural ensemble activity (brain control, ‘BC’). During MC, we found neurons in contralateral M1 to contain higher and more redundant information about target direction than ipsilateral M1 neurons, consistent with the laterality of movement control. During BC, we found that the M1 neurons directly incorporated into the BMI (‘direct’ neurons) contained the highest and most redundant target information compared to neurons that were not incorporated into the BMI (‘indirect’ neurons). This effect was even more significant when comparing to M1 neurons of the opposite hemisphere. Interestingly, when we retrained the BMI to use ipsilateral M1 activity, we found that these neurons were more redundant and contained higher information than contralateral M1 neurons, even though ensembles from this hemisphere were previously less redundant during natural arm movement. These results indicate that ensembles most associated to movement contain highest redundancy and information encoding, which suggests a role for redundancy in proficient natural and prosthetic motor control.     

Differential corticostriatal plasticity during fast and slow motor skill learning in mice

BACKGROUND: Motor skill learning usually comprises "fast" improvement in performance within the initial training session and "slow" improvement that develops across sessions. Previous studies have revealed changes in activity and connectivity in motor cortex and striatum during motor skill learning. However, the nature and dynamics of the plastic changes in each of these brain structures during the different phases of motor learning remain unclear. RESULTS: By using multielectrode arrays, we recorded the simultaneous activity of neuronal ensembles in motor cortex and dorsal striatum of mice during the different phases of skill learning on an accelerating rotarod. Mice exhibited fast improvement in the task during the initial session and also slow improvement across days. Throughout training, a high percentage of striatal (57%) and motor cortex (55%) neurons were task related; i.e., changed their firing rate while mice were running on the rotarod. Improvement in performance was accompanied by substantial plastic changes in both striatum and motor cortex. We observed parallel recruitment of task-related neurons in both structures specifically during the first session. Conversely, during slow learning across sessions we observed differential refinement of the firing patterns in each structure. At the neuronal ensemble level, we observed considerable changes in activity within the first session that became less evident during subsequent sessions. CONCLUSIONS: These data indicate that cortical and striatal circuits exhibit remarkable but dissociable plasticity during fast and slow motor skill learning and suggest that distinct neural processes mediate the different phases of motor skill learning.     

Patterns of spatio-temporal correlations in the neural activity of the cat motor cortex during trained forelimb movements

In order to study how neurons in the primary motor cortex (MI) are dynamically linked together during skilled movement, we recorded simultaneously from many cortical neurons in cats trained to perform a reaching and retrieval task using their forelimbs. Analysis of task-related spike activity in the MI of the hemisphere contralateral to the reaching forelimb (in identified forelimb or hindlimb representations) recorded through chronically implanted microwires, was followed by pairwise evaluation of temporally correlated activity in these neurons during task performance using shuffle corrected cross-correlograms. Over many months of recording, a variety of task-related modulations of neural activities were observed in individual efferent zones. Positively correlated activity (mainly narrow peaks at zero or short latencies) was seen during task performance frequently between neurons recorded within the forelimb representation of MI, rarely within the hindlimb area of MI, and never between forelimb and hindlimb areas. Correlated activity was frequently observed between neurons with different patterns of task-related activity or preferential activity during different task elements (reaching, feeding, etc.), and located in efferent zones with dissimilar representation as defined by intracortical microstimulation. The observed synchronization of action potentials among selected but functionally varied groups of MI neurons possibly reflects dynamic recruitment of network connections between efferent zones during skilled movement.     

Conserved fMRI and LFP signals during new associative learning in the human and macaque monkey medial temporal lobe

We measured local field potential (LFP) and blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) in the medial temporal lobes of monkeys and humans, respectively, as they performed the same conditional motor associative learning task. Parallel analyses were used to examine both data sets. Despite significantly faster learning in humans relative to monkeys, we found equivalent neural signals differentiating new versus highly familiar stimuli, first stimulus presentation, trial outcome, and learning strength in the entorhinal cortex and hippocampus of both species. Thus, the use of parallel behavioral tasks and analyses in monkeys and humans revealed conserved patterns of neural activity across the medial temporal lobe during an associative learning task.     

The Consolidation of Implicit Sequence Memory in Obstructive Sleep Apnea

Obstructive Sleep Apnea (OSA) Syndrome is a relatively frequent sleep disorder characterized by disrupted sleep patterns. It is a well-established fact that sleep has beneficial effect on memory consolidation by enhancing neural plasticity. Implicit sequence learning is a prominent component of skill learning. However, the formation and consolidation of this fundamental learning mechanism remains poorly understood in OSA. In the present study we examined the consolidation of different aspects of implicit sequence learning in patients with OSA. We used the Alternating Serial Reaction Time task to measure general skill learning and sequence-specific learning. There were two sessions: a learning phase and a testing phase, separated by a 10-hour offline period with sleep. Our data showed differences in offline changes of general skill learning between the OSA and control group. The control group demonstrated offline improvement from evening to morning, while the OSA group did not. In contrast, we did not observe differences between the groups in offline changes in sequence-specific learning. Our findings suggest that disrupted sleep in OSA differently affects neural circuits involved in the consolidation of sequence learning.     

Consolidation of dynamic motor learning is not disrupted by rTMS of primary motor cortex

Motor skills, once learned, are often retained over a long period of time. However, such learning first undergoes a period of consolidation after practice. During this time, the motor memory is susceptible to being disrupted by the performance of another motor-learning task. Recently, it was shown that repetitive transcranial magnetic stimulation (rTMS) over the primary motor cortex could disrupt the retention of a newly learned ballistic task in which subjects had to oppose their index finger and thumb as rapidly as possible. Here we investigate whether the motor cortex is similarly involved during the consolidation that follows learning novel dynamics. We applied rTMS to primary motor cortex shortly after subjects had either learned to compensate for a dynamic force field applied to their index finger or learned a ballistic finger abduction task. rTMS severely degraded the retention of the learning for the ballistic task but had no effect on retention of the dynamic force-field learning. This suggests that, unlike learning of simple ballistic skills, learning of dynamics may be stored in a more distributed manner, possibly outside the primary motor cortex.     

Increased resting-state perfusion after repeated encoding is related to later retrieval of declarative associative memories

Electrophysiological studies in animals have shown coordinated reactivation of neuronal ensembles during a restricted time period of behavioral inactivity that immediately followed active encoding. In the present study we directly investigated off-line processing of associative memory formation in the human brain. Subjects' regional cerebral blood flow (rCBF) as a surrogate marker of neural activity during rest was measured by MR-based perfusion imaging in a sample of 14 healthy male subjects prior to (Pre2) and after (Post) extensive learning of 24 face-name associations within a selective reminding task (SR). Results demonstrated significant Post-Pre2 rCBF increases in hippocampal and temporal lobe regions, while in a control comparison of two perfusion scans with no learning task in-between (Pre2-Pre1) no differences in rCBF emerged. Post perfusion scanning was followed by a surprise cued associative recall task from which two types of correctly retrieved names were obtained: older names already correctly retrieved at least once during one of the SR blocks, and recent names acquired during the last SR block immediately prior to the Post scan. In the anterior hippocampus individual perfusion increases were correlated with both correct retrievals of older and recent names. By contrast, older but not recently learned names showed a significant correlation with perfusion increases in the left lateral temporal cortex known to be associated with long-term memory. Recent, but not older names were correlated with dopaminergic midbrain structures reported to contribute to the persistence of memory traces for novel information. Although the direct investigation of off-line memory processing did not permit concomitant experimental control, neither intentional rehearsal, nor substantial variations in subjects' states of alertness appear to contribute to present results. We suggest that the observed rCBF increases might reflect processes that possibly contribute to the long-term persistence of memory traces.     

Rats’ learning of a new motor skill: Insight into the evolution of motor sequence learning

Recent behavioral and neural evidence has suggested that ethologically relevant sub-movements (movement primitives) are used by primates for more complex motor skill learning. These primitives include extending the hand, grasping an object, and holding food while moving it toward the mouth. In prior experiments with rats performing a reach-to-grasp-food task, we observed that especially during early task learning, rats appeared to have movement primitives similar to those seen in primates. Unlike primates, however, during task learning the rats performed these sub-movements in a disordered manner not seen in humans or macaques, e.g. with the rat chewing before placing the food pellet in its mouth. Here, in two experiments, we tested the hypothesis that for rats, learning this ecologically relevant skill involved learning to concatenate the sub-movements in the correct order. The results confirmed our initial observations, and suggested that several aspects of forepaw/hand use, taken for granted in primate studies, must be learned by rats to perform a logically connected and seemingly ecologically important series of sub-movements. We discuss our results from a comparative and evolutionary perspective.     

Nonvisual motor training influences biological motion perception

Experimental evidence suggests a link between perception and the execution of actions . In particular, it has been proposed that motor programs might directly influence visual action perception . According to this hypothesis, the acquisition of novel motor behaviors should improve their visual recognition, even in the absence of visual learning. We tested this prediction by using a new experimental paradigm that dissociates visual and motor learning during the acquisition of novel motor patterns. The visual recognition of gait patterns from point-light stimuli was assessed before and after nonvisual motor training. During this training, subjects were blindfolded and learned a novel coordinated upper-body movement based only on verbal and haptic feedback. The learned movement matched one of the visual test patterns. Despite the absence of visual stimulation during training, we observed a selective improvement of the visual recognition performance for the learned movement. Furthermore, visual recognition performance after training correlated strongly with the accuracy of the execution of the learned motor pattern. These results prove, for the first time, that motor learning has a direct and highly selective influence on visual action recognition that is not mediated by visual learning.