Human motor sequence learning drives transient changes in network topology and hippocampal connectivity early during memory consolidation.

In the last decade, the exclusive role of the hippocampus in human declarative learning has been challenged. Recently, we have shown that gains in performance observed in motor sequence learning (MSL) during the quiet rest periods interleaved with practice are associated with increased hippocampal activity, suggesting a role of this structure in motor memory reactivation. Yet, skill also develops offline as memory stabilizes after training and overnight. To examine whether the hippocampus contributes to motor sequence memory consolidation, here we used a network neuroscience strategy to track its functional connectivity offline 30 min and 24 h post learning using resting-state functional magnetic resonance imaging. Using a graph-analytical approach we found that MSL transiently increased network modularity, reflected in an increment in local information processing at 30 min that returned to baseline at 24 h. Within the same time window, MSL decreased the connectivity of a hippocampal-sensorimotor network, and increased the connectivity of a striatal-premotor network in an antagonistic manner. Finally, a supervised classification identified a low-dimensional pattern of hippocampal connectivity that discriminated between control and MSL data with high accuracy. The fact that changes in hippocampal connectivity were detected shortly after training supports a relevant role of the hippocampus in early stages of motor memory consolidation.

Motor Learning Promotes the Coupling between Fast Spindles and Slow Oscillations Locally over the Contralateral Motor Network.

Recent studies from us and others suggest that traditionally declarative structures mediate some aspects of the encoding and consolidation of procedural memories. This evidence points to the existence of converging physiological pathways across memory systems. Here, we examined whether the coupling between slow oscillations (SO) and spindles, a mechanism well established in the consolidation of declarative memories, is relevant for the stabilization of human motor memories. To this aim, we conducted an electroencephalography study in which we quantified various parameters of these oscillations during a night of sleep that took place immediately after learning a visuomotor adaptation (VMA) task. We found that VMA increased the overall density of fast (≥12 Hz), but not slow (<12 Hz), spindles during nonrapid eye movement sleep, stage 3 (NREM3). This modulation occurred rather locally over the hemisphere contralateral to the trained hand. Although adaptation learning did not affect the density of SOs, it substantially enhanced the number of fast spindles locked to the active phase of SOs. The fact that only coupled spindles predicted overnight memory retention points to the relevance of this association in motor memory consolidation. Our work provides evidence in favor of a common mechanism at the basis of the stabilization of declarative and motor memories.

Rapid hippocampal plasticity supports motor sequence learning.

Recent evidence suggests that gains in performance observed while humans learn a novel motor sequence occur during the quiet rest periods interleaved with practice (micro-offline gains, MOGs). This phenomenon is reminiscent of memory replay observed in the hippocampus during spatial learning in rodents. Whether the hippocampus is also involved in the production of MOGs remains currently unknown. Using a multimodal approach in humans, here we show that activity in the hippocampus and the precuneus increases during the quiet rest periods and predicts the level of MOGs before asymptotic performance is achieved. These functional changes were followed by rapid alterations in brain microstructure in the order of minutes, suggesting that the same network that reactivates during the quiet periods of training undergoes structural plasticity. Our work points to the involvement of the hippocampal system in the reactivation of procedural memories.

The Origins of Anterograde Interference in Visuomotor Adaptation.

Anterograde interference refers to the negative impact of prior learning on the propensity for future learning. There is currently no consensus on whether this phenomenon is transient or long lasting, with studies pointing to an effect in the time scale of hours to days. These inconsistencies might be caused by the method employed to quantify performance, which often confounds changes in learning rate and retention. Here, we aimed to unveil the time course of anterograde interference by tracking its impact on visuomotor adaptation at different intervals throughout a 24-h period. Our empirical and model-based approaches allowed us to measure the capacity for new learning separately from the influence of a previous memory. In agreement with previous reports, we found that prior learning persistently impaired the initial level of performance upon revisiting the task. However, despite this strong initial bias, learning capacity was impaired only when conflicting information was learned up to 1 h apart, recovering thereafter with passage of time. These findings suggest that when adapting to conflicting perturbations, impairments in performance are driven by two distinct mechanisms: a long-lasting bias that acts as a prior and hinders initial performance and a short-lasting anterograde interference that originates from a reduction in error sensitivity.

Improving Spatial Normalization of Brain Diffusion MRI to Measure Longitudinal Changes of Tissue Microstructure in the Cortex and White Matter.

BACKGROUND: Fractional anisotropy (FA) and mean diffusivity (MD) are frequently used to evaluate longitudinal changes in white matter (WM) microstructure. Recently, there has been a growing interest in identifying experience-dependent plasticity in gray matter using MD. Improving registration has thus become a major goal to enhance the detection of subtle longitudinal changes in cortical microstructure. PURPOSE: To optimize normalization of diffusion tensor images (DTI) to improve registration in gray matter and reduce variability associated with multisession registrations. STUDY TYPE: Prospective longitudinal study. SUBJECTS: Twenty-one healthy subjects (18-31 years old) underwent nine MRI scanning sessions each. FIELD STRENGTH/SEQUENCE: 3.0T, diffusion-weighted multiband-accelerated sequence, MP2RAGE sequence. ASSESSMENT: Diffusion-weighted images were registered to standard space using different pipelines that varied in the features used for normalization, namely, the nonlinear registration algorithm (FSL vs. ANTs), the registration target (FA-based vs. T1 -based templates), and the use of intermediate individual (FA-based or T1 -based) targets. We compared the across-session test-retest reproducibility error of these normalization approaches for FA and MD in white and gray matter. STATISTICAL TESTS: Reproducibility errors were compared using a repeated-measures analysis of variance with pipeline as the within-subject factor. RESULTS: The registration of FA data to the FMRIB58 FA atlas using ANTs yielded lower reproducibility errors in white matter (P < 0.0001) with respect to FSL. Moreover, using the MNI152 T1 template as the target of registration resulted in lower reproducibility errors for MD (P < 0.0001), whereas the FMRIB58 FA template performed better for FA (P < 0.0001). Finally, the use of an intermediate individual template improved reproducibility when registration of the FA images to the MNI152 T1 was carried out within modality (FA-FA) (P < 0.05), but not via a T1 -based individual template. DATA CONCLUSION: A normalization approach using ANTs to register FA images to the MNI152 T1 template via an individual FA template minimized test-retest reproducibility errors both for gray and white matter. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 1 J. Magn. Reson. Imaging 2020;52:766-775.

Functional Evidence for Memory Stabilization in Sensorimotor Adaptation: A 24-h Resting-State fMRI Study.

Adaptation learning is crucial to maintain precise motor control in face of environmental perturbations. Although much progress has been made in understanding the psychophysics and neurophysiology of sensorimotor adaptation (SA), the time course of memory consolidation remains elusive. The lack of a reproducible gradient of memory resistance using protocols of retrograde interference has even led to the proposal that memories produced through SA do not consolidate. Here, we pursued an alternative approach using resting-state fMRI to track changes in functional connectivity (FC) induced by learning. Given that consolidation leads to long-term memory, we hypothesized that a change in FC that predicted long-term memory but not short-term memory would provide indirect evidence for memory stabilization. Six scans were acquired before, 15 min, 1, 3, 5.5, and 24 h after training on a center-out task under veridical or distorted visual feedback. The experimental group showed an increment in FC of a network including motor, premotor, posterior parietal cortex, cerebellum, and putamen that peaked at 5.5 h. Crucially, the strengthening of this network correlated positively with long-term retention but negatively with short-term retention. Our work provides evidence, suggesting that adaptation memories stabilize within a 6-h window, and points to different mechanisms subserving short- and long-term memory.

Extinction interferes with the retrieval of visuomotor memories through a mechanism involving the sensorimotor cortex.

Savings is a fundamental property of learning. In motor adaptation, it refers to the improvement in learning observed when adaptation to a perturbation A (A1) is followed by re-adaptation to the same perturbation (A2). A common procedure to equate the initial level of error across sessions consists of restoring native sensorimotor coordinates by inserting null--unperturbed--trials (N) just before re-adaptation (washout). Here, we hypothesized that the washout is not innocuous but interferes with the expression of the new memory at recall. To assess this possibility, we measured savings following the A1NA2 protocol, where A was a 40° visual rotation. In Experiment 1, we increased the time window between N and A2 from 1 min to 24 h. This manipulation increased the amount of savings during middle to late phases of adaptation, suggesting that N interfered with the retrieval of A. In Experiment 2, we used repetitive TMS to evaluate if this interference was partly mediated by the sensorimotor cortex (SM). We conclude that the washout does not just restore the unperturbed sensorimotor coordinates, but inhibits the expression of the recently acquired visuomotor map through a mechanism involving SM. Our results resemble the phenomenon of extinction in classical conditioning.

The Relative Influence of Goal and Kinematics on Corticospinal Excitability Depends on the Information Provided to the Observer.

Viewing a person perform an action activates the observer's motor system. Whether this phenomenon reflects the action's kinematics or its final goal remains a matter of debate. One alternative to this apparent controversy is that the relative influence of goal and kinematics depends on the information available to the observer. Here, we addressed this possibility. For this purpose, we measured corticospinal excitability (CSE) while subjects viewed 3 different grasping actions with 2 goals: a large and a small object. Actions were directed to the large object, the small object, or corrected online in which case the goal switched during the movement. We first determined the kinematics and dynamics of the 3 actions during execution. This information was used in 2 other experiments to measure CSE while observers viewed videos of the same actions. CSE was recorded prior to movement onset and at 3 time points during the observed action. To discern between goal and kinematics, information about the goal was manipulated across experiments. We found that the goal influenced CSE only when its identity was known before movement onset. In contrast, a kinematic modulation of CSE was observed whether or not information regarding the goal was provided.

Feature interactions enable decoding of sensorimotor transformations for goal-directed movement.

Neurophysiology and neuroimaging evidence shows that the brain represents multiple environmental and body-related features to compute transformations from sensory input to motor output. However, it is unclear how these features interact during goal-directed movement. To investigate this issue, we examined the representations of sensory and motor features of human hand movements within the left-hemisphere motor network. In a rapid event-related fMRI design, we measured cortical activity as participants performed right-handed movements at the wrist, with either of two postures and two amplitudes, to move a cursor to targets at different locations. Using a multivoxel analysis technique with rigorous generalization tests, we reliably distinguished representations of task-related features (primarily target location, movement direction, and posture) in multiple regions. In particular, we identified an interaction between target location and movement direction in the superior parietal lobule, which may underlie a transformation from the location of the target in space to a movement vector. In addition, we found an influence of posture on primary motor, premotor, and parietal regions. Together, these results reveal the complex interactions between different sensory and motor features that drive the computation of sensorimotor transformations.

Direct mapping rather than motor prediction subserves modulation of corticospinal excitability during observation of actions in real time.

Motor facilitation refers to the specific increment in corticospinal excitability (CSE) elicited by the observation of actions performed by others. To date, the precise nature of the mechanism at the basis of this phenomenon is unknown. One possibility is that motor facilitation is driven by a predictive process reminiscent of the role of forward models in motor control. Alternatively, motor facilitation may result from a model-free mechanism by which the basic elements of the observed action are directly mapped onto their cortical representations. Our study was designed to discern these alternatives. To this aim, we recorded the time course of CSE for the first dorsal interosseous (FDI) and the abductor digiti minimi (ADM) during observation of three grasping actions in real time, two of which strongly diverged in kinematics from their natural (invariant) form. Although artificially slow movements used in most action observation studies might enhance the observer's discrimination performance, the use of videos in real time is crucial to maintain the time course of CSE within the physiological range of daily actions. CSE was measured at 4 time points within a 240-ms window that best captured the kinematic divergence from the invariant form. Our results show that CSE of the FDI, not the ADM, closely follows the functional role of the muscle despite the mismatch between the natural and the divergent kinematics. We propose that motor facilitation during observation of actions performed in real time reflects the model-free coding of perceived movement following a direct mapping mechanism.

Suprachiasmatic vasopressin and the circadian regulation of voluntary locomotor behavior.

A role for arginine vasopressin in the circadian regulation of voluntary locomotor behavior (wheel running activity) was investigated in the golden hamster, Mesocricetus auratus. Spontaneous nocturnal running was suppressed in a dose-dependent manner by systemic injections of vasopressin, and also in a concentration-dependent manner by microinjections directly into the hypothalamic suprachiasmatic nucleus. Pre-injections of a vasopressin V1 receptor antagonist into the nucleus reduced the suppression of behavior by vasopressin. Ethogram analyses revealed that peripheral drug injections predominantly increased grooming, flank marking, and sleep-related behaviors. Central injections did not induce sleep, but increased grooming and periods of 'quiet vigilance' (awake but not moving). Nocturnal behavioral profiles following either peripheral or central injections were similar to those shown by untreated animals in the hour prior to the onset of nocturnal wheel running. Site control vasopressin injections into the medial preoptic area or periaqueductal gray increased flank marking and grooming, but had no significant effect on locomotion, suggesting behavioral specificity of a vasopressin target near the suprachiasmatic nucleus. Both peripheral and central administration increased FOS-like immunoreactivity in the retinorecipient core of the suprachiasmatic nucleus. The distribution of FOS-positive cells overlapped the calbindin subregion, but was more extensive, and most calbindin-positive cells did not co-express FOS. We propose a model of temporal behavioral regulation wherein voluntary behavior, such as nocturnal locomotor activity, is inhibited by the activity of neurons in the suprachiasmatic ventrolateral core that project to the posterior hypothalamus and are driven by rhythmic vasopressin input from the dorsomedial shell.

One week of motor adaptation induces structural changes in primary motor cortex that predict long-term memory one year later.

The neural bases of motor adaptation have been extensively explored in human and nonhuman primates. A network including the cerebellum, primary motor cortex, and posterior parietal cortex appears to be crucial for this type of learning. Yet, to date, it is unclear whether these regions contribute directly or indirectly to the formation of motor memories. Here we trained subjects on a complex visuomotor rotation associated with long-term memory (in the order of months) to identify potential sites of structural plasticity induced by adaptation. One week of training led to (1) an increment in local gray matter concentration over the hand area of the contralateral primary motor cortex and (2) an increase in fractional anisotropy in an area underneath this region that correlated with the speed of learning. Moreover, the change in gray matter concentration measured immediately after training predicted improvements in the speed of learning during readaptation 1 year later. Our study suggests that motor adaptation induces structural plasticity in primary motor circuits. In addition, it provides the first piece of evidence indicating that early structural changes induced by motor learning may impact on behavior up to 1 year after training.

Visuomotor Adaptation Modulates the Clustering of Sleep Spindles Into Trains.

Sleep spindles are thought to promote memory consolidation. Recently, we have shown that visuomotor adaptation (VMA) learning increases the density of spindles and promotes the coupling between spindles and slow oscillations, locally, with the level of spindle-SO synchrony predicting overnight memory retention. Yet, growing evidence suggests that the rhythmicity in spindle occurrence may also influence the stabilization of declarative and procedural memories. Here, we examined if VMA learning promotes the temporal organization of sleep spindles into trains. We found that VMA increased the proportion of spindles and spindle-SO couplings in trains. In agreement with our previous work, this modulation was observed over the contralateral hemisphere to the trained hand, and predicted overnight memory retention. Interestingly, spindles grouped in a cluster showed greater amplitude and duration than isolated spindles. The fact that these features increased as a function of train length, provides evidence supporting a biological advantage of this temporal arrangement. Our work opens the possibility that the periodicity of NREM oscillations may be relevant in the stabilization of procedural memories.

Competition between parallel sensorimotor learning systems.

Sensorimotor learning is supported by at least two parallel systems: a strategic process that benefits from explicit knowledge and an implicit process that adapts subconsciously. How do these systems interact? Does one system's contributions suppress the other, or do they operate independently? Here, we illustrate that during reaching, implicit and explicit systems both learn from visual target errors. This shared error leads to competition such that an increase in the explicit system's response siphons away resources that are needed for implicit adaptation, thus reducing its learning. As a result, steady-state implicit learning can vary across experimental conditions, due to changes in strategy. Furthermore, strategies can mask changes in implicit learning properties, such as its error sensitivity. These ideas, however, become more complex in conditions where subjects adapt using multiple visual landmarks, a situation which introduces learning from sensory prediction errors in addition to target errors. These two types of implicit errors can oppose each other, leading to another type of competition. Thus, during sensorimotor adaptation, implicit and explicit learning systems compete for a common resource: error.

Functional integration across a gradient of corticostriatal channels controls UP state transitions in the dorsal striatum.

Coordinated near-threshold depolarized states in cortical and striatal neurons may contribute to form functionally segregated channels of information processing. Recent anatomical studies have identified pathways that could support spiraling interactions across corticostriatal channels, but a functional outcome of such spiraling remains to be identified. Here, we examined whether plateau depolarizations (UP states) in striatal neurons relate better to active epochs in local field potentials recorded from closely related cortical areas than to those recorded in less-related cortical areas. Our results show that, in anesthetized rats, the coordination between cortical areas and striatal regions obeys a mediolateral gradient and keeps track of slow wave trajectory across the neocortex. Moreover, activity in one cortical area induced phase advances in UP state onset and phase delays in UP state termination in nonmatching striatal regions, reflecting the existence of functional connections that could encode large-scale interactions between corticostriatal channels as subthreshold influences on striatal projection neurons.

Motor resonance may originate from sensorimotor experience.

In humans, the motor system can be activated by passive observation of actions or static pictures with implied action. The origin of this facilitation is of major interest to the field of motor control. Recently it has been shown that sensorimotor learning can reconfigure the motor system during action observation. Here we tested directly the hypothesis that motor resonance arises from sensorimotor contingencies by measuring corticospinal excitability in response to abstract non-action cues previously associated with an action. Motor evoked potentials were measured from the first dorsal interosseus (FDI) while human subjects observed colored stimuli that had been visually or motorically associated with a finger movement (index or little finger abduction). Corticospinal excitability was higher during the observation of a colored cue that preceded a movement involving the recorded muscle than during the observation of a different colored cue that preceded a movement involving a different muscle. Crucially this facilitation was only observed when the cue was associated with an executed movement but not when it was associated with an observed movement. Our findings provide solid evidence in support of the sensorimotor hypothesis of action observation and further suggest that the physical nature of the observed stimulus mediating this phenomenon may in fact be irrelevant.

The rate of visuomotor adaptation correlates with cerebellar white-matter microstructure.

Convergent experimental evidence points to the cerebellum as a key neural structure mediating adaptation to visual and proprioceptive perturbations. In a previous study, we have shown that activity in the anterior cerebellum varies with the rate of learning, with fast learners exhibiting more activity in this region than slow learners. Here, we investigated whether this variability in behavior may partly reflect inter-individual differences in the structural properties of cerebellar white-matter output tracts. For this purpose, we used diffusion-weighted magnetic resonance imaging to estimate fractional anisotropy (FA), and correlated the FA with the rate of adaptation to an optical rotation in 11 subjects. We found that FA in a region consistent with the superior cerebellar peduncle (SCP), containing fibers connecting the cerebellar cortex with motor and premotor cortex, was positively correlated with the rate of adaptation but not with the general level of performance or the initial deviation. The same pattern was observed in a region of the lateral posterior cerebellum. In contrast, FA in the angular gyrus of the posterior parietal cortex correlated positively both with the rate of adaptation and the overall level of performance. Our results show that the rate of learning a visuomotor task is associated with FA of cerebellar pathways.

Observing Grasping Actions Directed to Emotion-Laden Objects: Effects upon Corticospinal Excitability.

The motor system is recruited whenever one executes an action as well as when one observes the same action being executed by others. Although it is well established that emotion modulates the motor system, the effect of observing other individuals acting in an emotional context is particularly elusive. The main aim of this study was to investigate the effect induced by the observation of grasping directed to emotion-laden objects upon corticospinal excitability (CSE). Participants classified video-clips depicting the right-hand of an actor grasping emotion-laden objects. Twenty video-clips differing in terms of valence but balanced in arousal level were selected. Motor evoked potentials (MEPs) were then recorded from the first dorsal interosseous using transcranial magnetic stimulation (TMS) while the participants observed the selected emotional video-clips. During the video-clip presentation, TMS pulses were randomly applied at one of two different time points of grasping: (1) maximum grip aperture, and (2) object contact time. CSE was higher during the observation of grasping directed to unpleasant objects compared to pleasant ones. These results indicate that when someone observes an action of grasping directed to emotion-laden objects, the effect of the object valence promotes a specific modulation over the motor system.

Stimulation of the posterior parietal cortex interferes with arm trajectory adjustments during the learning of new dynamics.

Substantial neurophysiological evidence points to the posterior parietal cortex (PPC) as playing a key role in the coordinate transformation necessary for visually guided reaching. Our goal was to examine the role of PPC in the context of learning new dynamics of arm movements. We assessed this possibility by stimulating PPC with transcranial magnetic stimulation (TMS) while subjects learned to make reaching movements with their right hand in a velocity-dependent force field. We reasoned that, if PPC is necessary to adjust the trajectory of the arm as it interacts with a novel mechanical system, interfering with the functioning of PPC would impair adaptation. Single pulses of TMS were applied over the left PPC 40 msec after the onset of movement during adaptation. As a control, another group of subjects was stimulated over the visual cortex. During early stages of learning, the magnitude of the error (measured as the deviation of the hand paths) was similar across groups. By the end of the learning period, however, error magnitudes decreased to baseline levels for controls but remained significantly larger for the group stimulated over PPC. Our findings are consistent with a role of PPC in the adjustment of motor commands necessary for adapting to a novel mechanical environment.