Somatosensory targeted memory reactivation enhances motor performance via hippocampal-mediated plasticity.

Increasing evidence suggests that reactivation of newly acquired memory traces during postlearning wakefulness plays an important role in memory consolidation. Here, we sought to boost the reactivation of a motor memory trace during postlearning wakefulness (quiet rest) immediately following learning using somatosensory targeted memory reactivation (TMR). Using functional magnetic resonance imaging, we examined the neural correlates of the reactivation process as well as the effect of the TMR intervention on brain responses elicited by task practice on 24 healthy young adults. Behavioral data of the post-TMR retest session showed a faster learning rate for the motor sequence that was reactivated as compared to the not-reactivated sequence. Brain imaging data revealed that motor, parietal, frontal, and cerebellar brain regions, which were recruited during initial motor learning, were specifically reactivated during the TMR episode and that hippocampo-frontal connectivity was modulated by the reactivation process. Importantly, the TMR-induced behavioral advantage was paralleled by dynamical changes in hippocampal activity and hippocampo-motor connectivity during task practice. Altogether, the present results suggest that somatosensory TMR during postlearning quiet rest can enhance motor performance via the modulation of hippocampo-cortical responses.

Prefrontal stimulation prior to motor sequence learning alters multivoxel patterns in the striatum and the hippocampus.

Motor sequence learning (MSL) is supported by dynamical interactions between hippocampal and striatal networks that are thought to be orchestrated by the prefrontal cortex. In the present study, we tested whether individually-tailored theta-burst stimulation of the dorsolateral prefrontal cortex (DLPFC) prior to MSL can modulate multivoxel response patterns in the stimulated cortical area, the hippocampus and the striatum. Response patterns were assessed with multivoxel correlation structure analyses of functional magnetic resonance imaging data acquired during task practice and during resting-state scans before and after learning/stimulation. Results revealed that, across stimulation conditions, MSL induced greater modulation of task-related DLPFC multivoxel patterns than random practice. A similar learning-related modulatory effect was observed on sensorimotor putamen patterns under inhibitory stimulation. Furthermore, MSL as well as inhibitory stimulation affected (posterior) hippocampal multivoxel patterns at post-intervention rest. Exploratory analyses showed that MSL-related brain patterns in the posterior hippocampus persisted into post-learning rest preferentially after inhibitory stimulation. These results collectively show that prefrontal stimulation can alter multivoxel brain patterns in deep brain regions that are critical for the MSL process. They also suggest that stimulation influenced early offline consolidation processes as evidenced by a stimulation-induced modulation of the reinstatement of task pattern into post-learning wakeful rest.

A role for GABA in the modulation of striatal and hippocampal systems under stress.

Previous research has demonstrated that stress modulates the competitive interaction between the hippocampus and striatum, two structures known to be critically involved in motor sequence learning. These earlier investigations, however, have largely focused on blood oxygen-level dependent (BOLD) responses. No study to date has examined the link between stress, motor learning and levels of striatal and hippocampal gamma-aminobutyric acid (GABA). This knowledge gap is surprising given the known role of GABA in neuroplasticity subserving learning and memory. The current study thus examined: a) the effects of motor learning and stress on striatal and hippocampal GABA levels; and b) how learning- and stress-induced changes in GABA relate to the neural correlates of learning. To do so, fifty-three healthy young adults were exposed to a stressful or non-stressful control intervention before motor sequence learning. Striatal and hippocampal GABA levels were assessed at baseline and post-intervention/learning using magnetic resonance spectroscopy. Regression analyses indicated that stress modulated the link between striatal GABA levels and functional plasticity in both the hippocampus and striatum during learning as measured with fMRI. This study provides evidence for a role of GABA in the stress-induced modulation of striatal and hippocampal systems.

Hippocampal and striatal responses during motor learning are modulated by prefrontal cortex stimulation.

While it is widely accepted that motor sequence learning (MSL) is supported by a prefrontal-mediated interaction between hippocampal and striatal networks, it remains unknown whether the functional responses of these networks can be modulated in humans with targeted experimental interventions. The present proof-of-concept study employed a multimodal neuroimaging approach, including functional magnetic resonance (MR) imaging and MR spectroscopy, to investigate whether individually-tailored theta-burst stimulation of the dorsolateral prefrontal cortex can modulate responses in the hippocampus and the basal ganglia during motor learning. Our results indicate that while stimulation did not modulate motor performance nor task-related brain activity, it influenced connectivity patterns within hippocampo-frontal and striatal networks. Stimulation also altered the relationship between the levels of gamma-aminobutyric acid (GABA) in the stimulated prefrontal cortex and learning-related changes in both activity and connectivity in fronto-striato-hippocampal networks. This study provides the first experimental evidence, to the best of our knowledge, that brain stimulation can alter motor learning-related functional responses in the striatum and hippocampus.

Neural Correlates of Motor Skill Learning Are Dependent on Both Age and Task Difficulty.

Although a general age-related decline in neural plasticity is evident, the effects of age on neural plasticity after motor practice are inconclusive. Inconsistencies in the literature may be related to between-study differences in task difficulty. Therefore, we aimed to determine the effects of age and task difficulty on motor learning and associated brain activity. We used task-related electroencephalography (EEG) power in the alpha (8-12 Hz) and beta (13-30 Hz) frequency bands to assess neural plasticity before, immediately after, and 24-h after practice of a mirror star tracing task at one of three difficulty levels in healthy younger (19-24 yr) and older (65-86 yr) adults. Results showed an age-related deterioration in motor performance that was more pronounced with increasing task difficulty and was accompanied by a more bilateral activity pattern for older vs. younger adults. Task difficulty affected motor skill retention and neural plasticity specifically in older adults. Older adults that practiced at the low or medium, but not the high, difficulty levels were able to maintain improvements in accuracy at retention and showed modulation of alpha TR-Power after practice. Together, these data indicate that both age and task difficulty affect motor learning, as well as the associated neural plasticity.

Somatosensory Targeted Memory Reactivation Modulates Oscillatory Brain Activity but not Motor Memory Consolidation.

Previous research has shown that targeted memory reactivation (TMR) protocols using acoustic or olfactory stimuli can boost motor memory consolidation. While somatosensory information is crucial for motor control and learning, the effects of somatosensory TMR on motor memory consolidation remain elusive. Here, healthy young adults (n = 28) were trained on a sequential serial reaction time task and received, during the offline consolidation period that followed, sequential electrical stimulation of the fingers involved in the task. This somatosensory TMR procedure was applied during either a 90-minute diurnal sleep (NAP) or wake (NONAP) interval that was monitored with electroencephalography. Consolidation was assessed with a retest following the NAP/NONAP episode. Behavioral results revealed no effect of TMR on motor performance in either of the groups. At the brain level, somatosensory stimulation elicited changes in oscillatory activity in both groups. Specifically, TMR induced an increase in power in the mu band in the NONAP group and in the beta band in both the NAP and NONAP groups. Additionally, TMR elicited an increase in sigma power and a decrease in delta oscillations in the NAP group. None of these TMR-induced modulations of oscillatory activity, however, were correlated with measures of motor memory consolidation. The present results collectively suggest that while somatosensory TMR modulates oscillatory brain activity during post-learning sleep and wakefulness, it does not influence motor performance in an immediate retest.

Failure to Engage Neural Plasticity through Practice of a High-difficulty Task is Accompanied by Reduced Motor Skill Retention in Older Adults.

While the difficulty of a motor task can act as a stimulus for learning in younger adults, it is unknown how task difficulty interacts with age-related reductions in motor performance and altered brain activation. We examined the effects of task difficulty on motor performance and used electroencephalography (EEG) to probe task-related brain activation after acquisition and 24-h retention of a mirror star-tracing skill in healthy older adults (N = 36, 65-86 years). The results showed that the difficulty of the motor skill affected both the magnitude of motor skill learning and the underlying neural mechanisms. Behavioral data revealed that practicing a motor task at a high difficulty level hindered motor skill consolidation. The EEG data indicated that task difficulty modulated changes in brain activation after practice. Specifically, a decrease in task-related alpha power in frontal and parietal electrodes was only present after practice of the skill at the low and medium, but not the high difficulty level. Taken together, our findings show that a failure to engage neural plasticity through practice of a high-difficulty task is accompanied by reduced motor skill retention in older adults. The data help us better understand how older adults learn new motor skills and might have implications for prescribing motor skill practice according to its difficulty in rehabilitation settings.

Lateralized effects of post-learning transcranial direct current stimulation on motor memory consolidation in older adults: An fMRI investigation.

Previous research has consistently demonstrated that older adults have difficulties transforming recently learned movements into robust, long-lasting memories (i.e., motor memory consolidation). One potential avenue to enhance consolidation in older individuals is the administration of transcranial direct current stimulation (tDCS) to task-relevant brain regions after initial learning. Although this approach has shown promise, the underlying cerebral correlates have yet to be revealed. Moreover, it is unknown whether the effects of tDCS are lateralized, an open question with implications for rehabilitative approaches following predominantly unilateral neurological injuries. In this research, healthy older adults completed a sequential motor task before and 6 h after receiving anodal or sham stimulation to right or left primary motor cortex (M1) while functional magnetic resonance images were acquired. Unexpectedly, anodal stimulation to right M1 following left-hand sequence learning significantly hindered consolidation as compared to a sham control, whereas no differences were observed with left M1 stimulation following right-hand learning. Impaired performance following right M1 stimulation was paralleled by sustained engagement of regions known to be critical for early learning stages, including the caudate nucleus and the premotor and parietal cortices. Thus, post-learning tDCS in older adults not only exerts heterogenous effects across the two hemispheres but can also disrupt ongoing memory processing.

Somatosensory Electrical Stimulation Does Not Improve Motor Coordination in Patients with Unilateral Knee Osteoarthritis.

Non-surgical treatment of knee osteoarthritis (KOA) is often focused on the motor component of KOA even though there is evidence that sensory dysfunctions play an important role in the impaired control of the affected joint. Excitation of sensory afferents can increase motor function by exploiting the nervous system's ability to adapt to changing environments (i.e., neuronal plasticity). Therefore, the aim of this study was to explore the acute effects of a single session (30 min) of sensory intervention targeting neuronal plasticity using low-frequency (10 Hz) somatosensory electrical stimulation (SES) of the femoral nerve. We evaluated the effects of SES on the position and force control of the affected knee and self-reported pain in KOA patients (n = 14) in a sham-controlled randomized trial. The results showed that SES did not improve measures of lower-limb motor coordination compared to sham stimulation in KOA patients, nor did it improve self-reported knee function and pain (all p > 0.05). In conclusion, despite sensory involvement in KOA, the sensory intervention used in the present explorative study did not relieve self-reported pain, which may underlie the absence of an effect on measures of motor coordination. In sum, the present explorative study showed that SES alone does not improve motor coordination in KOA patients.

Somatosensory electrical stimulation improves skill acquisition, consolidation, and transfer by increasing sensorimotor activity and connectivity.

The interaction between the somatosensory and motor systems is important for normal human motor function and learning. Enhancing somatosensory input using somatosensory electrical stimulation (SES) can increase motor performance, but the neuronal mechanisms underlying these effects are largely unknown. With EEG, we examined whether skill acquisition, consolidation, and interlimb transfer after SES was related to increased activity in sensorimotor regions, as assessed by the N30 somatosensory evoked potential or rather increased connectivity between these regions, as assessed by the phase slope index (PSI). Right- and left-hand motor performance and EEG measures were taken before, immediately after, and 24 h ( day 2) after either SES ( n = 12; 5 men) or Control ( n = 12; 5 men). The results showed skill acquisition and consolidation in the stimulated right hand immediately after SES (6%) and on day 2 (9%) and interlimb transfer to the nonstimulated left hand on day 2 relative to Control (8%, all P < 0.05). Increases in N30 amplitudes correlated with skill acquisition while PSI from electrodes that represent the posterior parietal and primary somatosensory cortex to the electrode representing the primary motor cortex correlated with skill consolidation. In contrast, interlimb transfer did not correlate with the EEG-derived neurophysiological estimates obtained in the present study, which may indicate the involvement of subcortical structures in interlimb transfer after SES. In conclusion, weak peripheral somatosensory inputs in the form of SES improve skill acquisition, consolidation, and interlimb transfer that coincide with different cortical adaptations, including enhanced N30 amplitudes and PSI. NEW & NOTEWORTHY The relationship between adaptations in synaptic plasticity and motor learning following somatosensory electrical stimulation (SES) is incompletely understood. Here, we used for the first time a multifactorial approach that examined skill acquisition, consolidation, and interlimb transfer following 20 min of SES. In addition, we quantified sensorimotor integration and the magnitude and direction of connectivity with EEG. Following artificial electrical stimulation, increases in sensorimotor integration and connectivity were found to correlate with skill acquisition and consolidation, respectively.

Somatosensory Electrical Stimulation Does Not Augment Motor Skill Acquisition and Intermanual Transfer in Healthy Young Adults-A Pilot Study.

Sensory input can modify motor function and magnify interlimb transfer. We examined the effects of low-intensity somatosensory electrical stimulation (SES) on motor practice-induced skill acquisition and intermanual transfer. Participants practiced a visuomotor skill for 25 min and received SES to the practice or the transfer arm. Responses to single- and double-pulse transcranial magnetic stimulation were measured in both extensor carpi radialis. SES did not further increase skill acquisition (motor practice with right hand [RMP]: 30.8% and motor practice with right hand + somatosensory electrical stimulation to the right arm [RMP + RSES]: 27.8%) and intermanual transfer (RMP: 13.6% and RMP + RSES: 9.8%) when delivered to the left arm (motor practice with right hand + somatosensory electrical stimulation to the left arm [RMP + LSES]: 44.8% and 18.6%, respectively). Furthermore, transcranial magnetic stimulation measures revealed no changes in either hand. Future studies should systematically manipulate SES parameters to better understand the mechanisms of how SES affords motor learning benefits documented but not studied in patients.

Neuronal mechanisms of motor learning are age dependent.

There is controversy whether age-related neuroanatomical and neurophysiological changes in the central nervous system affect healthy old adults' abilities to acquire and retain motor skills. We examined the effects of age on motor skill acquisition and retention and potential underlying mechanisms by measuring corticospinal and intracortical excitability, using transcranial magnetic stimulation. Healthy young (n = 24, 22 years) and old (n = 22, 71 years) adults practiced a wrist flexion-extention visuomotor task or only watched the templates as an attentional control for 20 minutes. Old compared with young adults performed less well at baseline. Although the absolute magnitude of skill acquisition and retention was similar in the 2 age groups (age × intervention × time, p = 0.425), a comparison of baseline-similar age sub-groups revealed impaired skill acquisition but not retention in old versus young. Furthermore, the neuronal mechanisms differed as revealed by an opposite direction of associations in the age-groups between relative skill acquisition and intracortical facilitation during the task, and opposite changes during skill retention in corticospinal excitability at rest and during the task and intracortical inhibition during the task.

Motor Skill Acquisition and Retention after Somatosensory Electrical Stimulation in Healthy Humans.

Somatosensory electrical stimulation (SES) can increase motor performance, presumably through a modulation of neuronal excitability. Because the effects of SES can outlast the period of stimulation, we examined the possibility that SES can also enhance the retention of motor performance, motor memory consolidation, after 24 h (Day 2) and 7 days (Day 7), that such effects would be scaled by SES duration, and that such effects were mediated by changes in aspects of corticospinal excitability, short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF). Healthy young adults (n = 40) received either 20 (SES-20), 40 (SES-40), or 60 min (SES-60) of real SES, or sham SES (SES-0). The results showed SES-20 increased visuomotor performance on Day 2 (15%) and Day 7 (17%) and SES-60 increased visuomotor performance on Day 7 (11%; all p < 0.05) compared with SES-0. Specific responses to transcranial magnetic stimulation (TMS) increased immediately after SES (p < 0.05) but not on Days 2 and 7. In addition, changes in behavioral and neurophysiological parameters did not correlate, suggesting that paths and structures other than the ones TMS can assay must be (also) involved in the increases in visuomotor performance after SES. As examined in the present study, low-intensity peripheral electrical nerve stimulation did not have acute effects on healthy adults' visuomotor performance but SES had delayed effects in the form of enhanced motor memory consolidation that were not scaled by the duration of SES.