Bradley Ross King

Converging neuroimaging evidence indicates that the hippocampus is involved in motor sequence learning (MSL) and its consolidation at multiple timescales. However, direct evidence for a causal role of the hippocampus in these processes in healthy humans remains scarce, partly due to the inability of conventional non-invasive brain stimulation techniques to reach this deep brain structure. Here, we used temporal interference stimulation (TIS) - a technique enabling non-invasive stimulation targeted toward deep brain regions - to probe the functional role of the hippocampus in MSL and its consolidation. In two separate experiments, sixty-four young healthy adults (36 females) received, in within-subject counterbalanced designs, active (5 Hz envelope) or control (0 Hz envelope) hippocampal-targeted TIS either during active practice of an MSL task (task-TIS experiment, n = 32) or during the short rest periods interleaved with task practice known to support rapid forms of consolidation (rest-TIS experiment, n = 32). Consolidation was assessed at both the micro timescale (i.e., over the short "micro-offline" rest intervals interspersed with task practice) and macro timescale (i.e., over a 24-hour "macro-offline" retention interval). Our results indicate that TIS targeting the hippocampus during inter-practice rest periods - but not during task practice - significantly enhanced micro-offline gains in performance as compared to control stimulation. While this effect did not carry over to the 24-hour retention interval at the group level, participants with greater stimulation-induced micro-offline gains showed larger overnight performance improvements. These findings provide the first direct evidence that experimental interventions targeting the hippocampus modulate offline motor memory consolidation processes.

Primary motor cortex (M1) continuous theta-burst stimulation (cTBS) did not impair schema-mediated motor sequence learning compared with sham. M1 cTBS did not suppress corticospinal excitability at the group level. Across individuals, greater motor-evoked potential (MEP) suppression was related to higher baseline MEPs. Postintervention changes in MEP amplitude did not correlate with motor performance.

Many daily activities involve series of interrelated movements and thus the capacity to learn new motor sequences is vital for everyday functioning. Although learning new skills is especially prominent throughout childhood, remarkably few studies have examined the neural underpinnings of motor sequence learning (MSL) and memory consolidation in children. Twenty‐two children (7–11 years) and 23 adults (18–30 years) underwent functional magnetic resonance imaging while completing two sessions of a MSL task, separated by a 5‐h offline period of wakefulness. Analyses of the behavioral data revealed comparable initial learning in children and adults. However, and consistent with previous research, children exhibited superior motor memory consolidation over the 5‐h offline epoch. Neuroimaging analyses revealed that children exhibited smaller modulations in brain activity between task and rest epochs in a widespread network, including the sensorimotor cortex, supplementary motor area, cerebellum, putamen, and regions associated with the default mode network. Similar levels of activity during task and rest epochs in the hippocampus, dorsolateral prefrontal cortex and somatosensory cortex were associated with better motor memory consolidation in children. Results potentially suggest that the continued engagement of the developing brain during interleaved rest contributes to the childhood advantage in motor memory consolidation.

Previous research has demonstrated that children exhibit superior - as compared to adults - consolidation of newly acquired motor sequences across post-learning periods of wakefulness. Given that consolidation is thought to be supported by the reactivation of learning-related patterns of brain activity during the rest periods following active task practice, we hypothesized that the childhood advantage in offline consolidation may be linked to greater reactivation during post-learning wakefulness. Twenty-two children (7-11 years) and 23 adults (18-30 years) completed two sessions of a motor sequence learning task, separated by a 5-hour wake interval. Multivoxel analyses of task-related and resting-state functional magnetic resonance imaging data were employed to assess the persistence of learning-related patterns of neural activity into post-task rest epochs, reflective of reactivation processes. Behavioral results demonstrated the previously reported childhood advantage in offline consolidation over a post-learning wake interval. Imaging results revealed that children exhibited greater persistence of task-related hippocampal – but not putaminal - activity into post-learning rest as compared to adults. These findings suggest that the childhood advantage in awake motor memory consolidation may be supported, at least partially, by enhanced reactivation of task-dependent hippocampal activity patterns during offline epochs.

Children are frequently conceptualized as developing systems progressing toward the mature and optimal state of adulthood. However, as developmentalists, we know that there are instances in which children exhibit the best performance and thus can be considered a model of optimal functioning for that specific behavior. Here, we discuss behavioral and neuroimaging research that examines a childhood advantage in the domain of motor learning and memory consolidation. We argue that investigations into the neural processes underlying childhood advantages in motor learning offer a unique opportunity to increase our understanding of motor and brain development.

Background Transcranial direct current stimulation (tDCS) is one of the most widely used noninvasive neuromodulation methods. Despite its popularity, some recent studies highlighted issues about the reproducibility of earlier reported tDCS results. Until recently, it was assumed that tDCS elicits its neuromodulatory effects by increasing cortical excitability through direct polarization of cortical neurons. However, recent studies have shown that the electric field that reaches the cortex is relatively weak, whereas the electric field in the scalp underneath the stimulation electrodes is sufficiently strong to stimulate peripheral nerves, thereby potentially indirectly affecting cortical excitability and plasticity. Objective In this study, we aimed to replicate the effect of anodal tDCS in enhancing motor sequence learning and investigate if the effect is caused by the polarization of cortical neurons, or more indirectly through stimulation of peripheral nerve in the scalp, or a combination of both mechanisms. Methods In a double-blind, pre-registered study including 99 healthy young adults, we investigated the effect of 1mA anodal tDCS over the left primary motor cortex (M1) on motor sequence learning in three serial reaction time task (SRTT) sessions using a between-subjects design. In addition to the standard sham condition, we introduced an additional control condition in which the peripheral input was blocked using the BL10 topical anesthetic gel to investigate the potential contribution of peripheral nerve stimulation in mediating tDCS effects in motor sequence learning. Results Our results provided evidence of motor sequence learning in all three stimulation conditions (pConclusion We were unable to replicate previous findings indicating significant beneficial effects of tDCS on motor sequence learning. Consequently, we were unable to address our main research question of whether tDCS effects are driven by the resulting electric field in the cortex or by stimulation of peripheral nerves in the scalp. This non-replication of one of the presumably most reliable tDCS effects in a much larger sample size than the original studies, among the findings of comparable studies reporting similar outcomes, should prompt a renewed discussion regarding the efficacy of tDCS as a neuromodulation technique, particularly given the earlier reported concerns about its reproducibility and reliability.

Intro: Many daily activities involve series of interrelated movements and thus the capacity to learn new motor sequences is vital for everyday functioning. Although learning new skills is especially prominent throughout childhood, remarkably few studies have examined the neural underpinnings of motor sequence learning (MSL) and memory consolidation in children. Methods: Twenty-two children (7-11 years) and 23 adults (18-30 years) underwent functional magnetic resonance imaging while completing two sessions of a MSL task, separated by a 5-hour offline period of wakefulness. Results: Analyses of the behavioral data revealed comparable initial learning in children and adults. However, and consistent with previous research, children exhibited superior motor memory consolidation over the 5-hour offline epoch. Neuroimaging analyses revealed that children exhibited smaller modulations in brain activity between task and rest epochs in a widespread network, including the sensorimotor cortex, supplementary motor area, cerebellum, putamen and regions associated with the default mode network. Similar levels of activity during task and rest epochs in the hippocampus, dorsolateral prefrontal cortex and somatosensory cortex were associated with better motor memory consolidation in children. Conclusion: Results potentially suggest that the continued engagement of the developing brain during interleaved rest contributes to the childhood advantage in motor memory consolidation.

Whereas memory consolidation research has traditionally focused on longer temporal windows (i.e., hours to days) following an initial learning episode, recent research has also examined the functional significance of the shorter rest epochs interspersed with blocks of task practice (i.e., “micro-offline” intervals on the timescale of seconds to minutes). In the motor sequence learning (MSL) domain, evidence from young, healthy individuals suggests that micro-offline epochs afford a rapid consolidation process that is supported by the hippocampus. Consistent with these findings, amnesic patients with hippocampal damage were recently found to exhibit degraded micro-offline performance improvements. These offline losses were compensated for by larger performance gains during online practice. Given the known role of the striatum in online MSL, we hypothesized that individuals with dysfunction of the striatal system would exhibit impaired online, yet enhanced micro-offline, learning (i.e., a pattern of results opposite to that observed in patients with hippocampal damage). We tested this hypothesis using Parkinson's disease (PD) as a model of striatal dysfunction. Forty-two drug–naive individuals with a clinical diagnosis of unilateral PD and 30 healthy control subjects completed a MSL paradigm (participants included both men and women). Relative to age-similar controls, individuals with PD exhibited deficits during online task practice that were paralleled by greater improvements over micro-offline intervals. Results could not be explained by disease-related deficits in movement execution. These data suggest that striatal dysfunction disrupts online learning, yet total learning remains unchanged because of greater micro-offline performance improvements that potentially reflect hippocampal-mediated compensatory processes.

Memory systems in humans are less segregated than initially thought as learning tasks from different memory domains (e.g., declarative versus procedural) can recruit similar brain areas. However, it remains unclear whether the functional role of these overlapping brain regions – and the hippocampus in particular – is domain-general. Here, we test the hypothesis that the hippocampus encodes and preserves the temporal order of sequential information irrespective of the nature of that information. We used multivariate pattern analyses (MVPA) of functional magnetic resonance imaging (fMRI) data acquired during the execution of learned sequences of movements and objects to assess brain patterns related to procedural and declarative memory processes, respectively. We also tested whether the hippocampus represents information about temporal order of items (here movements and objects in the motor and declarative domains, respectively) in a learned sequence irrespective of their nature. We also examined such coding in brain regions involved in both motor (primary and premotor cortices) and object (perirhinal cortex and parahippocampus) sequence learning. Our results suggest that hippocampal and perirhinal multivoxel activation patterns do not carry information about specific items or temporal position in a random series of objects or movements. Rather, these regions code for the representation of items in their learned temporal position in sequences irrespective of their nature (i.e., item-position coding). In contrast, although all other ROIs showed evidence of item-position coding, this representation could – at least partially – be attributed to the coding of other information such as position information. Altogether, our findings indicate that regions in the medial temporal lobe represent the temporal order of sequential information similarly in both the declarative and the motor memory domains. Our data suggest that these regions contribute to the development of item-position maps that might provide a cognitive framework for sequential behaviors irrespective of their nature.