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.

Memory instability as a gateway to generalization.

Our present frequently resembles our past. Patterns of actions and events repeat throughout our lives like a motif. Identifying and exploiting these patterns are fundamental to many behaviours, from creating grammar to the application of skill across diverse situations. Such generalization may be dependent upon memory instability. Following their formation, memories are unstable and able to interact with one another, allowing, at least in principle, common features to be extracted. Exploiting these common features creates generalized knowledge that can be applied across varied circumstances. Memory instability explains many of the biological and behavioural conditions necessary for generalization and offers predictions for how generalization is produced.

To Replay, Perchance to Consolidate.

After a memory is formed, it continues to be processed by the brain. These "off-line" processes consolidate the memory, leading to its enhancement and to changes in memory circuits. Potentially, these memory changes are driven by off-line replay of the pattern of neuronal activity present when the memory was being formed. A new study by Dhaksin Ramanathan and colleagues, published in PLOS Biology, demonstrates that replay occurs predominately after the acquisition of a new motor skill and that it is related to changes in memory performance and to the subsequent changes in memory circuits. Together, these observations reveal the importance of neuronal replay in the consolidation of novel motor skills.

The time course of task-specific memory consolidation effects in resting state networks.

Previous studies have reported functionally localized changes in resting-state brain activity following a short period of motor learning, but their relationship with memory consolidation and their dependence on the form of learning is unclear. We investigate these questions with implicit or explicit variants of the serial reaction time task (SRTT). fMRI resting-state functional connectivity was measured in human subjects before the tasks, and 0.1, 0.5, and 6 h after learning. There was significant improvement in procedural skill in both groups, with the group learning under explicit conditions showing stronger initial acquisition, and greater improvement at the 6 h retest. Immediately following acquisition, this group showed enhanced functional connectivity in networks including frontal and cerebellar areas and in the visual cortex. Thirty minutes later, enhanced connectivity was observed between cerebellar nuclei, thalamus, and basal ganglia, whereas at 6 h there was enhanced connectivity in a sensory-motor cortical network. In contrast, immediately after acquisition under implicit conditions, there was increased connectivity in a network including precentral and sensory-motor areas, whereas after 30 min a similar cerebello-thalamo-basal ganglionic network was seen as in explicit learning. Finally, 6 h after implicit learning, we found increased connectivity in medial temporal cortex, but reduction in precentral and sensory-motor areas. Our findings are consistent with predictions that two variants of the SRTT task engage dissociable functional networks, although there are also networks in common. We also show a converging and diverging pattern of flux between prefrontal, sensory-motor, and parietal areas, and subcortical circuits across a 6 h consolidation period.

A physiological signal that prevents motor skill improvements during consolidation.

Different memories follow different processing pathways. For example, some motor skill memories are enhanced over wakefulness, whereas others are instead enhanced over sleep. The processing pathway that a motor skill memory follows may be determined by functional changes within motor circuits. We tested this idea using transcranial magnetic stimulation to measure corticospinal excitability at 6, 21, 36, 96, and 126 min after participants learnt tasks that either were or were not enhanced over wakefulness. There was no change in corticospinal excitability after learning a motor skill that was subsequently enhanced; whereas, there was a substantial transient decrease in corticospinal excitability after learning a motor skill that was not enhanced. In subsequent experiments, we abolished the decrease in corticospinal excitability by applying theta burst stimulation to either the dorsolateral prefrontal or primary motor cortex, and induced motor skill improvements during consolidation. The motor skill improvements in each experiment were correlated with the corticospinal excitability after learning. Together, these experiments suggest that corticospinal excitability changes act as a physiological signal, which prevents improvements from developing over wakefulness, and so when this signal is abolished improvements are induced. Our observations show that the human brain can actively prevent the processing of memories, and provides insights into the mechanisms that control the fate of memories.

Maintaining vs. enhancing motor sequence memories: respective roles of striatal and hippocampal systems.

It is now accepted that hippocampal- and striatal-dependent memory systems do not act independently, but rather interact during both memory acquisition and consolidation. However, the respective functional roles of the hippocampus and the striatum in these processes remain unknown. Here, functional magnetic resonance imaging (fMRI) was used in a daytime sleep/wake protocol to investigate this knowledge gap. Using a protocol developed earlier in our lab (Albouy et al., 2013a), the manipulation of an explicit sequential finger-tapping task, allowed us to isolate allocentric (spatial) and egocentric (motor) representations of the sequence, which were supported by distinct hippocampo- and striato-cortical networks, respectively. Importantly, a sleep-dependent performance enhancement emerged for the hippocampal-dependent memory trace, whereas performance was maintained for the striatal-dependent memory trace, irrespective of the sleep condition. Regression analyses indicated that the interaction between these two systems influenced subsequent performance improvements. While striatal activity was negatively correlated with performance enhancement after both sleep and wakefulness in the allocentric representation, hippocampal activity was positively related to performance improvement for the egocentric representation, but only if sleep was allowed after training. Our results provide the first direct evidence of a functional dissociation in consolidation processes whereby memory stabilization seems supported by the striatum in a time-dependent manner whereas memory enhancement seems linked to hippocampal activity and sleep-dependent processes.

Is neuroenhancement by noninvasive brain stimulation a net zero-sum proposition?

In the past several years, the number of studies investigating enhancement of cognitive functions through noninvasive brain stimulation (NBS) has increased considerably. NBS techniques, such as transcranial magnetic stimulation and transcranial current stimulation, seem capable of enhancing cognitive functions in patients and in healthy humans, particularly when combined with other interventions, including pharmacologic, behavioral and cognitive therapies. The "net zero-sum model", based on the assumption that brain resources are subjected to the physical principle of conservation of energy, is one of the theoretical frameworks proposed to account for such enhancement of function and its potential cost. We argue that to guide future neuroenhancement studies, the net-zero sum concept is helpful, but only if its limits are tightly defined.

Resting state connectivity immediately following learning correlates with subsequent sleep-dependent enhancement of motor task performance.

There is ongoing debate concerning the functions of resting-state brain activity. Prior work demonstrates that memory encoding enhances subsequent resting-state functional connectivity within task-relevant networks and that these changes predict better recognition. Here, we used functional connectivity MRI (fcMRI) to examine whether task-induced changes in resting-state connectivity correlate with performance improvement after sleep. In two separate sessions, resting-state scans were acquired before and after participants performed a motor task. In one session participants trained on the motor sequence task (MST), a well-established probe of sleep-dependent memory consolidation, and were tested the next day, after a night of sleep. In the other session they performed a motor control task (MCT) that minimized learning. In an accompanying behavioral control study, participants trained on the MST and were tested after either a night of sleep or an equivalent interval of daytime wake. Both the fcMRI and the sleep control groups showed significant improvement of MST performance, while the wake control group did not. In the fcMRI group, increased connectivity in bilateral motor cortex following MST training correlated with this next-day improvement. This increased connectivity did not appear to reflect initial learning since it did not correlate with learning during training and was not greater after MST training than MCT performance. Instead, we hypothesize that this increased connectivity processed the new memories for sleep-dependent consolidation. Our findings demonstrate that physiological processes immediately after learning correlate with sleep-dependent performance improvement and suggest that the wakeful resting brain prepares memories of recent experiences for later consolidation during sleep.

Neuroscience: Memory modification without catastrophe.

Adaptive behaviour is supported by changes in neuronal networks. Insight into maintaining these memories - preventing their catastrophic loss - despite further network changes occurring due to novel learning is provided in a new study.

Distinct frequencies balance segregation with interaction between different memory types within a prefrontal circuit.

Once formed, the fate of memory is uncertain. Subsequent offline interactions between even different memory types (actions versus words) modify retention.1,2,3,4,5,6 These interactions may occur due to different oscillations functionally linking together different memory types within a circuit.7,8,9,10,11,12,13 With memory processing driving the circuit, it may become less susceptible to external influences.14 We tested this prediction by perturbing the human brain with single pulses of transcranial magnetic stimulation (TMS) and simultaneously measuring the brain activity changes with electroencephalography (EEG15,16,17). Stimulation was applied over brain areas that contribute to memory processing (dorsolateral prefrontal cortex, DLPFC; primary motor cortex, M1) at baseline and offline, after memory formation, when memory interactions are known to occur.1,4,6,10,18 The EEG response decreased offline (compared with baseline) within the alpha/beta frequency bands when stimulation was applied to the DLPFC, but not to M1. This decrease exclusively followed memory tasks that interact, revealing that it was due specifically to the interaction, not task performance. It remained even when the order of the memory tasks was changed and so was present, regardless of how the memory interaction was produced. Finally, the decrease within alpha power (but not beta) was correlated with impairment in motor memory, whereas the decrease in beta power (but not alpha) was correlated with impairment in word-list memory. Thus, different memory types are linked to different frequency bands within a DLPFC circuit, and the power of these bands shapes the balance between interaction and segregation between these memories.

Prefrontal stimulation as a tool to disrupt hippocampal and striatal reactivations underlying fast motor memory consolidation.

BACKGROUND: Recent evidence suggests that hippocampal replay in humans support rapid motor memory consolidation during epochs of wakefulness interleaved with task practice. OBJECTIVES/HYPOTHESES: The goal of this study was to test whether such reactivation patterns can be modulated with experimental interventions and in turn influence fast consolidation. We hypothesized that non-invasive brain stimulation targeting hippocampal and striatal networks via the prefrontal cortex would influence brain reactivation and the rapid form of motor memory consolidation. METHODS: Theta-burst stimulation was applied to a prefrontal cluster functionally connected to both the hippocampus and striatum of young healthy participants before they learned a motor sequence task in a functional magnetic resonance imaging (fMRI) scanner. Neuroimaging data acquired during task practice and the interleaved rest epochs were analyzed to comprehensively characterize the effect of stimulation on the neural processes supporting fast motor memory consolidation. RESULTS: Our results collectively show that active, as compared to control, theta-burst stimulation of the prefrontal cortex hindered fast motor memory consolidation. Converging evidence from both univariate and multivariate analyses of fMRI data indicate that active stimulation disrupted hippocampal and caudate responses during inter-practice rest, presumably altering the reactivation of learning-related patterns during the micro-offline consolidation episodes. Last, stimulation altered the link between the brain and the behavioral markers of the fast consolidation process. CONCLUSION: These results suggest that stimulation targeting deep brain regions via the prefrontal cortex can be used to modulate hippocampal and striatal reactivations in the human brain and influence motor memory consolidation.

Acute evening high-intensity interval training may attenuate the detrimental effects of sleep restriction on long-term declarative memory.

Recent evidence shows that a nap and acute exercise synergistically enhanced memory. Additionally, human-based cross-sectional studies and animal experiments suggest that physical exercise may mitigate the cognitive impairments of poor sleep quality and sleep restriction, respectively. We evaluated whether acute exercise may offset sleep restriction's impairment of long-term declarative memory compared to average sleep alone. A total of 92 (82% females) healthy young adults (24.6 ± 4.2 years) were randomly allocated to one of four evening groups: sleep restriction only (S5, 5-6 h/night), average sleep only (S8, 8-9 h/night), high-intensity interval training (HIIT) before restricted sleep (HIITS5), or HIIT before average sleep (HIITS8). Groups either followed a 15-min remote HIIT video or rest period in the evening (7:00 p.m.) prior to encoding 80 face-name pairs. Participants completed an immediate retrieval task in the evening. The next morning a delayed retrieval task was given after their subjectively documented sleep opportunities. Long-term declarative memory performance was assessed with the discriminability index (d') during the recall tasks. While our results showed that the d' of S8 (0.58 ± 1.37) was not significantly different from those of HIITS5 (-0.03 ± 1.64, p = 0.176) and HIITS8 (-0.20 ± 1.28, p = 0.092), there was a difference in d' compared to S5 (-0.35 ± 1.64, p = 0.038) at the delayed retrieval. These results suggest that the acute evening HIIT partially reduced the detrimental effects of sleep restriction on long-term declarative memory.

Does Cardiorespiratory Fitness Protect Memory from Sleep Deprivation?

INTRODUCTION: Animal studies have demonstrated that physical exercise can protect memory from the effects of sleep deprivation (SD). We examined whether having a high cardiorespiratory fitness (V̇O 2peak ) is associated with an enhanced capacity to encode episodic memory after one night of SD. METHODS: Twenty-nine healthy young participants were allocated into either an SD group ( n = 19) that underwent 30 h of uninterrupted wakefulness, or a sleep control (SC) group ( n = 10) that followed a regular sleep routine. Following either the SD or SC period, participants were asked to view 150 images as the encoding part of the episodic memory task. Ninety-six hours after viewing the images, participants returned to the laboratory to perform the recognition part of the episodic memory task, which required the visual discrimination of the 150 images previously presented from 75 new images introduced as distractors. Cardiorespiratory fitness (V̇O 2peak ) was assessed with a bike ergometer graded exercise test. Group differences in memory performance were assessed with independent t tests and associations between V̇O 2peak and memory with multiple linear regression. RESULTS: The SD group showed a significant increase in subjective fatigue (mean difference [MD] [standard error {SE}] = 38.94 [8.82]; P = 0.0001) and a worse capacity to identify the original 150 images (MD [SE] = -0.18 [0.06]; P = 0.005) and discriminate them from distractors (MD [SE] = -0.78 [0.21] P = 0.001). When adjusted for fatigue, higher V̇O 2peak was significantly associated with better memory scores in the SD (R 2 = 0.41; ß [SE] = 0.03 [0.01]; P = 0.015) but not in the SC group ( R2 = 0.23; ß [SE] = 0.02 [0.03]; P = 0.408). CONCLUSIONS: These results confirm that SD before encoding impairs the capacity to create robust episodic memories and provide preliminary support to the hypothesis that maintaining high levels of cardiorespiratory fitness could have a protective effect against the disruptive effects of sleep loss on memory.

Memory leaks: information shared across memory systems.

The brain is highly segregated. Multiple mechanisms ensure that different types of memories are processed independently. Nonetheless, information leaks out across these memory systems. Only recently has the diversity of these leaks been revealed. Different memory types (skills vs. facts) can interact in simple ways, either allowing or preventing their further processing, or in more complex ways, allowing the sharing of abstract information between memories. Leaks occur from memories dependent upon hippocampal circuits, which have properties critical for leaks and activity patterns related to memory interactions. This hippocampal contribution is likely achieved in concert with cortical areas. Leaks between memories enable the application of knowledge in novel situations, explain learning dynamics, and solve important problems inherent to memory formation.

A distraction can impair or enhance motor performance.

Humans have a prodigious capacity to perform multiple tasks simultaneously. Being distracted while, for example, performing a complex motor skill adds complexity to a task and thus leads to a performance impairment. Yet, it may not be just the presence or absence of a distraction that affects motor performance. Instead, the characteristics of the distraction may play a critical role in affecting human motor performance. Here, we show that performance of a motor sequence can be substantially enhanced by simultaneously learning an independent color sequence. In contrast, performance of the same motor sequence was impaired by concurrently counting the number of red cues that were in the color sequence. The color and motor sequences had different lengths (10 vs 12 items), different numbers of elements (five vs four elements), and different temporal patterns (randomly intermittent vs continuous) and thus were independent of one another. These observations show that distracting information does not always impair motor performance, and so is not a sufficient explanation for the impaired performance. Instead, the influence that a distraction exerts upon performance is mediated by the type of processes engaged: when similar core processes are engaged, motor performance is enhanced, whereas when very different processes are engaged (i.e., counting and sequence performance), performance is impaired. Thus, these observations deepen our understanding of how a distraction, depending on its characteristics, can either impair or enhance performance and may offer novel approaches to optimizing human cognition.

Inducing motor skill improvements with a declarative task.

During sequence learning, individuals show motor-skill acquisition and an ability to verbally describe items within the sequence. We disrupted this latter, declarative component by having participants learn a word list immediately after sequence learning. This induced off-line skill improvements. We conclude that off-line memory processing relies not only on the engagement of neuroplastic mechanisms but also on the disengagement of an interaction between declarative and procedural memory systems.

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.

Memories replayed: reactivating past successes and new dilemmas.

Our experiences continue to be processed 'offline' in the ensuing hours of both wakefulness and sleep. During these different brain states, the memory formed during our experience is replayed or reactivated. Here, we discuss the unique challenges in studying offline reactivation, the growth in both the experimental and analytical techniques available across different animals from rodents to humans to capture these offline events, the important challenges this innovation has brought, our still modest understanding of how reactivation drives diverse synaptic changes across circuits, and how these changes differ (if at all), and perhaps complement, those at memory formation. Together, these discussions highlight critical emerging issues vital for identifying how reactivation affects circuits, and, in turn, behaviour, and provides a broader context for the contributions in this special issue. This article is part of the Theo Murphy meeting issue 'Memory reactivation: replaying events past, present and future'.

A Common Task Structure Links Together the Fate of Different Types of Memories.

Our memories frequently have features in common. For example, a learned sequence of words or actions can follow a common rule, which determines their serial order, despite being composed of very different events [1, 2]. This common abstract structure might link the fates of memories together. We tested this idea by creating different types of memory task: a sequence of words or actions that either did or did not have a common structure. Participants learned one of these memory tasks and then they learned another type of memory task 6 h later, either with or without the same structure. We then tested the newly formed memory's susceptibility to interference. We found that the newly formed memory was protected from interference when it shared a common structure with the earlier memory. Specifically, learning a sequence of words protected a subsequent sequence of actions learned hours later from interference, and conversely, learning a sequence of actions protected a subsequent sequence of words learned hours later from interference provided the sequences shared a common structure. Yet this protection of the newly formed memory came at a cost. The earlier memory had disrupted recall when it had the same rather than a different structure to the newly formed and protected memory. Thus, a common structure can determine what is retained (i.e., protected) and what is modified (i.e., disrupted). Our work reveals that a shared common structure links the fate of otherwise different types of memories together and identifies a novel mechanism for memory modification.

Exercising before a nap benefits memory better than napping or exercising alone.

Sleep leads to the enhancement of memory, and physical exercise also improves memory along with beneficial effects on sleep quality. Potentially, sleep and exercise may operate independently upon memory; alternatively, they may operate synergistically to boost memory above and beyond exercise or sleep alone. We tested this hypothesis in 115 young healthy adults (23 ± 3.9 years) randomly allocated to one of the four conditions in a 2 (exercise vs. no exercise) × 2 (nap vs. no nap) design. The exercise intervention consisted of a 40-minute, moderate intensity cycling, while the no exercise condition was an equivalent period of rest. This was followed by a learning session in which participants memorized a set of 45 neutral pictures for a later test. Subsequently, participants were exposed to either a 60-minute sleep period (nap) or an equivalent time of resting wakefulness, followed by a visual recognition test. We found a significant interaction between the effects of exercise and nap (p = 0.014, η p2 = 0.053), without significant main effects of exercise or nap conditions. Participants who experienced both exercise plus nap were significantly more accurate (83.8 ± 2.9) than those who only napped (81.1 ± 5.4, p = 0.027) and those who only exercised (78.6 ± 10.3, p = 0.012). Within the combined nap plus exercise group, higher recognition accuracies were associated with higher sleep spindle densities (r = 0.46, p = 0.015). Our results demonstrate that short-term exercise and a nap improve recognition memory over a nap or exercise alone. Exercise and sleep are not independent factors operating separately upon memory but work together to enhance long-term memory.