Nitzan Censor

Noninvasive brain stimulation: from physiology to network dynamics and back

Noninvasive brain stimulation techniques have been widely used for studying the physiology of the CNS, identifying the functional role of specific brain structures and, more recently, exploring large-scale network dynamics. Here we review key findings that contribute to our understanding of the mechanisms underlying the physiological and behavioral effects of these techniques. We highlight recent innovations using noninvasive stimulation to investigate global brain network dynamics and organization. New combinations of these techniques, in conjunction with neuroimaging, will further advance the utility of their application.

A link between perceptual learning, adaptation and sleep

Between-sessions gains in the texture discrimination task have been attributed to memory consolidation. A strong dependence of consolidation on sleep was suggested though not always supported by experimental results. Here we suggest that the interaction between consolidation and sleep depends on the adaptation level obtained during the training session. We find that both discrimination thresholds and learning depend on the number of trials used during training, with more trials producing higher discrimination thresholds due to suppressive processes related to adaptation. In addition, while learning benefits from increasing number of trials, a further increase in number of trials reduces learning. Consolidation may benefit from between-session sleep in the adapted states.

Common mechanisms of human perceptual and motor learning

The adult mammalian brain has a remarkable capacity to learn in both the perceptual and motor domains through the formation and consolidation of memories. Such practice-enabled procedural learning results in perceptual and motor skill improvements. Here, we examine evidence supporting the notion that perceptual and motor learning in humans exhibit analogous properties, including similarities in temporal dynamics and the interactions between primary cortical and higher-order brain areas. These similarities may point to the existence of a common general mechanism for learning in humans.

Modification of Existing Human Motor Memories Is Enabled by Primary Cortical Processing during Memory Reactivation

One of the most challenging tasks of the brain is to constantly update the internal neural representations of existing memories. Animal studies have used invasive methods such as direct microfusion of protein inhibitors to designated brain areas, in order to study the neural mechanisms underlying modification of already existing memories after their reactivation during recall [1-4]. Because such interventions are not possible in humans, it is not known how these neural processes operate in the human brain. In a series of experiments we show here that when an existing human motor memory is reactivated during recall, modification of the memory is blocked by virtual lesion [5] of the related primary cortical human brain area. The virtual lesion was induced by noninvasive repetitive transcranial magnetic stimulation guided by a frameless stereotactic brain navigation system and each subjects brain image. The results demonstrate that primary cortical processing in the human brain interacting with pre-existing reactivated memory traces is critical for successful modification of the existing related memory. Modulation of reactivated memories by noninvasive cortical stimulation may have important implications for human memory research and have far-reaching clinical applications.

Using repetitive transcranial magnetic stimulation to study the underlying neural mechanisms of human motor learning and memory

In the last two decades, there has been a rapid development in the research of the physiological brain mechanisms underlying human motor learning and memory. While conventional memory research performed on animal models uses intracellular recordings, microfusion of protein inhibitors to specific brain areas and direct induction of focal brain lesions, human research has so far utilized predominantly behavioural approaches and indirect measurements of neural activity. Repetitive transcranial magnetic stimulation (rTMS), a safe non‐invasive brain stimulation technique, enables the study of the functional role of specific cortical areas by evaluating the behavioural consequences of selective modulation of activity (excitation or inhibition) on memory generation and consolidation, contributing to the understanding of the neural substrates of motor learning. Depending on the parameters of stimulation, rTMS can also facilitate learning processes, presumably through purposeful modulation of excitability in specific brain regions. rTMS has also been used to gain valuable knowledge regarding the timeline of motor memory formation, from initial encoding to stabilization and long‐term retention. In this review, we summarize insights gained using rTMS on the physiological and neural mechanisms of human motor learning and memory. We conclude by suggesting possible future research directions, some with direct clinical implications.

Causal Role of Prefrontal Cortex in Strengthening of Episodic Memories through Reconsolidation

Memory consolidation is a dynamic process. Reactivation of consolidated memories triggers reconsolidation, a time-limited period during which memories can be modified. Episodic memory refers to our ability to recall specific past events about what happened, including where and when. However, it is unknown whether noninvasive stimulation of the neocortex during reconsolidation might strengthen existing episodic memories in humans. To modify these memories, we applied repetitive transcranial magnetic stimulation (rTMS) over right lateral prefrontal cortex (PFC), a region involved in the reactivation of episodic memories. We report that rTMS of PFC after memory reactivation strengthened verbal episodic memories, an effect documented by improved recall 24 hr postreactivation compared to stimulation of PFC without reactivation and vertex (control site) after reactivation. In contrast, there was no effect of stimulation 1 hr postreactivation (control experiment), showing that memory strengthening is time dependent, consistent with the reconsolidation theory. Thus, we demonstrated that right lateral PFC plays a causal role in strengthening of episodic memories through reconsolidation in humans. Reconsolidation may serve as an opportunity to modify existing memories with noninvasive stimulation of a critical brain region, an issue of fundamental importance for memory research and clinical applications.

Benefits of efficient consolidation: Short training enables long-term resistance to perceptual adaptation induced by intensive testing

Intensive training or testing reduces performance on perceptual and sensorimotor tasks. Here we show, for the visual texture discrimination task, that such adaptation-related performance decrements are practically eliminated following practice with a small number of trials and sleep. Thus, short training produces consolidation of an effective memory within the visual neural network, resistant to the performance decrements that are usually induced by intensive testing. We suggest a link between perceptual adaptation and learning: resistance is achieved by sleep dependent consolidation of distributed changes in network connectivity before saturated due to over-training. This link between memory generation, perceptual adaptation and memory consolidation may have an essential role in the underlying mechanisms of perceptual and motor learning. Therefore, intensive training yielding performance decrements in other modalities, such as the sensorimotor system, may be viewed in the context of the mechanisms suggested here.

Interference with Existing Memories Alters Offline Intrinsic Functional Brain Connectivity

The notion that already existing memories can be modified after their reactivation has received an increasing amount of experimental support, with empirical data accumulating across species and memory paradigms. However, there is no evidence for systems-level task-free intrinsic signatures of memory modification. Here, using a combination of behavioral, brain stimulation, and neuroimaging paradigms, we report that noninvasive transcranial magnetic stimulation interference with a reactivated motor memory altered offline task-free corticostriatal interregional functional connectivity, reducing it compared to stimulation in which the reactivated memory was intact. Furthermore, the modulated functional connectivity predicted offline memory modification. This reduction in functional connectivity recovered after additional execution of the memorized task, and the interference did not affect control cerebellar-cortical functional connectivity. This demonstrates that intrinsic task-free offline brain activity can be modulated by noninvasive interaction with existing memories and strongly correlates with behavioral measurements of changes in memory strength.

Cortico-subcortical neuronal circuitry associated with reconsolidation of human procedural memories.

The ability of the mammalian brain to modify existing memories through reconsolidation may be crucial for skill acquisition. The neural mechanisms of memory modification have been commonly studied at the cellular level. Yet surprisingly, the human brain systems-level mechanisms involved in day-to-day modification of existing procedural memories remain largely unknown. Here, we studied differences in functional magnetic resonance imaging (fMRI) regional signal activity and inter-regional functional connectivity in subjects in whom motor memory modification was interfered with by repetitive transcranial magnetic stimulation (rTMS), relative to subjects with intact memory modification. As a consequence, subjects with impaired memory modification had lower activity in the supplementary motor area (SMA) and weaker functional connectivity between M1, SMA, anterior cerebellum consistently engaged in early learning, and sensorimotor striatum active in later learning stages. These findings, identifying a link between engagement of this network and successful memory modification, suggest that memory reconsolidation may represent a transitional bridge between early and late procedural learning, underlying efficient skill acquisition.

Early-vision brain responses which predict human visual segmentation and learning.

Brain processes underlying visual segmentation have been widely studied, being part of the basic processes underlying perception. However, the underlying constraints on perceptual thresholds, set by neuronal processing, remain unclear. Here, the relationship between human visual performance and brain activity was examined using the backward-masked texture segmentation task. Performance showed dependence on the time-interval between target and mask as well as on the amount of prior practice. Correspondingly, early components of human event-related potentials (ERPs) recorded over occipital electrodes showed strong interactions between target and mask responses, suggesting interference with perception processes when the presented mask interacts with sustained target processing. These interactions, revealing an otherwise undetected extended processing time course beyond the early component of the target response, enabled us to quantify individual neuronal thresholds that closely matched the behavioral thresholds (r = 0.93, p = 0.00003). Furthermore, these neuronal thresholds could be improved by practice, suggesting neuronal mechanisms affected by perceptual learning. Predicting performance level not directly detected in the ERP but rather by further interactions shown here in early stages of the visual hierarchy may have important implications in the study of human perception. Practice seems to reduce the temporal interactions between the successive stimuli, revealing brain processes underlying perceptual learning.