Marco Sandrini

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.

The use of transcranial magnetic stimulation in cognitive neuroscience: A new synthesis of methodological issues

Transcranial magnetic stimulation (TMS) has become a mainstay of cognitive neuroscience, thus facing new challenges due to its widespread application on behaviorally silent areas. In this review we will summarize the main technical and methodological considerations that are necessary when using TMS in cognitive neuroscience, based on a corpus of studies and technical improvements that has become available in most recent years. Although TMS has been applied only relatively recently on a large scale to the study of higher functions, a range of protocols that elucidate how this technique can be used to investigate a variety of issues is already available, such as single pulse, paired pulse, dual-site, repetitive and theta burst TMS. Finally, we will touch on recent promising approaches that provide powerful new insights about causal interactions among brain regions (i.e., TMS with other neuroimaging techniques) and will enable researchers to enhance the functional resolution of TMS (i.e., state-dependent TMS). We will end by briefly summarizing and discussing the implications of the newest safety guidelines.

State-Dependent TMS Reveals a Hierarchical Representation of Observed Acts in the Temporal, Parietal, and Premotor Cortices

A transcranial magnetic stimulation (TMS) adaptation paradigm was used to investigate the neural representation of observed motor behavior in the inferior parietal lobule (IPL), ventral premotor cortex (PMv), and in the cortex around the superior temporal sulcus (STS). Participants were shown adapting movies of a hand or a foot acting on different objects and were asked to compare to the movie, a motor act shown in test pictures. The invariant features between adapting and test stimuli fitted a 2 x 2 design: same or different action made by the same or different effector. Neuronavigated TMS pulses were delivered at the onset of each test picture. TMS over the left and right PMv and over the left IPL induced a selective shortening of reaction times (RTs) to stimuli showing a repeated (adapted) action, regardless of the effector performing it. In a second experiment, TMS applied over the left STS induced shortening of RTs for adapted actions but only if also the effector was repeated. The results indicate that observed motor behavior is encoded with the body part that performs it in the temporal lobe. A hierarchically higher level of representation is carried by neural populations in the parietofrontal regions, where acts are encoded in an abstract way.

Double dissociation of working memory load effects induced by bilateral parietal modulation

Transcranial magnetic stimulation and neuroimaging data have revealed bilateral posterior parietal cortex (PPC) involvement during verbal n-back working memory (WM). In this task as n (i.e., WM load) increases, subjects show poorer behavioral performance as well as greater activation of this brain area. Moreover, there is evidence that a brief period of practice or even increased familiarity with the task can improve WM performance and lead to activation changes in the PPC. The aim of this study was to investigate, using transcranial direct current stimulation (tDCS), the effects on WM load performance induced by different PPC modulation after increased familiarity with the task. After a short practice, we tested verbal WM using an n-back task (1-back vs. 2-back) before and after the application of bilateral tDCS over PPCs (left anodal-right cathodal, left cathodal-right anodal or sham). ANOVA showed a significant interaction between tDCS and task. In the 1-back task, left anodal-right cathodal modulation abolished improvement in reaction times observed in the other two modulation conditions. Conversely, in the 2-back task the same effect was observed after left cathodal-right anodal modulation relative to the other two modulation conditions. This double dissociation demonstrates either a differential engagement of each PPC or changes in the interhemispheric balance of activity across this brain region. Neuroimaging studies show parametric activation of the PPC as difficulty increases, but activation does not switch sides. Thus, our observed effects cannot be attributed to increased task difficulty, the stimuli used, or the response requirements. Rather, we suggest that these findings reflect the use of different processing strategies to perform these two tasks. In conclusion, after increased familiarity with the task, different tDCS modulations lead to changes in a task-related region depending on differences in processing strategies in 1-back vs. 2-back.

Combining transcranial direct current stimulation and neuroimaging: novel insights in understanding neuroplasticity.

In recent years, noninvasive brain stimulation techniques like transcranial direct current stimulation (tDCS) have gained immense popularity owing to their effects on modulating cortical activity and consequently motor and cognitive performance. However, the neurophysiology underlying such neuroplastic changes is less understood. This article critically evaluates the contemporary approach of combined tDCS and neuroimaging as a means to provide novel insights in understanding the neurophysiological and neuroplastic processes modulated by this brain stimulation technique. We end by briefly suggesting further lines of inquiry.

Noninvasive brain stimulation in neurorehabilitation

Stroke is the major cause of long-term disability worldwide, with impaired manual dexterity being a common feature. In the past few years, noninvasive brain stimulation (NIBS) techniques, such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), have been investigated as adjuvant strategies to neurorehabilitative interventions. These NIBS techniques can be used to modulate cortical excitability during and for several minutes after the end of the stimulation period. Depending on the stimulation parameters, cortical excitability can be reduced (inhibition) or enhanced (facilitation). Differential modulation of cortical excitability in the affected and unaffected hemisphere of patients with stroke may induce plastic changes within neural networks active during functional recovery. The aims of this chapter are to describe results from these proof-of-principle trials and discuss possible putative mechanisms underlying such effects. Neurophysiological and neuroimaging changes induced by application of NIBS are reviewed briefly.

Noninvasive stimulation of prefrontal cortex strengthens existing episodic memories and reduces forgetting in the elderly

Memory consolidation is a dynamic process. Reactivation of consolidated memories by a reminder triggers reconsolidation, a time-limited period during which existing memories can be modified (i.e., weakened or strengthened). Episodic memory refers to our ability to recall specific past events about what happened, including where and when. Difficulties in this form of long-term memory commonly occur in healthy aging. Because episodic memory is critical for daily life functioning, the development of effective interventions to reduce memory loss in elderly individuals is of great importance. Previous studies in young adults showed that the dorsolateral prefrontal cortex (DLPFC) plays a causal role in strengthening of verbal episodic memories through reconsolidation. The aim of the present study was to explore the extent to which facilitatory transcranial direct current stimulation (anodal tDCS) over the left DLPFC would strengthen existing episodic memories through reconsolidation in elderly individuals. On Day 1, older adults learned a list of 20 words. On Day 2 (24 h later), they received a reminder or not, and after 10 min tDCS was applied over the left DLPFC. Memory recall was tested on Day 3 (48 h later) and Day 30 (1 month later). Surprisingly, anodal tDCS over the left DLPFC (i.e., with or without the reminder) strengthened existing verbal episodic memories and reduced forgetting compared to sham stimulation. These results provide a framework for testing the hypothesis that facilitatory tDCS of left DLPFC might strengthen existing episodic memories and reduce memory loss in older adults with amnestic mild cognitive impairment.

Modifying somatosensory processing with non-invasive brain stimulation.

Purposeful manipulation of cortical plasticity and excitability within somatosensory regions may have therapeutic potential. Non-invasive brain stimulation (NBS) techniques such as transcranial magnetic stimulation (TMS) or transcranial direct current stimulation (tDCS) have shown promise towards this end with certain NBS protocols augmenting somatosensory processing and others down-regulating it. Here, we review NBS protocols which, when applied to primary somatosensory cortex, facilitate cortical excitability and tactile acuity (i.e., high-frequency repetitive TMS (rTMS), intermittent theta burst stimulation (TBS), paired associative stimulation (PAS) N20-5 to 0, anodal tDCS), and protocols that inhibit the same (i.e., low-frequency rTMS, continuous TBS, PAS N20-20, cathodal tDCS). Other studies have targeted multisensory regions of the brain to modulate somatosensory processing. These studies in full present a wide array of strategies in which NBS can be utilized to influence somatosensory processing in a behaviorally and clinically relevant capacity.

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.

Modulating reconsolidation: a link to causal systems-level dynamics of human memories

A vital property of the brain is its plasticity, which manifests as changes in behavioral performance. Invasive studies at the cellular level in animal models reveal time-restricted windows during which existing memories that are reactivated become susceptible to modification through reconsolidation, and evidence suggests similar effects in humans. In this review we summarize recent work utilizing noninvasive brain stimulation in humans to uncover the systems-level mechanisms underlying memory reconsolidation. This novel understanding of memory dynamics may have far-reaching clinical implications, including the potential to modulate reconsolidation in patients with memory disorders.