Characterizing the cortical oscillatory response to TMS pulse

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Paired Associative Stimulation drives the emergence of motor resonance

Abstract Background Associative plasticity, the neurophysiological bases of Hebbian learning, has been implied in the formation of the association between sensory and motor representations of actions in the Mirror Neuron System; however, such inductor role still needs empirical support. Objective/hypothesis We have assessed whether Paired Associative Stimulation (PAS), known to activate Hebbian associative plasticity, can induce the formation of atypical (absent in normal conditions), visuo-motor associations, reshaping motor resonance. Methods Healthy participants underwent a novel PAS protocol (mirror-PAS, m-PAS), during which they were exposed to repeated pairings of transcranial magnetic stimulation (TMS) applied over the right primary motor cortex (M1), time-locked with the view of index-finger movements of the right (ipsilateral) hand. In a first experiment, the inter-stimulus interval (ISI) between visual-action stimuli and TMS pulses was varied. Before and after each m-PAS session, motor resonance was assessed by recording Motor Evoked Potentials induced by single-pulse TMS applied to the right M1, during the observation of both contralateral (left) and ipsilateral (right) index-finger movements. In the second experiment, the specificity of the m-PAS was assessed by presenting a visual stimulus depicting a non-biological movement. Results Before m-PAS, the facilitation of corticospinal excitability occurred only during the view of contralateral (with respect to the TMS side) index-finger movements. The m-PAS induced new ipsilateral motor resonance responses, indexed by atypical facilitation of corticospinal excitability by the view of ipsilateral hand movements. This effect occurred only if the associative stimulation followed the chronometry of motor control (ISI of 25 ms) and if the visual stimulus of the m-PAS depicts a biological movement (human hand action). Conclusions The present findings provide the first empirical evidence that Hebbian learning induced by a PAS protocol shapes the visual-motor matching properties of the human Mirror Neuron System

Simultaneous transcranial electrical and magnetic stimulation boost gamma oscillations in the dorsolateral prefrontal cortex

Neural oscillations in the gamma frequency band have been identified as a fundament for synaptic plasticity dynamics and their alterations are central in various psychiatric and neurological conditions. Transcranial magnetic stimulation (TMS) and alternating electrical stimulation (tACS) may have a strong therapeutic potential by promoting gamma oscillations expression and plasticity. Here we applied intermittent theta-burst stimulation (iTBS), an established TMS protocol known to induce LTP-like cortical plasticity, simultaneously with transcranial alternating current stimulation (tACS) at either theta (theta tACS) or gamma (gamma tACS) frequency on the dorsolateral prefrontal cortex (DLPFC). We used TMS in combination with electroencephalography (EEG) to evaluate changes in cortical activity on both left/right DLPFC and over the vertex. We found that simultaneous iTBS with gamma tACS but not with theta tACS resulted in an enhancement of spectral gamma power, a trend in shift of individual peak frequency towards faster oscillations and an increase of local connectivity in the gamma band. Furthermore, the response to the neuromodulatory protocol, in terms of gamma oscillations and connectivity, were directly correlated with the initial level of cortical excitability. These results were specific to the DLPFC and confined locally to the site of stimulation, not being detectable in the contralateral DLPFC. We argue that the results described here could promote a new and effective method able to induce long-lasting changes in brain plasticity useful to be clinically applied to several psychiatric and neurological conditions

Real-time cortical dynamics during motor inhibition

The inhibition of action is a fundamental executive mechanism of human behaviour that involve a complex neural network. In spite of the progresses made so far, many questions regarding the brain dynamics occurring during action inhibition are still unsolved. Here, we used a novel approach optimized to investigate real-time effective brain dynamics, which combines transcranial magnetic stimulation (TMS) with simultaneous electroencephalographic (EEG) recordings. 22 healthy volunteers performed a motor Go/NoGo task during TMS of the hand-hotspot of the primary motor cortex (M1) and whole-scalp EEG recordings. We reconstructed source-based real-time spatiotemporal dynamics of cortical activity and cortico-cortical connectivity throughout the task. Our results showed a task-dependent bi-directional change in theta/gamma supplementary motor cortex (SMA) and M1 connectivity that, when participants were instructed to inhibit their response, resulted in an increase of a specific TMS-evoked EEG potential (N100), likely due to a GABA-mediated inhibition. Interestingly, these changes were linearly related to reaction times, when participants were asked to produce a motor response. In addition, TMS perturbation revealed a task-dependent long-lasting modulation of SMA-M1 natural frequencies, i.e. alpha/beta activity. Some of these results are shared by animal models and shed new light on the physiological mechanisms of motor inhibition in humans

Cerebellar Non-Invasive Brain Stimulation: A Frontier in Chronic Pain Therapy

Chronic pain poses a widespread and distressing challenge; it can be resistant to conventional therapies, often having significant side effects. Non-invasive brain stimulation (NIBS) techniques offer promising avenues for the safe and swift modulation of brain excitability. NIBS approaches for chronic pain management targeting the primary motor area have yielded variable outcomes. Recently, the cerebellum has emerged as a pivotal hub in human pain processing; however, the clinical application of cerebellar NIBS in chronic pain treatment remains limited. This review delineates the cerebellum’s role in pain modulation, recent advancements in NIBS for cerebellar activity modulation, and novel biomarkers for assessing cerebellar function in humans. Despite notable progress in NIBS techniques and cerebellar activity assessment, studies targeting cerebellar NIBS for chronic pain treatment are limited in number. Nevertheless, positive outcomes in pain alleviation have been reported with cerebellar anodal transcranial direct current stimulation. Our review underscores the potential for further integration between cerebellar NIBS and non-invasive assessments of cerebellar function to advance chronic pain treatment strategies

The effect of frontoparietal paired associative stimulation on decision-making and working memory

Previous single-site neurostimulation experiments have unsuccessfully attempted to shift decision-making away from habitual control, a fast, inflexible cognitive strategy, towards goal-directed control, a flexible, though computationally expensive strategy. We employed a dual-target neurostimulation approach in 30 healthy participants, using cortico-cortical paired associative stimulation (ccPAS) to target two key nodes: lateral prefrontal cortex (LPFC) and intraparietal sulcus (IPS), to test whether decision-making can be artificially shifted from habitual toward goal-directed control. Participants received three active stimulations, delivered at least six days apart (each involving 100 paired pulses over the IPS and LPFC, varying the interstimulus interval): two interventional, time-relevant ccPAS (10 msec interval) and one control, non-time-relevant ccPAS (100 msec interval). Following stimulation, participants completed a sequential learning task, measuring goal-directed/habitual control, and a working memory task. IPS→LPFC ccPAS (stimulating IPS, then LPFC with a 10 msec interval) shifted decision-making from habitual toward goal-directed control, compared to control ccPAS. There was no effect of LPFC→IPS ccPAS, nor an effect of any PAS condition on working memory. Previous studies have shown ccPAS effects outside the motor domain targeting prefrontal regions on response inhibition, attentional bias, and alpha asymmetry. The present study measures the behavioural effects of parietal-prefrontal PAS, focusing on a highly complex decision-making task and working memory. If confirmed in larger studies, this would be the first instance of neurostimulation successfully shifting decision-making from habitual to goal-directed control, putatively via inducing long-term potentiation between the IPS and LPFC. However, we found no effect in the other direction (LPFC→IPS ccPAS), and no effect on working memory overall. PAS is a relatively new neuromodulatory technique in the cognitive arsenal, and this study could help guide future approaches in healthy and disordered decision-making

Neuromodulation of Spike-Timing-Dependent Plasticity: Past, Present, and Future.

Spike-timing-dependent synaptic plasticity (STDP) is a leading cellular model for behavioral learning and memory with rich computational properties. However, the relationship between the millisecond-precision spike timing required for STDP and the much slower timescales of behavioral learning is not well understood. Neuromodulation offers an attractive mechanism to connect these different timescales, and there is now strong experimental evidence that STDP is under neuromodulatory control by acetylcholine, monoamines, and other signaling molecules. Here, we review neuromodulation of STDP, the underlying mechanisms, functional implications, and possible involvement in brain disorders.BBSR

Spike-timing-dependent plasticity in the human dorso-lateral prefrontal cortex

Changes in the synaptic strength of neural connections are induced by repeated coupling of activity of interconnected neurons with precise timing, a phenomenon known as spike-timing-dependent plasticity (STDP). It is debated if this mechanism exists in large-scale cortical networks in humans. We combined transcranial magnetic stimulation (TMS) with concurrent electroencephalography (EEG) to directly investigate the effects of two paired associative stimulation (PAS) protocols (fronto-parietal and parieto-frontal) of pre and post-synaptic inputs within the human fronto-parietal network. We found evidence that the dorsolateral prefrontal cortex (DLPFC) has the potential to form robust STDP. Long-term potentiation/depression of TMS-evoked cortical activity is prompted after that DLPFC stimulation is followed/preceded by posterior parietal stimulation. Such bidirectional changes are paralleled by sustained increase/decrease of high-frequency oscillatory activity, likely reflecting STDP responsivity. The current findings could be important to drive plasticity of damaged cortical circuits in patients with cognitive or psychiatric disorders

Spike-Timing-Dependent Plasticity Alters Sensory Network Connectivity

A fundamental question in neuroscience is: how does a sensory system optimize detection of behaviorally relevant stimuli, when those stimuli and the sensory environment are constantly changing? Spike-timing-dependent plasticity (STDP), in which synapse strength changes based on the relative timing of pre- and post-synaptic spiking, has been implicated in changes in neuronal connectivity thought to underlie learning and memory. Synaptic strength changes caused by STDP have been shown in optic tectum, visual cortex, hippocampus, and other brain regions in vitro across many organisms like fish, frogs, and mice. Although it is possible that STDP mechanisms underlie changes in sensory neuron connectivity, the relationship between sensory stimulation and central sensory neuronal response is complex and often involves populations of neurons that differ in the timing and frequency of spiking, resulting in complex spatiotemporal patterns of synaptic input to postsynaptic neurons. The organism I studied, weakly electric fish, produce and receive electric organ discharges (EODs) used to electrolocate and communicate. Taking advantage of the electrosensory system, weakly electric fishes are a system in which spiking patterns are themselves the behaviorally relevant stimulus. Previous work showed that STDP predictably altered synaptic xi responses and inter-pulse interval tuning in vitro (Ma and Carlson, unpublished). Using whole-cell intracellular recordings to repetitively pair sensory stimulation with intracellular spiking in vivo, I manipulated the relative timing of pre- and post-synaptic spiking in central sensory neurons in awake, behaving animals. I found that STDP alters sensory responses of central electrosensory neurons in vivo but there was more variability in the changes in sensory responses in vivo relative to the in vitro changes in synaptic responses (Chapter 2). Whether the in vivo data “fit” or “did not fit” the pattern predicted by the in vitro results was correlated with variations in synaptic potential landmarks. That variations in synaptic potential landmarks correlated with deviations from the pattern shown in vitro results suggest that whether the data “fit” or “did not fit” the in vitro hypothesis is influenced by polysynaptic activity, including inhibitory interneurons (Chapter 2). I now asked whether STDP could alter sensory tuning to behaviorally relevant stimuli in vivo. Using whole-cell intracellular recordings, I recorded postsynaptic potential responses to two different sensory stimuli before and after pairing postsynaptic spiking with only one of those sensory stimuli. I found that some in vivo responses followed the pattern predicted by STDP sensory tuning experiments done in vitro and some in vivo responses that did not. Whether the in vivo sensory tuning data “fit” or “did not fit” the pattern predicted by the in vitro sensory tuning changes was correlated with variations in synaptic potential landmarks. That variations in the synaptic potential landmarks correlated with differences in the in vitro and in vivo sensory tuning suggest that whether the in vivo tuning results did or did not “fit” the in vitro tuning prediction is influenced by polysynaptic activity, including inhibitory interneurons (Chapter 3). Next, I wanted to ask whether intrinsic network activity could alter sensory tuning based solely on the input of behaviorally relevant stimuli. Using extracellular evoked potential recordings and a freely behaving paradigm, I recorded postsynaptic potential responses and behavioral output to two xii different sensory stimuli before and after repeating only one of those sensory stimuli, with no pairing of postsynaptic spiking. I did not find any significant differences in the evoked potentials or behavior as a result of repetition of a sensory stimulus (Chapter 4). Thus, in this dissertation I showed that STDP can alter the sensory responses of central electrosensory neurons, but that STDP rules operating at identified synapses may not drive predictable changes in sensory responses and sensory tuning at the circuit or behavioral level. In conclusion, for altering sensory tuning in adult organisms in a changing sensory environment in vivo, the role of STDP is more complex than had been predicted from previous work in vitr

Motor imagery and motor illusion: from plasticity to a translational approach

Motor imagery e illusione motoria: dalla plasticit\ue0 ad un approccio traslazional