Noninvasive Neuromodulation Goes Deep.

Modulating deep regions of the brain with noninvasive technology has challenged researchers for decades. In a new study, Grossman et al. leverage the emergence of a slowly oscillating "beat" from intersecting high-frequency electric fields to stimulate deep brain regions, opening a frontier in the biophysics and technology of brain stimulation.

Spike-timing-dependent plasticity induction reveals dissociable supplementary- and premotor-motor pathways to automatic imitation.

Humans tend to spontaneously imitate others' behavior, even when detrimental to the task at hand. The action observation network (AON) is consistently recruited during imitative tasks. However, whether automatic imitation is mediated by cortico-cortical projections from AON regions to the primary motor cortex (M1) remains speculative. Similarly, the potentially dissociable role of AON-to-M1 pathways involving the ventral premotor cortex (PMv) or supplementary motor area (SMA) in automatic imitation is unclear. Here, we used cortico-cortical paired associative stimulation (ccPAS) to enhance or hinder effective connectivity in PMv-to-M1 and SMA-to-M1 pathways via Hebbian spike-timing-dependent plasticity (STDP) to test their functional relevance to automatic and voluntary motor imitation. ccPAS affected behavior under competition between task rules and prepotent visuomotor associations underpinning automatic imitation. Critically, we found dissociable effects of manipulating the strength of the two pathways. While strengthening PMv-to-M1 projections enhanced automatic imitation, weakening them hindered it. On the other hand, strengthening SMA-to-M1 projections reduced automatic imitation but also reduced interference from task-irrelevant cues during voluntary imitation. Our study demonstrates that driving Hebbian STDP in AON-to-M1 projections induces opposite effects on automatic imitation that depend on the targeted pathway. Our results provide direct causal evidence of the functional role of PMv-to-M1 projections for automatic imitation, seemingly involved in spontaneously mirroring observed actions and facilitating the tendency to imitate them. Moreover, our findings support the notion that SMA exerts an opposite gating function, controlling M1 to prevent overt motor behavior when inadequate to the context.

Cardiac activity impacts cortical motor excitability.

Human cognition and action can be influenced by internal bodily processes such as heartbeats. For instance, somatosensory perception is impaired both during the systolic phase of the cardiac cycle and when heartbeats evoke stronger cortical responses. Here, we test whether these cardiac effects originate from overall changes in cortical excitability. Cortical and corticospinal excitability were assessed using electroencephalographic and electromyographic responses to transcranial magnetic stimulation while concurrently monitoring cardiac activity with electrocardiography. Cortical and corticospinal excitability were found to be highest during systole and following stronger neural responses to heartbeats. Furthermore, in a motor task, hand-muscle activity and the associated desynchronization of sensorimotor oscillations were stronger during systole. These results suggest that systolic cardiac signals have a facilitatory effect on motor excitability-in contrast to sensory attenuation that was previously reported for somatosensory perception. Thus, it is possible that distinct time windows exist across the cardiac cycle, optimizing either perception or action.

Transcranial magnetic stimulation to frontal but not occipital cortex disrupts endogenous attention.

Covert endogenous (voluntary) attention improves visual performance. Human neuroimaging studies suggest that the putative human homolog of macaque frontal eye fields (FEF+) is critical for this improvement, whereas early visual areas are not. Yet, correlational MRI methods do not manipulate brain function. We investigated whether rFEF+ or V1/V2 plays a causal role in endogenous attention. We used transcranial magnetic stimulation (TMS) to alter activity in the visual cortex or rFEF+ when observers performed an orientation discrimination task while attention was manipulated. On every trial, they received double-pulse TMS at a predetermined site (stimulated region) around V1/V2 or rFEF+. Two cortically magnified gratings were presented, one in the stimulated region (contralateral to the stimulated area) and another in the symmetric (ipsilateral) nonstimulated region. Grating contrast was varied to measure contrast response functions (CRFs) for all attention and stimulation combinations. In experiment 1, the CRFs were similar at the stimulated and nonstimulated regions, indicating that early visual areas do not modulate endogenous attention during stimulus presentation. In contrast, occipital TMS eliminates exogenous (involuntary) attention effects on performance [A. Fernández, M. Carrasco,Curr. Biol. 30, 4078-4084 (2020)]. In experiment 2, rFEF+ stimulation decreased the overall attentional effect; neither benefits at the attended location nor costs at the unattended location were significant. The frequency and directionality of microsaccades mimicked this pattern: Whereas occipital stimulation did not affect microsaccades, rFEF+ stimulation caused a higher microsaccade rate directed toward the stimulated hemifield. These results provide causal evidence of the role of this frontal region for endogenous attention.

Causal evidence for a coordinated temporal interplay within the language network.

Recent neurobiological models on language suggest that auditory sentence comprehension is supported by a coordinated temporal interplay within a left-dominant brain network, including the posterior inferior frontal gyrus (pIFG), posterior superior temporal gyrus and sulcus (pSTG/STS), and angular gyrus (AG). Here, we probed the timing and causal relevance of the interplay between these regions by means of concurrent transcranial magnetic stimulation and electroencephalography (TMS-EEG). Our TMS-EEG experiments reveal region- and time-specific causal evidence for a bidirectional information flow from left pSTG/STS to left pIFG and back during auditory sentence processing. Adapting a condition-and-perturb approach, our findings further suggest that the left pSTG/STS can be supported by the left AG in a state-dependent manner.

Noninvasive modulation of human corticostriatal activity.

Corticostriatal activity is an appealing target for nonpharmacological treatments of brain disorders. In humans, corticostriatal activity may be modulated with noninvasive brain stimulation (NIBS). However, a NIBS protocol with a sound neuroimaging measure demonstrating a change in corticostriatal activity is currently lacking. Here, we combine transcranial static magnetic field stimulation (tSMS) with resting-state functional MRI (fMRI). We first present and validate the ISAAC analysis, a well-principled framework that disambiguates functional connectivity between regions from local activity within regions. All measures of the framework suggested that the region along the medial cortex displaying greater functional connectivity with the striatum is the supplementary motor area (SMA), where we applied tSMS. We then use a data-driven version of the framework to show that tSMS of the SMA modulates the local activity in the SMA proper, in the adjacent sensorimotor cortex, and in the motor striatum. We finally use a model-driven version of the framework to clarify that the tSMS-induced modulation of striatal activity can be primarily explained by a change in the shared activity between the modulated motor cortical areas and the motor striatum. These results suggest that corticostriatal activity can be targeted, monitored, and modulated noninvasively in humans.

Static Magnetic Field Stimulation Enhances Shunting Inhibition via a SLC26 Family Cl- Channel, Inducing Intrinsic Plasticity.

Magnetic fields are being used for detailed anatomical and functional examination of the human brain. In addition, evidence for their efficacy in treatment of brain dysfunctions is accumulating. Transcranial static magnetic field stimulation (tSMS) is a recently developed technique for noninvasively modifying brain functions. In tSMS, a strong and small magnet when placed over the skull can temporarily suppress brain functions. Its modulatory effects persist beyond the time of stimulation. However, the neurophysiological mechanisms underlying tSMS-induced plasticity remain unclear. Here, using acute motor cortical slice preparation obtained from male C57BL/6N mice, we show that tSMS alters the intrinsic electrical properties of neurons by altering the activity of chloride (Cl-) channels in neurons. Exposure of mouse pyramidal neurons to a static magnetic field (SMF) at a strength similar to human tSMS temporarily decreased their excitability and induced transient neuronal swelling. The effects of SMF were blocked by DIDS and GlyH-101, but not by NPPB, consistent with the pharmacological profile of SLC26A11, a transporter protein with Cl- channel activity. Whole-cell voltage-clamp recordings of the GlyH-101-sensitive Cl- current component showed significant enhancement of the component at both subthreshold and depolarized membrane potentials after SMF application, resulting in shunting inhibition and reduced repetitive action potential (AP) firing at the respective potentials. Thus, this study provides the first neurophysiological evidence for the inhibitory effect of tSMS on neuronal activity and advances our mechanistic understanding of noninvasive human neuromodulation.

The Consolidation of Newly Learned Movements Depends upon the Somatosensory Cortex in Humans.

Studies using magnetic brain stimulation indicate the involvement of somatosensory regions in the acquisition and retention of newly learned movements. Recent work found an impairment in motor memory when retention was tested shortly after the application of continuous theta-burst stimulation (cTBS) to the primary somatosensory cortex, compared with stimulation of the primary motor cortex or a control zone. This finding that the somatosensory cortex is involved in motor memory retention whereas the motor cortex is not, if confirmed, could alter our understanding of human motor learning. It would indicate that plasticity in sensory systems underlies newly learned movements, which is different than the commonly held view that adaptation learning involves updates to a motor controller. Here we test this idea. Participants were trained in a visuomotor adaptation task, with visual feedback gradually shifted. Following adaptation, cTBS was applied either to M1, S1, or an occipital cortex control area. Participants were tested for retention 24 h later. It was observed that S1 stimulation led to reduced retention of prior learning, compared with stimulation of M1 or the control area (with no significant difference between M1 and control). In a further control, cTBS was applied to S1 following training with unrotated feedback, in which no learning occurred. This had no effect on movement in the retention test indicating the effects of S1 stimulation on movement are learning specific. The findings are consistent with the S1 participation in the encoding of learning-related changes to movements and in the retention of human motor memory.

Internal Representations Are Prioritized by Frontoparietal Theta Connectivity and Suppressed by alpha Oscillation Dynamics: Evidence from Concurrent Transcranial Magnetic Stimulation EEG and Invasive EEG.

Control over internal representations requires the prioritization of relevant information and suppression of irrelevant information. The frontoparietal network exhibits prominent neural oscillations during these distinct cognitive processes. Yet, the causal role of this network-scale activity is unclear. Here, we targeted theta-frequency frontoparietal coherence and dynamic alpha oscillations in the posterior parietal cortex using online rhythmic transcranial magnetic stimulation (TMS) in women and men while they prioritized or suppressed internally maintained working memory (WM) representations. Using concurrent high-density EEG, we provided evidence that we acutely drove the targeted neural oscillation and TMS improved WM capacity only when the evoked activity corresponded with the desired cognitive process. To suppress an internal representation, we increased the amplitude of lateralized alpha oscillations in the posterior parietal cortex contralateral to the irrelevant visual field. For prioritization, we found that TMS to the prefrontal cortex increased theta-frequency connectivity in the prefrontoparietal network contralateral to the relevant visual field. To understand the spatial specificity of these effects, we administered the WM task to participants with implanted electrodes. We found that theta connectivity during prioritization was directed from the lateral prefrontal to the superior posterior parietal cortex. Together, these findings provide causal evidence in support of a model where a frontoparietal theta network prioritizes internally maintained representations and alpha oscillations in the posterior parietal cortex suppress irrelevant representations.

Belief Updating during Social Interactions: Neural Dynamics and Causal Role of Dorsomedial Prefrontal Cortex.

In competitive interactions, humans have to flexibly update their beliefs about another person's intentions in order to adjust their own choice strategy, such as when believing that the other may exploit their cooperativeness. Here we investigate both the neural dynamics and the causal neural substrate of belief updating processes in humans. We used an adapted prisoner's dilemma game in which participants explicitly predicted the coplayer's actions, which allowed us to quantify the prediction error between expected and actual behavior. First, in an EEG experiment, we found a stronger medial frontal negativity (MFN) for negative than positive prediction errors, suggesting that this medial frontal ERP component may encode unexpected defection of the coplayer. The MFN also predicted subsequent belief updating after negative prediction errors. In a second experiment, we used transcranial magnetic stimulation (TMS) to investigate whether the dorsomedial prefrontal cortex (dmPFC) causally implements belief updating after unexpected outcomes. Our results show that dmPFC TMS impaired belief updating and strategic behavioral adjustments after negative prediction errors. Taken together, our findings reveal the time course of the use of prediction errors in social decisions and suggest that the dmPFC plays a crucial role in updating mental representations of others' intentions.

Dopamine D2 Receptor Modulates Exercise Related Effect on Cortical Excitation/Inhibition and Motor Skill Acquisition.

Exercise is known to benefit motor skill learning in health and neurological disease. Evidence from brain stimulation, genotyping, and Parkinson's disease studies converge to suggest that the dopamine D2 receptor, and shifts in the cortical excitation and inhibition (E:I) balance, are prime candidates for the drivers of exercise-enhanced motor learning. However, causal evidence using experimental pharmacological challenge is lacking. We hypothesized that the modulatory effect of the dopamine D2 receptor on exercise-induced changes in the E:I balance would determine the magnitude of motor skill acquisition. To test this, we measured exercise-induced changes in excitation and inhibition using paired-pulse transcranial magnetic stimulation (TMS) in 22 healthy female and male humans, and then had participants learn a novel motor skill-the sequential visual isometric pinch task (SVIPT). We examined the effect of D2 receptor blockade (800 mg sulpiride) on these measures within a randomized, double-blind, placebo-controlled design. Our key result was that motor skill acquisition was driven by an interaction between the D2 receptor and E:I balance. Specifically, poorer skill learning was related to an attenuated shift in the E:I balance in the sulpiride condition, whereas this interaction was not evident in placebo. Our results demonstrate that exercise-primed motor skill acquisition is causally influenced by D2 receptor activity on motor cortical circuits.

Effects of transcranial magnetic stimulation on the human brain recorded with intracranial electrocorticography.

Transcranial magnetic stimulation (TMS) is increasingly used as a noninvasive technique for neuromodulation in research and clinical applications, yet its mechanisms are not well understood. Here, we present the neurophysiological effects of TMS using intracranial electrocorticography (iEEG) in neurosurgical patients. We first evaluated safety in a gel-based phantom. We then performed TMS-iEEG in 22 neurosurgical participants with no adverse events. We next evaluated intracranial responses to single pulses of TMS to the dorsolateral prefrontal cortex (dlPFC) (N = 10, 1414 electrodes). We demonstrate that TMS is capable of inducing evoked potentials both locally within the dlPFC and in downstream regions functionally connected to the dlPFC, including the anterior cingulate and insular cortex. These downstream effects were not observed when stimulating other distant brain regions. Intracranial dlPFC electrical stimulation had similar timing and downstream effects as TMS. These findings support the safety and promise of TMS-iEEG in humans to examine local and network-level effects of TMS with higher spatiotemporal resolution than currently available methods.

Human perceptual and metacognitive decision-making rely on distinct brain networks.

Perceptual decisions depend on the ability to exploit available sensory information in order to select the most adaptive option from a set of alternatives. Such decisions depend on the perceptual sensitivity of the organism, which is generally accompanied by a corresponding level of certainty about the choice made. Here, by use of corticocortical paired associative transcranial magnetic stimulation protocol (ccPAS) aimed at inducing plastic changes, we shaped perceptual sensitivity and metacognitive ability in a motion discrimination task depending on the targeted network, demonstrating their functional dissociation. Neurostimulation aimed at boosting V5/MT+-to-V1/V2 back-projections enhanced motion sensitivity without impacting metacognition, whereas boosting IPS/LIP-to-V1/V2 back-projections increased metacognitive efficiency without impacting motion sensitivity. This double-dissociation provides causal evidence of distinct networks for perceptual sensitivity and metacognitive ability in humans.

Hasty sensorimotor decisions rely on an overlap of broad and selective changes in motor activity.

Humans and other animals are able to adjust their speed-accuracy trade-off (SAT) at will depending on the urge to act, favoring either cautious or hasty decision policies in different contexts. An emerging view is that SAT regulation relies on influences exerting broad changes on the motor system, tuning its activity up globally when hastiness is at premium. The present study aimed to test this hypothesis. A total of 50 participants performed a task involving choices between left and right index fingers, in which incorrect choices led either to a high or to a low penalty in 2 contexts, inciting them to emphasize either cautious or hasty policies. We applied transcranial magnetic stimulation (TMS) on multiple motor representations, eliciting motor-evoked potentials (MEPs) in 9 finger and leg muscles. MEP amplitudes allowed us to probe activity changes in the corresponding finger and leg representations, while participants were deliberating about which index to choose. Our data indicate that hastiness entails a broad amplification of motor activity, although this amplification was limited to the chosen side. On top of this effect, we identified a local suppression of motor activity, surrounding the chosen index representation. Hence, a decision policy favoring speed over accuracy appears to rely on overlapping processes producing a broad (but not global) amplification and a surround suppression of motor activity. The latter effect may help to increase the signal-to-noise ratio of the chosen representation, as supported by single-trial correlation analyses indicating a stronger differentiation of activity changes in finger representations in the hasty context.

The pathobiology of psychomotor slowing in psychosis: altered cortical excitability and connectivity.

Psychomotor slowing is a frequent symptom of schizophrenia. Short-interval intracortical inhibition assessed by transcranial magnetic stimulation demonstrated inhibitory dysfunction in schizophrenia. The inhibitory deficit results from additional noise during information processing in the motor system in psychosis. Here, we tested whether cortical inhibitory dysfunction was linked to psychomotor slowing and motor network alterations. In this cross-sectional study, we included 60 patients with schizophrenia and psychomotor slowing determined by the Salpêtrière Retardation Rating Scale, 23 patients without slowing and 40 healthy control participants. We acquired single and double-pulse transcranial magnetic stimulation effects from the left primary motor cortex, resting-state functional connectivity and diffusion imaging on the same day. Groups were compared on resting motor threshold, amplitude of the motor evoked potentials, as well as short-interval intracortical inhibition. Regression analyses calculated the association between motor evoked potential amplitudes or cortical inhibition with seed-based resting-state functional connectivity from the left primary motor cortex and fractional anisotropy at whole brain level and within major motor tracts. In patients with schizophrenia and psychomotor slowing, we observed lower amplitudes of motor evoked potentials, while the short-interval intracortical inhibition/motor evoked potentials amplitude ratio was higher than in healthy controls, suggesting lower cortical inhibition in these patients. Patients without slowing also had lower amplitudes of motor evoked potentials. Across the combined patient sample, cortical inhibition deficits were linked to more motor coordination impairments. In patients with schizophrenia and psychomotor slowing, lower amplitudes of motor evoked potentials were associated with lower fractional anisotropy in motor tracts. Moreover, resting-state functional connectivity between the primary motor cortex, the anterior cingulate cortex and the cerebellum increased with stronger cortical inhibition. In contrast, in healthy controls and patients without slowing, stronger cortical inhibition was linked to lower resting-state functional connectivity between the left primary motor cortex and premotor or parietal cortices. Psychomotor slowing in psychosis is linked to less cortical inhibition and aberrant functional connectivity of the primary motor cortex. Higher neural noise in the motor system may drive psychomotor slowing and thus may become a treatment target.

Distinct neuronal circuits mediate cortical hyperexcitability in amyotrophic lateral sclerosis.

Cortical hyperexcitability is an important pathophysiological mechanism in amyotrophic lateral sclerosis (ALS), reflecting a complex interaction of inhibitory and facilitatory interneuronal processes that evolves in the degenerating brain. The advances in physiological techniques have made it possible to interrogate progressive changes in the motor cortex. Specifically, the direction of transcranial magnetic stimulation (TMS) stimulus within the primary motor cortex can be utilized to influence descending corticospinal volleys and to thereby provide information about distinct interneuronal circuits. Cortical motor function and cognition was assessed in 29 ALS patients with results compared to healthy volunteers. Cortical dysfunction was assessed using threshold-tracking TMS to explore alterations in short interval intracortical inhibition (SICI), short interval intracortical facilitation (SICF), the index of excitation and stimulus response curves using a figure-of-eight coil with the coil oriented relative to the primary motor cortex in a posterior-anterior, lateral-medial and anterior-posterior direction. Mean SICI, between interstimulus interval of 1-7 ms, was significantly reduced in ALS patients compared to healthy controls when assessed with the coil oriented in posterior-anterior (P = 0.044) and lateral-medial (P = 0.005) but not the anterior-posterior (P = 0.08) directions. A significant correlation between mean SICI oriented in a posterior-anterior direction and the total Edinburgh Cognitive and Behavioural ALS Screen score (Rho = 0.389, P = 0.037) was evident. In addition, the mean SICF, between interstimulus interval 1-5 ms, was significantly increased in ALS patients when recorded with TMS coil oriented in posterior-anterior (P = 0.035) and lateral-medial (P < 0.001) directions. In contrast, SICF recorded with TMS coil oriented in the anterior-posterior direction was comparable between ALS and controls (P = 0.482). The index of excitation was significantly increased in ALS patients when recorded with the TMS coil oriented in posterior-anterior (P = 0.041) and lateral-medial (P = 0.003) directions. In ALS patients, a significant increase in the stimulus response curve gradient was evident compared to controls when recorded with TMS coil oriented in posterior-anterior (P < 0.001), lateral-medial (P < 0.001) and anterior-posterior (P = 0.002) directions. The present study has established that dysfunction of distinct interneuronal circuits mediates the development of cortical hyperexcitability in ALS. Specifically, complex interplay between inhibitory circuits and facilitatory interneuronal populations, that are preferentially activated by stimulation in posterior-to-anterior or lateral-to-medial directions, promotes cortical hyperexcitability in ALS. Mechanisms that underlie dysfunction of these specific cortical neuronal circuits will enhance understanding of the pathophysiological processes in ALS, with the potential to uncover focussed therapeutic targets.

Changes in cerebellar output abnormally modulate cortical myoclonus sensorimotor hyperexcitability.

Cortical myoclonus is produced by abnormal neuronal discharges within the sensorimotor cortex, as demonstrated by electrophysiology. Our hypothesis is that the loss of cerebellar inhibitory control over the motor cortex, via cerebello-thalamo-cortical connections, could induce the increased sensorimotor cortical excitability that eventually causes cortical myoclonus. To explore this hypothesis, in the present study we applied anodal transcranial direct current stimulation over the cerebellum of patients affected by cortical myoclonus and healthy controls and assessed its effect on sensorimotor cortex excitability. We expected that anodal cerebellar transcranial direct current stimulation would increase the inhibitory cerebellar drive to the motor cortex and therefore reduce the sensorimotor cortex hyperexcitability observed in cortical myoclonus. Ten patients affected by cortical myoclonus of various aetiology and 10 aged-matched healthy control subjects were included in the study. All participants underwent somatosensory evoked potentials, long-latency reflexes and short-interval intracortical inhibition recording at baseline and immediately after 20 min session of cerebellar anodal transcranial direct current stimulation. In patients, myoclonus was recorded by the means of surface EMG before and after the cerebellar stimulation. Anodal cerebellar transcranial direct current stimulation did not change the above variables in healthy controls, while it significantly increased the amplitude of somatosensory evoked potential cortical components, long-latency reflexes and decreased short-interval intracortical inhibition in patients; alongside, a trend towards worsening of the myoclonus after the cerebellar stimulation was observed. Interestingly, when dividing patients in those with and without giant somatosensory evoked potentials, the increment of the somatosensory evoked potential cortical components was observed mainly in those with giant potentials. Our data showed that anodal cerebellar transcranial direct current stimulation facilitates-and does not inhibit-sensorimotor cortex excitability in cortical myoclonus syndromes. This paradoxical response might be due to an abnormal homeostatic plasticity within the sensorimotor cortex, driven by dysfunctional cerebello-thalamo-cortical input to the motor cortex. We suggest that the cerebellum is implicated in the pathophysiology of cortical myoclonus and that these results could open the way to new forms of treatment or treatment targets.

Posterior parietal cortex is causally involved in reward valuation but not in probability weighting during risky choice.

This study provides evidence that the posterior parietal cortex is causally involved in risky decision making via the processing of reward values but not reward probabilities. In the within-group experimental design, participants performed a binary lottery choice task following transcranial magnetic stimulation of the right posterior parietal cortex, left posterior parietal cortex, and a right posterior parietal cortex sham (placebo) stimulation. The continuous theta-burst stimulation protocol supposedly downregulating the cortical excitability was used. Both, mean-variance and the prospect theory approach to risky choice showed that the posterior parietal cortex stimulation shifted participants toward greater risk aversion compared with sham. On the behavioral level, after the posterior parietal cortex stimulation, the likelihood of choosing a safer option became more sensitive to the difference in standard deviations between lotteries, compared with sham, indicating greater risk avoidance within the mean-variance framework. We also estimated the shift in prospect theory parameters of risk preferences after posterior parietal cortex stimulation. The hierarchical Bayesian approach showed moderate evidence for a credible change in risk aversion parameter toward lower marginal reward value (and, hence, lower risk tolerance), while no credible change in probability weighting was observed. In addition, we observed anecdotal evidence for a credible increase in the consistency of responses after the left posterior parietal cortex stimulation compared with sham.

Neuroplasticity of the left dorsolateral prefrontal cortex in patients with treatment-resistant depression as indexed with paired associative stimulation: a TMS-EEG study.

Major depressive disorder affects over 300 million people globally, with approximately 30% experiencing treatment-resistant depression (TRD). Given that impaired neuroplasticity underlies depression, the present study focused on neuroplasticity in the dorsolateral prefrontal cortex (DLPFC). Here, we aimed to investigate the differences in neuroplasticity between 60 individuals with TRD and 30 age- and sex-matched healthy controls (HCs). To induce neuroplasticity, participants underwent a paired associative stimulation (PAS) paradigm involving peripheral median nerve stimulation and transcranial magnetic stimulation (TMS) targeting the left DLPFC. Neuroplasticity was assessed by using measurements combining TMS with EEG before and after PAS. Both groups exhibited significant increases in the early component of TMS-evoked potentials (TEP) after PAS (P < 0.05, paired t-tests with the bootstrapping method). However, the HC group demonstrated a greater increase in TEPs than the TRD group (P = 0.045, paired t-tests). Additionally, event-related spectral perturbation analysis highlighted that the gamma power significantly increased after PAS in the HC group, whereas it was decreased in the TRD group (P < 0.05, paired t-tests with the bootstrapping method). This gamma power modulation revealed a significant group difference (P = 0.006, paired t-tests), indicating an inverse relationship for gamma power modulation. Our findings underscore the impaired neuroplasticity of the DLPFC in individuals with TRD.

Effects of accelerated intermittent theta-burst stimulation in modulating brain of Alzheimer's disease.

Intermittent theta-burst stimulation (iTBS) is emerging as a noninvasive therapeutic strategy for Alzheimer's disease (AD). Recent advances highlighted a new accelerated iTBS (aiTBS) protocol, consisting of multiple sessions per day and higher overall pulse doses, in brain modulation. To examine the possibility of applying the aiTBS in treating AD patients, we enrolled 45 patients in AD at early clinical stages, and they were randomly assigned to either receive real or sham aiTBS. Neuropsychological scores were evaluated before and after treatment. Moreover, we detected cortical excitability and oscillatory activity changes in AD, by the single-pulse TMS in combination with EEG (TMS-EEG). Real stimulation showed markedly better performances in the group average of Auditory Verbal Learning Test scores compared to baseline. TMS-EEG revealed that aiTBS has reinforced this memory-related cortical mechanism by increasing cortical excitability and beta oscillatory activity underlying TMS target. We also found an enhancement of local natural frequency after aiTBS treatment. The novel findings implicated that high-dose aiTBS targeting left DLPFC is rapid-acting, safe, and tolerable in AD patients. Furthermore, TMS-related increase of specific neural oscillation elucidates the mechanisms of the AD cognitive impairment ameliorated by aiTBS.