Non-invasive Brain Stimulation Methods Research Articles

Molecular Changes in the Ischemic Brain as Non-Invasive Brain Stimulation Targets—TMS and tDCS Mechanisms, Therapeutic Challenges, and Combination Therapies

Ischemic stroke is one of the leading causes of death and disability. As the currently used neurorehabilitation methods present several limitations, the ongoing research focuses on the use of non-invasive brain stimulation (NIBS) techniques such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). NIBS methods were demonstrated to modulate neural excitability and improve motor and cognitive functioning in neurodegenerative diseases. However, their mechanisms of action are not fully elucidated, and the clinical outcomes are often unpredictable. This review explores the molecular processes underlying the effects of TMS and tDCS in stroke rehabilitation, including oxidative stress reduction, cell death, stimulation of neurogenesis, and neuroprotective phenotypes of glial cells. A highlight is put on the newly emerging therapeutic targets, such as ferroptotic and pyroptotic pathways. In addition, the issue of interindividual variability is discussed, and the role of neuroimaging techniques is investigated to get closer to personalized medicine. Furthermore, translational challenges of NIBS techniques are analyzed, and limitations of current clinical trials are investigated. The paper concludes with suggestions for further neurorehabilitation stroke treatment, putting the focus on combination and personalized therapies, as well as novel protocols of brain stimulation techniques.

Neuromodulation of inhibitory control using phase-lagged transcranial alternating current stimulation

BackgroundTranscranial alternating current stimulation (tACS) is a prominent non-invasive brain stimulation method for modulating neural oscillations and enhancing human cognitive function. This study aimed to investigate the effects of individualized theta tACS delivered in-phase and out-of-phase between the dorsal anterior cingulate cortex (dACC) and left dorsolateral prefrontal cortex (lDLPFC) during inhibitory control performance.MethodsThe participants engaged in a Stroop task with phase-lagged theta tACS over individually optimized high-density electrode montages targeting the dACC and lDLPFC. We analyzed task performance, event-related potentials, and prestimulus electroencephalographic theta and alpha power.ResultsWe observed significantly reduced reaction times following out-of-phase tACS, accompanied by reduced frontocentral N1 and N2 amplitudes, enhanced parieto-occipital P1 amplitudes, and pronounced frontocentral late sustained potentials. Out-of-phase stimulation also resulted in significantly higher prestimulus frontocentral theta and alpha activity.ConclusionsThese findings suggest that out-of-phase theta tACS potently modulates top-down inhibitory control, supporting the feasibility of phase-lagged tACS to enhance inhibitory control performance.

Repetitive transcranial magnetic stimulation ameliorates cognitive deficits in mice with radiation-induced brain injury by attenuating microglial pyroptosis and promoting neurogenesis via BDNF pathway

BackgroundRadiation-induced brain injury (RIBI) is a common and severe complication during radiotherapy for head and neck tumor. Repetitive transcranial magnetic stimulation (rTMS) is a novel and non-invasive method of brain stimulation, which has been applied in various neurological diseases. rTMS has been proved to be effective for treatment of RIBI, while its mechanisms have not been well understood.MethodsRIBI mouse model was established by cranial irradiation, K252a was daily injected intraperitoneally to block BDNF pathway. Immunofluorescence staining, immunohistochemistry and western blotting were performed to examine the microglial pyroptosis and hippocampal neurogenesis. Behavioral tests were used to assess the cognitive function and emotionality of mice. Golgi staining was applied to observe the structure of dendritic spine in hippocampus.ResultsrTMS significantly promoted hippocampal neurogenesis and mitigated neuroinflammation, with ameliorating pyroptosis in microglia, as well as downregulation of the protein expression level of NLRP3 inflammasome and key pyroptosis factor Gasdermin D (GSDMD). BDNF signaling pathway might be involved in it. After blocking BDNF pathway by K252a, a specific BDNF pathway inhibitor, the neuroprotective effect of rTMS was markedly reversed. Evaluated by behavioral tests, the cognitive dysfunction and anxiety-like behavior were found aggravated with the comparison of mice in rTMS intervention group. Moreover, the level of hippocampal neurogenesis was found to be attenuated, the pyroptosis of microglia as well as the levels of GSDMD, NLRP3 inflammasome and IL-1β were upregulated.ConclusionOur study indicated that rTMS notably ameliorated RIBI-induced cognitive disorders, by mitigating pyroptosis in microglia and promoting hippocampal neurogenesis via mediating BDNF pathway.

Effect of Transcranial Alternating Current Stimulation on Motor Performance

Transcranial alternating current stimulation (tACS) is a non-invasive method of brain stimulation that can modulate oscillatory brain activity in the cortical region. By applying alternating current through two electrodes attached to a subject’s head, it is possible to entrain the oscillation of the cortex directly under one electrode to a specific frequency. This study finds that applying tACS to the primary motor cortex and cerebellar hemisphere improves motor performance. The study also shows the effect of tACS on the supplementary motor cortex to modulate the maintenance and update of motor plans in a bimanual motor task. These recent findings show that individualized tACS interventions can be tailored by selecting the stimulation area and frequency depending on the subject’s performance level and exercise task. By further investigating the effects of tACS on motor performance, it is believed that tACS can be applied in rehabilitation.

Tackling social anxiety with targeted brain stimulation: investigating the effects of transcranial static magnetic field stimulation on self-focused attention.

Previous studies suggested that self-focused attention (SFA), implicated in social anxiety disorder (SAD), correlates with heightened activity in the right frontopolar area (rFPA), which is the right prefrontal cortex just behind the forehead. Transcranial static magnetic field stimulation (tSMS) is a non-invasive brain stimulation method capable of temporarily suppressing brain function beneath the magnet. We explored whether tSMS on individuals with tendencies toward SAD elicited (1) suppressing rFPA activation during the resting-state and (2) reducing SFA during a subsequent speech task. Twenty-three university students with social anxiety performed two speech tasks. Between tasks, the tSMS group received neodymium magnet stimulation while the sham group received fake magnet stimulation on the rFPA for 20 min. Resting-state rFPA activities was measured using functional near-infrared spectroscopy (fNIRS), while SFA (body sensations and observer perspective), field perspective, and detached mindfulness (DM) perspective were assessed via questionnaires during both speech tasks. The observer perspective means SFA to self-imagery from others' viewpoint, while the field and DM perspectives mean appropriately focusing on the external environment. The results indicated that tSMS intervention decreased rFPA activity from pre- to post-intervention rest. Then, tSMS reduced SFA to bodily sensations and increased DM perspective from pre- to post-intervention speech, especially in those with high levels of social anxiety. Furthermore, tSMS enhanced the field perspective regardless of social anxiety tendency. The results suggest that tSMS may suppress overactivity in rFPA, reduce SFA to body sensation, and increase adaptive attention in highly socially anxious individuals. Our study suggests the possibility of the clinical application of tSMS for treating SAD.

Long-term Effect of Multichannel tDCS Protocol in Patients with Central Cortex Epilepsies Associated with Epilepsia Partialis Continua.

Epilepsia partialis continua (EPC) is a rare type of focal motor status epilepticus that causes continuous muscle jerking in a specific part of the body. Experiencing this type of seizure, along with other seizure types, such as focal motor seizures and focal to bilateral tonic-clonic seizures, can result in a disabling situation. Non-invasive brain stimulation methods like transcranial direct current stimulation (tDCS) show promise in reducing seizure frequency (SF) when medications are ineffective. However, research on tDCS for EPC and related seizures is limited. We evaluated personalized multichannel tDCS in drug-resistant EPC of diverse etiologies for long-term clinical efficacy We report three EPC patients undergoing a long-term protocol of multichannel tDCS. The patients received several cycles (11, 9, and 3) of five consecutive days of stimulation at 2mA for 2 × 20min, targeting the epileptogenic zone (EZ), including the central motor cortex with cathodal electrodes. The primary measurement was SF changes. In three cases, EPC was due to Rasmussen's Encephalitis (case 1), focal cortical dysplasia (case 2), or remained unknown (case 3). tDCS cycles were administered over 6 to 22 months. The outcomes comprised a reduction of at least 75% in seizure frequency for two patients, and in one case, a complete cessation of severe motor seizures. However, tDCS had no substantial impact on the continuous myoclonus characterizing EPC. No serious side effects were reported. Long-term application of tDCS cycles is well tolerated and can lead to a considerable reduction in disabling seizures in patients with various forms of epilepsy with EPC.

Neuroprotective effects of repetitive transcranial magnetic stimulation on Alzheimer's disease: Undetermined therapeutic protocols and mechanisms

AbstractAlzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by gradual deterioration of cognitive functions, for which an effective treatment is currently unavailable. Repetitive transcranial magnetic stimulation (rTMS), a well‐established noninvasive brain stimulation method, is utilized in clinical settings to address various neuropsychiatric conditions, such as depression, neuropathic pain, and poststroke dysfunction. Increasing evidence suggests that rTMS may enhance cognitive abilities in individuals with AD. However, its optimal therapeutic protocols and precise mechanisms are currently unknown, impeding its clinical implementation. In the present review, we aimed to summarize and discuss the efficacy‐related parameters in rTMS treatment, encompassing stimulus frequency, stimulus pattern, stimulus intensity, and the configuration of the stimulus coil. Furthermore, we reviewed promising rTMS therapeutic protocols involving various combinations of these factors, that were examined in clinical studies. Based on our analysis, we propose that a multisite high‐frequency rTMS (HF‐rTMS) regimen has value in AD therapy, and that promising single‐site protocols, such as HF‐rTMS, applied over the left dorsolateral prefrontal cortex, precuneus, or cerebellum are required to be validated in larger clinical studies. Lastly, we provide a comprehensive review of the potential mechanisms underlying the neuroprotective effects of rTMS on cognition in AD in terms of brain network modulation as well as cellular and molecular reactions. In conclusion, the interaction of diverse mechanisms may be responsible for the total therapeutic effect of rTMS on AD. This review provides theoretical and practical evidence for the future clinical application and scientific research of rTMS in AD.

Transcranial focused ultrasound of the amygdala modulates fear network activation and connectivity

BackgroundCurrent noninvasive brain stimulation methods are incapable of directly modulating subcortical brain regions critically involved in psychiatric disorders. Transcranial Focused Ultrasound (tFUS) is a newer form of noninvasive stimulation that could modulate the amygdala, a subcortical region implicated in fear. ObjectiveWe investigated the effects of active and sham tFUS of the amygdala on fear circuit activation, skin conductance responses (SCR), and self-reported anxiety during a fear-inducing task. We also investigated amygdala tFUS’ effects on amygdala-fear circuit resting-state functional connectivity. MethodsThirty healthy individuals were randomized in this double-blinded study to active or sham tFUS of the left amygdala. We collected fMRI scans, SCR, and self-reported anxiety during a fear-inducing task (participants viewed red or green circles which indicated the risk of receiving an aversive stimulus), as well as resting-state scans, before and after tFUS. ResultsCompared to sham tFUS, active tFUS was associated with decreased (pre to post tFUS) blood-oxygen-level-dependent fMRI activation in the amygdala (F(1,25) = 4.86, p = 0.04, η2 = 0.16) during the fear task, and lower hippocampal (F(1,27) = 4.41, p = 0.05, η2 = 0.14), and dorsal anterior cingulate cortex (F(1,27) = 6.26, p = 0.02; η2 = 0.19) activation during the post tFUS fear task. The decrease in amygdala activation was correlated with decreased subjective anxiety (r = 0.62, p = 0.03). There was no group effect in SCR changes from pre to post tFUS (F(1,23) = 0.85, p = 0.37). The active tFUS group also showed decreased amygdala-insula (F(1,28) = 4.98, p = 0.03) and amygdala-hippocampal (F(1,28) = 7.14, p = 0.01) rsFC, and increased amygdala-ventromedial prefrontal cortex (F(1,28) = 3.52, p = 0.05) resting-state functional connectivity. ConclusionstFUS can change functional connectivity and brain region activation associated with decreased anxiety. Future studies should investigate tFUS’ therapeutic potential for individuals with clinical levels of anxiety.

Transcranial Low-Intensity Focused Ultrasound Stimulation of the Visual Thalamus Produces Long-Term Depression of Thalamocortical Synapses in the Adult Visual Cortex.

Transcranial focused ultrasound stimulation (tFUS) is a noninvasive neuromodulation technique, which can penetrate deeper and modulate neural activity with a greater spatial resolution (on the order of millimeters) than currently available noninvasive brain stimulation methods, such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). While there are several studies demonstrating the ability of tFUS to modulate neuronal activity, it is unclear whether it can be used for producing long-term plasticity as needed to modify circuit function, especially in adult brain circuits with limited plasticity such as the thalamocortical synapses. Here we demonstrate that transcranial low-intensity focused ultrasound (LIFU) stimulation of the visual thalamus (dorsal lateral geniculate nucleus, dLGN), a deep brain structure, leads to NMDA receptor (NMDAR)-dependent long-term depression of its synaptic transmission onto layer 4 neurons in the primary visual cortex (V1) of adult mice of both sexes. This change is not accompanied by large increases in neuronal activity, as visualized using the cFos Targeted Recombination in Active Populations (cFosTRAP2) mouse line, or activation of microglia, which was assessed with IBA-1 staining. Using a model (SONIC) based on the neuronal intramembrane cavitation excitation (NICE) theory of ultrasound neuromodulation, we find that the predicted activity pattern of dLGN neurons upon sonication is state-dependent with a range of activity that falls within the parameter space conducive for inducing long-term synaptic depression. Our results suggest that noninvasive transcranial LIFU stimulation has a potential for recovering long-term plasticity of thalamocortical synapses in the postcritical period adult brain.

Rhythmically Modulating Neural Entrainment during Exposure to Regularities Influences Statistical Learning.

The ability to discover regularities in the environment, such as syllable patterns in speech, is known as statistical learning. Previous studies have shown that statistical learning is accompanied by neural entrainment, in which neural activity temporally aligns with repeating patterns over time. However, it is unclear whether these rhythmic neural dynamics play a functional role in statistical learning or whether they largely reflect the downstream consequences of learning, such as the enhanced perception of learned words in speech. To better understand this issue, we manipulated participants' neural entrainment during statistical learning using continuous rhythmic visual stimulation. Participants were exposed to a speech stream of repeating nonsense words while viewing either (1) a visual stimulus with a "congruent" rhythm that aligned with the word structure, (2) a visual stimulus with an incongruent rhythm, or (3) a static visual stimulus. Statistical learning was subsequently measured using both an explicit and implicit test. Participants in the congruent condition showed a significant increase in neural entrainment over auditory regions at the relevant word frequency, over and above effects of passive volume conduction, indicating that visual stimulation successfully altered neural entrainment within relevant neural substrates. Critically, during the subsequent implicit test, participants in the congruent condition showed an enhanced ability to predict upcoming syllables and stronger neural phase synchronization to component words, suggesting that they had gained greater sensitivity to the statistical structure of the speech stream relative to the incongruent and static groups. This learning benefit could not be attributed to strategic processes, as participants were largely unaware of the contingencies between the visual stimulation and embedded words. These results indicate that manipulating neural entrainment during exposure to regularities influences statistical learning outcomes, suggesting that neural entrainment may functionally contribute to statistical learning. Our findings encourage future studies using non-invasive brain stimulation methods to further understand the role of entrainment in statistical learning.

Effects of Non-invasive Brain Stimulation on Hereditary Ataxia: a Systematic Review and Meta-analysis.

Numerous studies have demonstrated the potential of non-invasive brain stimulation (NIBS) techniques as a viable treatment option for cerebellar ataxia. However, there is a notable dearth of research investigating the efficacy of NIBS specifically for hereditary ataxia (HA), a distinct subgroup within the broader category of cerebellar ataxia. This study aims to conduct a comprehensive systematic review and meta-analysis in order to assess the efficacy of various NIBS methods for the treatment of HA. A thorough review of the literature was conducted, encompassing both English and Chinese articles, across eight electrical databases. The focus was on original articles investigating the therapeutic effectiveness of non-invasive brain stimulation for hereditary ataxia, with a publication date prior to March 2023. Subsequently, a meta-analysis was performed specifically on randomized controlled trials (RCTs) that fulfilled the eligibility criteria, taking into account the various modalities of non-invasive brain stimulation. A meta-analysis was conducted, comprising five RCTs, which utilized the Scale for the Assessment and Rating of Ataxia (SARA) as the outcome measure to evaluate the effects of transcranial magnetic stimulation (TMS). The findings revealed a statistically significant mean decrease of 1.77 in the total SARA score following repetitive TMS (rTMS) (p=0.006). Subgroup analysis based on frequency demonstrated a mean decrease of 1.61 in the total SARA score after high-frequency rTMS (p=0.05), while no improvement effects were observed after low-frequency rTMS (p=0.48). Another meta-analysis was performed on three studies, utilizing ICARS scores, to assess the impact of rTMS. The results indicated that there were no statistically significant differences in pooled ICARS scores between the rTMS group and the sham group (MD=0.51, 95%CI: -5.38 to 6.39; p=0.87). These findings align with the pooled results of two studies that evaluated alterations in post-intervention BBS scores (MD=0.74, 95%CI: -5.48 to 6.95; p=0.82). Despite the limited number of studies available, this systematic review and meta-analysis have revealed promising potential benefits of rTMS for hereditary ataxia. However, it is strongly recommended that further high-quality investigations be conducted in this area. Furthermore, the significance of standardized protocols for NIBS in future studies was also emphasized.

Theta Frequency Electromagnetic Stimulation Enhances Functional Recovery After Stroke

AbstractExtremely low-frequency, low-intensity electromagnetic field (ELF-EMF) therapy is a non-invasive brain stimulation method that can modulate neuroprotection and neuroplasticity. ELF-EMF was recently shown to enhance recovery in human stroke in a small pilot clinical trial (NCT04039178). ELF-EMFs encompass a wide range of frequencies, typically ranging from 1 to 100 Hz, and their effects can vary depending on the specific frequency employed. However, whether and to what extent the effectiveness of ELF-EMFs depends on the frequency remains unclear. In the present study, we aimed to assess the efficacy of different frequency-intensity protocols of ELF-EMF in promoting functional recovery in a mouse cortical stroke model with treatment initiated 4 days after the stroke, employing a series of motor behavior tests. Our findings demonstrate that a theta-frequency ELF-EMF (5 Hz) effectively enhances functional recovery in a reach-to-grasp task, whereas neither gamma-frequency (40 Hz) nor combination frequency (5–16-40 Hz) ELF-EMFs induce a significant effect. Importantly, our histological analysis reveals that none of the ELF-EMF protocols employed in our study affect infarct volume, inflammatory, or glial activation, suggesting that the observed beneficial effects may be mediated through non-neuroprotective mechanisms. Our data indicate that ELF-EMFs have an influence on functional recovery after stroke, and this effect is contingent upon the specific frequency used. These findings underscore the critical importance of optimizing the protocol parameters to maximize the beneficial effects of ELF-EMF. Further research is warranted to elucidate the underlying mechanisms and refine the protocol parameters for optimal therapeutic outcomes in stroke rehabilitation.

Our Experience with rTMS in a Stroke

Background Repetitive Transcranial Magnetic Stimulation (r-TMS), a non-invasive brain stimulation method, appears promising in augmenting post-stroke recovery and requires further evaluation. Aims and Objective To study the effect of r-TMS treatment on motor function in patients with strokes of different duration and types. Methods A prospective, single center study was conducted to study the effect of bilateral motor cortex rTMS treatment in 100 consecutive patients with either ischemic or hemorrhagic stroke of any duration. Measured outcomes were changes in NIHSS, MRC grading for motor power, MAS (modified Ashworth scale) for spasticity and mRS (modified Rankin Score) from baseline to follow-up visit at 90 days. Paired T test was used for comparing the outcomes. Results 77% subjects were males, 82% had ischemic stroke, median age was 58.5 years, and median NIHSS score was 11. We observed favorable changes in outcome measures after treatment. mRS < = 2 at 90 days was observed in 85.71% of patients with acute stroke, 64.51% of subacute and 55.88% of chronic strokes (p value < 0.002). Acute stroke had higher rates of limb power improvement (94.28%) than subacute (70.96%) or chronic strokes (41.17%) (p value = < 0.01). Post-stroke spasticity reduction was also observed after rTMS. Patients with infarcts or hemorrhages had no significant differences. No significant adverse events were seen. Conclusion rTMS appears to be safe in our study population and could be effectively delivered at different time points to augment post-stroke motor recovery.

Dissociation of Centrally and Peripherally Induced Transcranial Magnetic Stimulation Effects in Nonhuman Primates.

Transcranial magnetic stimulation (TMS) is a noninvasive brain stimulation method that is rapidly growing in popularity for studying causal brain-behavior relationships. However, its dose-dependent centrally induced neural mechanisms and peripherally induced sensory costimulation effects remain debated. Understanding how TMS stimulation parameters affect brain responses is vital for the rational design of TMS protocols. Studying these mechanisms in humans is challenging because of the limited spatiotemporal resolution of available noninvasive neuroimaging methods. Here, we leverage invasive recordings of local field potentials in a male and a female nonhuman primate (rhesus macaque) to study TMS mesoscale responses. We demonstrate that early TMS-evoked potentials show a sigmoidal dose-response curve with stimulation intensity. We further show that stimulation responses are spatially specific. We use several control conditions to dissociate centrally induced neural responses from auditory and somatosensory coactivation. These results provide crucial evidence regarding TMS neural effects at the brain circuit level. Our findings are highly relevant for interpreting human TMS studies and biomarker developments for TMS target engagement in clinical applications.SIGNIFICANCE STATEMENT Transcranial magnetic stimulation (TMS) is a widely used noninvasive brain stimulation method to stimulate the human brain. To advance its utility for clinical applications, a clear understanding of its underlying physiological mechanisms is crucial. Here, we perform invasive electrophysiological recordings in the nonhuman primate brain during TMS, achieving a spatiotemporal precision not available in human EEG experiments. We find that evoked potentials are dose dependent and spatially specific, and can be separated from peripheral stimulation effects. This means that TMS-evoked responses can indicate a direct physiological stimulation response. Our work has important implications for the interpretation of human TMS-EEG recordings and biomarker development.

Regaining control over opioid use? The potential application of auricular transcutaneous vagus nerve stimulation to improve opioid treatment in China.

Opioid use disorder (OUD) is a critical problem in China and is accompanied by depression and deficits in cognitive control. In China, the most successful intervention for OUD is the community drug rehabilitation where methadone maintenance treatment (MMT) plays a key role. Even though methadone for the treatment of OUD can be helpful, it can cause severe somatic side-effects, which limit its effectivity. Even worse, it can have detrimental effects on cognitive control, which is crucial to regain control over drug intake. Here, we consider the potential use of auricular transcutaneous vagus nerve stimulation (atVNS) as an addition to MMT for opioid withdrawal treatment. Compared to other non-invasive brain stimulation methods, atVNS also targets the locus coeruleus (LC) important for noradrenaline (NA) synthesis. NA is an essential neurotransmitter impacted in opioid withdrawal and also critically involved in cognitive control processes. Its ADD-ON to MMT might be a useful mean to improve mood and enhance cognitive control processes impacted in OUD. We discuss the translational advantages of atVNS in China such as the cultural acceptance of the modality of treatment similar to electroacupuncture. Additionally, the wearability of the ear electrode and at-home self-administration without intense medical supervision makes of atVNS a useful tool to enhance clinical and cognitive outcomes especially in everyday life situation. We discuss how atVNS can be integrated in tele-medical health approaches allowing that innovative treatments can widely be disseminated and continued even in situations of restricted medical access.

Transcranial alternating current stimulation for the treatment of major depressive disorder: from basic mechanisms toward clinical applications.

Non-pharmacological treatment is essential for patients with major depressive disorder (MDD) that is medication resistant or who are unable to take medications. Transcranial alternating current stimulation (tACS) is a non-invasive brain stimulation method that manipulates neural oscillations. In recent years, tACS has attracted substantial attention for its potential as an MDD treatment. This review summarizes the latest advances in tACS treatment for MDD and outlines future directions for promoting its clinical application. We first introduce the neurophysiological mechanism of tACS and its novel developments. In particular, two well-validated tACS techniques have high application potential: high-definition tACS targeting local brain oscillations and bifocal tACS modulating interarea functional connectivity. Accordingly, we summarize the underlying mechanisms of tACS modulation for MDD. We sort out the local oscillation abnormalities within the reward network and the interarea oscillatory synchronizations among multiple MDD-related networks in MDD patients, which provide potential modulation targets of tACS interventions. Furthermore, we review the latest clinical studies on tACS treatment for MDD, which were based on different modulation mechanisms and reported alleviations in MDD symptoms. Finally, we discuss the main challenges of current tACS treatments for MDD and outline future directions to improve intervention target selection, tACS implementation, and clinical validations.

The Cerebellum and the Motor Cortex: Multiple Networks Controlling Multiple Aspects of Behavior.

The cerebellum and its thalamic projections to the primary motor cortex (M1) are well known to play an essential role in executing daily actions. Anatomic investigations in animals and postmortem humans have established the reciprocal connections between these regions; however, how these pathways can shape cortical activity in behavioral contexts and help promote recovery in neuropathological conditions remains not well understood. The present review aims to provide a comprehensive description of these pathways in animals and humans and discuss how novel noninvasive brain stimulation (NIBS) methods can be used to gain a deeper understanding of the cerebellar-M1 connections. In the first section, we focus on recent animal literature that details how information sent from the cerebellum and thalamus is integrated into an broad network of cortical motor neurons. We then discuss how NIBS approaches in humans can be used to reliably assess the connectivity between the cerebellum and M1. Moreover, we provide the latest perspectives on using advanced NIBS approaches to investigate and modulate multiple cerebellar-cortical networks involved in movement behavior and plasticity. Finally, we discuss how these emerging methods have been used in translation research to produce long-lasting modifications of cerebellar-thalamic-M1 to restore cortical activity and motor function in neurologic patients.

Enhancement of dynamic visual acuity using transcranial alternating current stimulation with gamma burst entrained on alpha wave troughs

BackgroundCross-frequency phase-amplitude coupling (PAC) of cortical oscillations is observed within and across cortical regions during higher-order cognitive processes. Particularly, the PAC of alpha and gamma waves in the occipital cortex is closely associated with visual perception. In theory, gamma oscillation is a neuronal representation of visual stimuli, which drives the duty cycle of visual perception together with alpha oscillation. Therefore, it is believed that the timing of entrainment in alpha-gamma PAC may play a critical role in the performance of visual perception. We hypothesized that transcranial alternating current stimulation (tACS) with gamma waves entrained at the troughs of alpha waves would enhance the dynamic visual acuity (DVA).MethodWe attempted to modulate the performance of DVA by using tACS. The waveforms of the tACS were tailored to target PAC over the occipital cortex. The waveforms contained gamma (80 Hz) waves oscillating at either the peaks or troughs of alpha (10 Hz) waves. Participants performed computerized DVA task before, immediately after, and 10 min after each stimulation sessions. EEG and EOG were recorded during the DVA task to assess inter-trial phase coherence (ITPC), the alpha-gamma PAC at occipital site and the eye movements.ResultstACS with gamma waves entrained at alpha troughs effectively enhanced DVA, while the tACS with gamma waves entrained at alpha peaks did not affect DVA performance. Importantly, analyses of EEG and EOG showed that the enhancement of DVA performance originated solely from the neuromodulatory effects, and was not related to the modulation of saccadic eye movements. Consequently, DVA, one of the higher-order cognitive abilities, was successfully modulated using tACS with a tailored waveform.ConclusionsOur experimental results demonstrated that DVA performances were enhanced when tACS with gamma bursts entrained on alpha wave troughs were applied over the occipital cortex. Our findings suggest that using tACS with tailored waveforms, modulation of complex neuronal features could effectively enhance higher-order cognitive abilities such as DVA, which has never been modulated with conventional noninvasive brain stimulation methods.

Transcranial magnetic stimulation as a promising method of treatment in depression and various neuropsychiatric conditions. A literature review

Background: Transcranial magnetic stimulation (TMS) is a method of non-invasive and painless brain stimulation with an electromagnetic field, which induces changes in the electric field in the brain leading to the cortical activity modulation and stimulation of neurons. Currently, transcranial magnetic stimulation is increasingly used in the diagnosis and treatment of various neuropsychiatric conditions, such as depression, schizophrenia, neurodegenerative diseases, and more. TMS can be used as a method of enhancing the effect of pharmacotherapy as well as a regular treatment.
 Aim of the study: The study's aim is to summarize the current state of knowledge on transcranial magnetic stimulation as a method of treatment in depression and various neuropsychiatric conditions.
 Material and methods: The study is based on the literature available in scientific databases such as PubMed, using the following keywords: „transcranial magnetic stimulation”, „tms”, “depression” and “treatment-resistant depression”.
 Results and conclusions: Transcranial magnetic stimulation is a non-invasive, painless and generally safe method of diagnosis and treatment of many neuropsychiatric diseases, such as depression, schizophrenia, obsessive-compulsive disorders, neurodegenerative diseases, tinnitus, addiction to psychoactive substances and many more. TMS is a well-documented, approved, and recommended treatment primarily for treatment-resistant depression due to its effectiveness, mild side effect profile and good tolerability. Recently there are more and more reports on the effectiveness of TMS in the diagnosis and treatment of other neuropsychiatric conditions, but further research and setting guidelines are needed, so is increasing the availability of the method for patients.

Transcranial alternating current stimulation over multiple brain areas with non-zero phase delays other than 180 degrees modulates visuospatial working memory performance

While zero-phase lag synchronization between multiple brain regions has been widely observed, relatively recent reports indicate that systematic phase delays between cortical regions reflect the direction of communications between cortical regions. For example, it has been suggested that a non-zero phase delay of electroencephalography (EEG) signals at the gamma frequency band between the bilateral parietal areas may reflect the direction of communication between these areas. We hypothesized that the direction of communication between distant brain areas might be modulated by multi-site transcranial alternating current stimulation (tACS) with specific phase delays other than 0° and 180°. In this study, a new noninvasive brain stimulation (NIBS) method called multi-site multi-phase tACS (msmp-tACS) was proposed. The efficacy of the proposed method was tested in a case study using a visuospatial working memory (VWM) paradigm in which the optimal stimulation conditions including amplitudes and phases of multiple scalp electrodes were determined using finite element analysis adopting phasor representation. msmp-tACS was applied over the bilateral intraparietal sulci (IPS) and showed that 80 Hz tACS with the phase for the right IPS leading that for the left IPS by 90° (= 3.125 ms) partialized VWM performance toward the right visual hemifield. The three stimulation conditions were synchronized, RL, and LR, which refers to stimulation condition with no phase lag, stimulation phase of right IPS (rIPS) leading left IPS (lIPS) by 90° and the stimulation of lIPS leading rIPS by 90°, respectively. The lateralization of VWM significantly shifted towards right visual hemifield under the RL condition compared to the synchronized and LR conditions. The shift in VWM was the result of the stimulation affecting both left and right visual hemifield trials to certain degrees, rather than significantly increasing or decreasing VWM capacity of a specific visual hemifield. Altered brain dynamics caused by msmp-tACS partialized VWM performance, likely due to modulation of effective connectivity between the rIPS and lIPS. Our results suggest that msmp-tACS is a promising NBS method that can effectively modulate cortical networks that cannot be readily modulated with conventional multi-site stimulation methods.