No effects of cerebellar transcranial random noise stimulation on cerebellar brain inhibition, visuomotor learning, and pupil diameter.

Cerebellar brain inhibition (CBI) is an inhibitory output from the cerebellum to the primary motor cortex, which is decreased in early motor learning. Transcranial random noise stimulation (tRNS) is a noninvasive brain stimulation to induce brain plastic changes; however, the effects of cerebellar tRNS on CBI and motor learning have not been investigated yet to our knowledge. In this study, whether cerebellar tRNS decreases CBI and improves motor learning was examined, and pupil diameter was measured to examine physiological changes due to the effect of tRNS on motor learning. Thirty-four healthy subjects were assigned to either the cerebellar tRNS group or the Sham group. The subjects performed visuomotor tracking task with ten trials each in the early and late learning stages while receiving the stimulus intervention. CBI and motor evoked potentials were measured before the learning task, after the early learning stage, and after the late learning stage, and pupil diameter was measured during the task. There was no change in CBI in both groups. No group differences in motor learning rates were observed at any learning stages. Pupil diameter was smaller in the late learning stage than in the early learning stage in both groups. The cerebellar tRNS was suggested not to induce changes in CBI and improvement in motor learning, and it did not affect pupil diameter.

Transcranial Electrical Stimulation: Clinical Implication and Practice for Treatment of Psychiatric Illness.

Brain electrical stimulation, particularly non-invasive brain stimulation (NIBS) techniques such as transcranial electrical stimulation (tES), have emerged as a promising treatment for various psychiatric disorders, including depression, anxiety, and post-traumatic stress disorder. tES techniques, such as transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), and transcranial random noise stimulation (tRNS), are cost-effective and safe interventions that are designed to affect neuronal circuits in the brain using various modalities. Although tES has shown effectiveness in the treatment of psychiatric disorders, there is a lack of comprehensive papers that consider its clinical implications. Therefore, this review aims to evaluate the clinical implications of tES and provide practical guidance for the treatment of psychiatric illnesses. Moreover, this review provides an overview of tES techniques and their mechanisms of action and summarizes recent clinical studies that have examined the use of tES for psychiatric disorders.

The efficacy of transcranial random noise stimulation in treating tinnitus: a systematic review.

PURPOSE: This review aims to examine the effects of transcranial random noise stimulation (tRNS) on tinnitus and to determine the optimal treatment parameters, if possible. METHODS: A comprehensive search, including MEDLINE, PubMed, EMBASE, CINAHL, SCOPUS, and PEDro, was conducted to determine experiments studying the effects of tRNS on tinnitus from inception to March 1, 2024. The Physiotherapy Evidence Database (PEDro) scale was used to evaluate the quality of the included studies. RESULTS: Seven studies met the eligibility criteria. A total of 616 patients with non-pulsatile tinnitus (mean age 50.93 years; 66% males) were included in this review. The included studies ranged from 3 to 8 out of 10 (median = 7) on the PEDro scale. The results showed that tRNS is an effective intervention in reducing tinnitus symptoms. CONCLUSIONS: The evidence for the effects of tRNS on people with chronic non-pulsatile tinnitus is promising. Administering tRNS with an intensity of 1-2 mA, high-frequency (101-650 Hz), using a 35 cm² electrode size over the auditory cortex and DLPFC, for 20 min with eight sessions may demonstrate the desired tRNS effects. The tRNS stimulation should be contralateral for unilateral tinnitus and bilaterally for bilateral tinnitus. Combining tRNS with other concurrent interventions may show superior effects in reducing tinnitus compared to tRNS alone. Further high-quality studies with larger sample sizes are strongly needed.

The effects of prefrontal tDCS and hf-tRNS on the processing of positive and negative emotions evoked by video clips in first- and third-person.

The causal role of the cerebral hemispheres in positive and negative emotion processing remains uncertain. The Right Hemisphere Hypothesis proposes right hemispheric superiority for all emotions, while the Valence Hypothesis suggests the left/right hemisphere's primary involvement in positive/negative emotions, respectively. To address this, emotional video clips were presented during dorsolateral prefrontal cortex (DLPFC) electrical stimulation, incorporating a comparison of tDCS and high frequency tRNS stimulation techniques and manipulating perspective-taking (first-person vs third-person Point of View, POV). Four stimulation conditions were applied while participants were asked to rate emotional video valence: anodal/cathodal tDCS to the left/right DLPFC, reverse configuration (anodal/cathodal on the right/left DLPFC), bilateral hf-tRNS, and sham (control condition). Results revealed significant interactions between stimulation setup, emotional valence, and POV, implicating the DLPFC in emotions and perspective-taking. The right hemisphere played a crucial role in both positive and negative valence, supporting the Right Hemisphere Hypothesis. However, the complex interactions between the brain hemispheres and valence also supported the Valence Hypothesis. Both stimulation techniques (tDCS and tRNS) significantly modulated results. These findings support both hypotheses regarding hemispheric involvement in emotions, underscore the utility of video stimuli, and emphasize the importance of perspective-taking in this field, which is often overlooked.

Transcranial random noise stimulation (tRNS) improves hot and cold executive functions in children with attention deficit-hyperactivity disorder (ADHD).

Children with attention deficit-hyperactivity disorder (ADHD) have impaired hot and cold executive functions, which is thought to be related to impaired ventromedial and dorsolateral prefrontal cortex (vmPFC and dlPFC) functions. The present study aimed to assess the impact concurrent stimulation of dlPFC and vmPFC through transcranial random noise stimulation (tRNS), a non-invasive brain stimulation tool which enhances cortical excitability via application of alternating sinusoidal currents with random frequencies and amplitudes over the respective target regions on hot and cold executive functions. Eighteen children with ADHD received real and sham tRNS over the left dlPFC and the right vmPFC in two sessions with one week interval. The participants performed Circle Tracing, Go/No-Go, Wisconsin Card Sorting, and Balloon Analogue Risk Tasks during stimulation in each session. The results showed improved ongoing inhibition, prepotent inhibition, working memory, and decision making, but not set-shifting performance, during real, as compared to sham stimulation. This indicates that simultaneous stimulation of the dlPFC and the vmPFC improves hot and cold executive functions in children with ADHD.

Recent Progress and Future Directions of Transcranial Electrical Stimulation for Analgesia / 生物化学与生物物理进展

Transcranial electrical stimulation (tES) is a non-invasive neural modulation technique known for its high safety, patient compliance, and portability. It holds promise as a potential non-pharmacological method for analgesia. However, challenges persist in utilizing tES for pain management, including inconsistent research findings and limited understanding of its analgesic mechanisms. Therefore, by summarizing the advances in the analgesic researches employing the 3 primary tES techniques, transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), and transcranial random noise stimulation (tRNS), we reviewed the analgesic effects on both acute and chronic pain, as well as the neural mechanisms underlying the analgesic effect of each technique. Accumulating evidence suggests that the analgesic effects of tDCS are significant, but studies on analgesic effects of tACS and tRNS remain limited. And the exact mechanisms of pain relief through tES turned out to be not yet well established. Furthermore, we systematically discussed the limitations of analgesia-related studies employing tES techniques across various aspects, involving research design, stimulation protocol formulation, neural response observation, analgesic effect assessment, and safety considerations. To address these limitations and advance clinical translation, we emphasized utilizing promising stimulation techniques and offered practical suggestions for future research endeavors. Specifically, employing numerical simulation of electric field guided by magnetic resonance imaging (MRI) would reduce variability of outcomes due to individual differences in head anatomy. For this purpose, it is advisable to establish standardized head models based on MRI data from the Chinese populations and validate simulated electric field results in tES research to diminish confounding factors concerning anatomy. Meanwhile, novel techniques like multi-site brain stimulation and interferential stimulation (IFS) could broaden the range of stimulation sites in both scope and depth. Multi-site brain stimulation facilitates modulation of entire neural networks, enabling more sophisticated investigations into the complexity of pain. IFS can reach deep brain tissues without invasive surgical procedures, achieving more comprehensive modulation. Regarding neural response observations, establishing a tES-neuroimaging synchronized platform would enable revealing its mechanisms and personalizing protocols based on inter-subject neural response variability detected through recordings. By integrating tES with various neuroimaging techniques, such as functional MRI, electroencephalography (EEG) and magnetoencephalography, into one unified platform, researchers could examine brain activities in baseline before stimulation, dynamic changes in brain activities during stimulation, and sustained brain responses after stimulation. Additionally, collecting finer-grained data on participant characteristics and pain intensity would enhance the sensitivity of future studies. In designing clinical trials to evaluate chronic pain treatments and reporting the results, adopting the six core outcome domain measures recommended by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) could prove beneficial. Lastly, safety considerations can never be overemphasized in future tES studies especially when combining tES with MRI and EEG techniques. These efforts may help to broaden the research scope, reconcile inconsistencies in findings and elucidate the analgesic mechanisms of tES, thus facilitating the development of pragmatic pain management strategies such as combination therapies and home therapies. Ultimately, these suggestions will maximize the clinical application value of tES in pain treatment to achieve pain relief for patients.

Effects of transcranial electrical stimulation of the right posterior parietal cortex on physical control responses.

The posterior parietal cortex plays an important role in postural stability by adapting to changes in input from the visual, vestibular, and proprioceptive systems. However, little is known regarding whether transcranial electrical stimulation of the posterior parietal cortex affects reactive postural responses. This study aimed to investigate changes in physical control responses to anodal and cathodal transcranial direct current stimulation and transcranial random noise stimulation of the right posterior parietal cortex using a simultaneous inertial measurement unit. The joint movements of the lower limb of 33 healthy volunteers were measured while standing on a soft-foam surface with eyes closed during various stimulation modalities. These modalities included anodal, cathodal transcranial direct current stimulation, and sham stimulation in Experiment 1, and transcranial random noise and sham stimulations in Experiment 2. The results showed that cathodal stimulation significantly decreased the joint angular velocity in the hip rotation, ankle inversion-eversion, and abduction-adduction directions compared to anodal or sham stimulation in Experiment 1. In contrast, there were no significant differences in physical control responses with transcranial random noise stimulation coeducation in Experiment 2. These findings suggest that transcranial electrical stimulation of the right posterior parietal cortex may modulate physical control responses; however, the effect depends on the stimulus modality.

Mechanistic account of the left auditory cortex for tone-matching in schizophrenia: A pilot transcranial random noise stimulation (tRNS) sham-controlled study.

OBJECTIVE: Deficits in the ability to match tones following brief delay and their contribution to higher-order cognitive alterations have been repeatedly documented in schizophrenia. The aim was to explore if left fronto-temporal high-frequency transcranial random noise stimulation (hf-tRNS), with electrodes placed over brain regions involved in tone-matching would significantly modulate performances in participants with schizophrenia. METHODS: In a randomized, double-blind sham-controlled study, 10 participants with schizophrenia were allocated to receive ten sessions of either active or sham hf-tRNS. The anode was placed over the left prefrontal cortex and the cathode over the left temporoparietal junction. A tone-matching task was administered before and after the hf-tRNS. RESULTS: We calculated the changes in tone-matching performance before and after hf-tRNS session in each group. A significant between-group difference was observed for the difficult tone-matching conditions (W= 14.500, p = 0.032), with tone-matching improvement in the sham group and no improvement in the active group. DISCUSSION: hf-tRNS could disrupt the test-retest learning effect in the tone-matching task in individuals with schizophrenia. It is likely that this disruption resulted from cathodal-induced inhibition of the functional coupling between auditory cortical areas that correlates with tone-matching performance in patients. CONCLUSION: The findings contribute to our understanding of hf-tRNS effects on early auditory processing in schizophrenia.

Effects of transcranial direct current stimulation and transcranial random noise stimulation on working memory and task-related EEG in major depressive disorder.

OBJECTIVE: To compare effects of transcranial direct current stimulation (tDCS) and transcranial random noise stimulation with a direct-current offset (tRNS + DC-offset) on working memory (WM) performance and task-related electroencephalography (EEG) in individuals with Major Depressive Disorder (MDD). METHODS: Using a sham-controlled, parallel-groups design, 49 participants with MDD received either anodal tDCS (N = 16), high-frequency tRNS + DC-offset (N = 16), or sham stimulation (N = 17) to the left dorsolateral prefrontal cortex (DLPFC) for 20-minutes. The Sternberg WM task was completed with concurrent EEG recording before and at 5- and 25-minutes post-stimulation. Event-related synchronisation/desynchronisation (ERS/ERD) was calculated for theta, upper alpha, and gamma oscillations during WM encoding and maintenance. RESULTS: tDCS significantly increased parieto-occipital upper alpha ERS/ERD during WM maintenance, observed on EEG recorded 5- and 25-minutes post-stimulation. tRNS + DC-offset did not significantly alter WM-related oscillatory activity when compared to sham stimulation. Neither tDCS nor tRNS + DC-offset improved WM performance to a significantly greater degree than sham stimulation. CONCLUSIONS: Although tDCS induced persistent effects on WM-related oscillatory activity, neither tDCS nor tRNS + DC-offset enhanced WM performance in MDD. SIGNIFICANCE: This reflects the first sham-controlled comparison of tDCS and tRNS + DC-offset in MDD. These findings directly contrast with evidence of tRNS-induced enhancements in WM in healthy individuals.

Characterising modulatory effects of high-intensity high frequency transcranial random noise stimulation using the perceptual template model.

Neural noise is an inherent property of all nervous systems. However, our understanding of the mechanisms by which noise influences perception is still limited. To elucidate this relationship, we require techniques that can safely modulate noise in humans. Transcranial random noise stimulation (tRNS) has been proposed to induce noise into cortical processing areas according to the principles of stochastic resonance (SR). Specifically, it has been demonstrated that small to moderate intensities of noise improve performance. To date, however, high intensity tRNS effects on neural noise levels have not been directly quantified, nor have the detrimental effects proposed by SR been demonstrated in early visual function. Here, we applied 3 mA high-frequency tRNS to primary visual cortex during an orientation-discrimination task across increasing external noise levels and used the Perceptual Template Model to quantify the mechanisms by which noise changes perceptual performance in healthy observers. Results show that, at a group level, high-intensity tRNS worsened perceptual performance. Our computational analysis reveals that this change in performance was underpinned by an increased amount of additive noise and a reduced ability to filter external noise compared to sham stimulation. Interestingly, while most observers experienced detrimental effects, a subset of participants demonstrated improved performance. Preliminary evidence suggests that differences in baseline internal noise levels might account for these individual differences. Together, these results refine our understanding of the mechanisms underlying the influence of neural noise on perception and have important implications for the application of tRNS as a research tool.

Corrigendum: Efficacy of non-invasive brain stimulation for disorders of consciousness: a systematic review and meta-analysis.

[This corrects the article DOI: 10.3389/fnins.2023.1219043.].

Efficacy of non-invasive brain stimulation for disorders of consciousness: a systematic review and meta-analysis.

Objective: The aim of this study is to evaluate the efficacy of non-invasive brain stimulation (NIBS) in patients with disorders of consciousness (DoC) and compare differences in efficacy between different stimulation modalities. Methods: We searched the PubMed, Cochrane Library, Web of Science, and EMBASE databases for all studies published in English from inception to April 2023. Literature screening and quality assessment were performed independently by two investigators. Weighted mean differences (WMDs) and 95% confidence intervals (CIs) were used to evaluate the therapeutic effects of NIBS. The Cochrane Q test and I2 statistic were used to evaluate heterogeneity between studies. Subgroup analysis was performed to identify the source of heterogeneity, and differences in efficacy between different stimulation modalities were compared by Bayesian analysis. Results: A total of 17 studies with 377 DoC patients were included. NIBS significantly improved the state of consciousness in DoC patients when compared to sham stimulation (WMD: 0.81; 95% CI: 0.46, 1.17; I2 = 78.2%, p = 0.000). When divided into subgroups according to stimulation modalities, the heterogeneity of each subgroup was significantly lower than before (I2: 0.00-30.4%, p >0.05); different stimulation modalities may be the main source of such heterogeneity. Bayesian analysis, based on different stimulation modalities, indicated that a patient's state of consciousness improved most significantly after repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral prefrontal cortex (DLPFC). Diagnosis-based subgroup analysis showed that NIBS significantly improved the state of consciousness in patients with a minimal consciousness state (WMD: 1.11; 95% CI: 0.37, 1.86) but not in patients with unresponsive wakefulness syndrome or a vegetative state (WMD: 0.31; 95% CI: -0.09, 0.71). Subgroup analysis based on observation time showed that single treatment did not improve the state of consciousness in DoC patients (WMD: 0.28; 95% CI: -0.27, 0.82) while multiple treatments could (WMD: 1.05; 95% CI: 0.49, 1.61). Furthermore, NIBS had long-term effects on DoC patients (WMD: 0.79; 95% CI: 0.08-1.49). Conclusion: Available evidence suggests that the use of NIBS on patients with DoC is more effective than sham stimulation, and that rTMS of the left DLPFC may be the most prominent stimulation modality.

Top-down and bottom-up stimulation techniques combined with action observation treatment in stroke rehabilitation: a perspective.

Stroke is a central nervous system disease that causes structural lesions and functional impairments of the brain, resulting in varying types, and degrees of dysfunction. The bimodal balance-recovery model (interhemispheric competition model and vicariation model) has been proposed as the mechanism of functional recovery after a stroke. We analyzed how combinations of motor observation treatment approaches, transcranial electrical (TES) or magnetic (TMS) stimulation and peripheral electrical (PES) or magnetic (PMS) stimulation techniques can be taken as accessorial physical therapy methods on symptom reduction of stroke patients. We suggest that top-down and bottom-up stimulation techniques combined with action observation treatment synergistically might develop into valuable physical therapy strategies in neurorehabilitation after stroke. We explored how TES or TMS intervention over the contralesional hemisphere or the lesioned hemisphere combined with PES or PMS of the paretic limbs during motor observation followed by action execution have super-additive effects to potentiate the effect of conventional treatment in stroke patients. The proposed paradigm could be an innovative and adjunctive approach to potentiate the effect of conventional rehabilitation treatment, especially for those patients with severe motor deficits.

The effects of transcranial electrical stimulation of the left dorsolateral prefrontal cortex on tactile spatial discrimination performance.

The dorsolateral prefrontal cortex (DLPFC) plays a key role in tactile perceptual discrimination performance. Both transcranial random noise stimulation (tRNS) and anodal transcranial pulsed current stimulation (tPCS) have been shown to modulate neural activity in cortical regions. In this study, we aimed to determine whether tRNS and anodal tPCS over the left DLPFC would improve tactile perceptual discrimination performance of the right index finger in healthy neurological individuals. Subjects underwent a grating orientation task before, immediately after, and 30 min after applying tRNS in Experiment 1 or anodal tPCS in Experiment 2. tRNS application on the left DLPFC tended to enhance tactile perceptual discrimination performance. In contrast, the application of anodal tPCS over the left DLPFC did not affect tactile perceptual discrimination performance. These findings indicate that transcranial electrical stimulation to the left DLPFC may improve tactile perceptual discrimination performance, with effects that depend on stimulus modality.

Mechanisms of Action of Noninvasive Brain Stimulation with Weak Non-Constant Current Stimulation Approaches.

Objective: Non-constant current stimulation (NCCS) is a neuromodulatory method in which weak alternating, pulsed or random currents are delivered to the human head via scalp or earlobe electrodes. This approach is widely used in basic and translational studies. However, the underlying mechanisms of NCCS, which lead to biological and behavioral effects in the brain, remain largely unknown. In this review, we characterize NCCS techniques currently being utilized in neuroscience investigations, including transcranial alternating current stimulation (tACS), transcranial pulsed current stimulation (tPCS), transcranial random noise stimulation (tRNS), and cranial electrotherapy stimulation (CES). Method: We unsystematically searched all relevant conference papers, journal articles, chapters, and textbooks on the biological mechanisms of NCCS techniques. Results: The fundamental idea of NCCS is that these low-level currents can interact with neuronal activity, modulate neuroplasticity and entrain cortical networks, thus, modifying cognition and behavior. We elucidate the mechanisms of action for each NCCS technique. These techniques may cause microscopic effects (such as affecting ion channels and neurotransmission systems) and macroscopic effects (such as affecting brain oscillations and functional connectivity) on the brain through different mechanisms of action (such as neural entrainment and stochastic resonance). Conclusion: The appeal of NCCS is its potential to modulate neuroplasticity noninvasively, along with the ease of use and good tolerability. Promising and interesting evidence has been reported for the capacity of NCCS to affect neural circuits and the behaviors under their control. Today, the challenge is to utilize this advancement optimally. Continuing methodological advancements with NCCS approaches will enable researchers to better understand how NCCS can be utilized for the modulation of nervous system activity and subsequent behaviors, with possible applications to non-clinical and clinical practices.

Transcranial random noise stimulation over the left dorsolateral prefrontal cortex attenuates pain expectation and perception.

OBJECTIVE: The dorsolateral prefrontal cortex (DLPFC) has been increasingly used as a neuromodulatory target in pain management. Transcranial random noise stimulation (tRNS) was shown to effectively elevate cortical excitability. Hence, this study aimed to characterize how tRNS over the left DLPFC affects pain expectation and perception, as well as the efficacy of conditioned-pain modulation (CPM) that reflects the function of the endogenous pain-inhibitory pathway. METHODS: Using a randomized, double-blinded, and sham-controlled design, healthy participants were randomly recruited to receive tRNS with a direct current offset or sham stimulation. Their expectations and perceptions of painful electrocutaneous stimuli, as well as CPM efficacy were assessed before, immediately after, and 30 min after tRNS. RESULTS: Compared with sham stimulation, perceived-pain ratings to the painful stimuli, and expected-pain ratings before painful stimuli, attenuated immediately after tRNS, whereas this analgesic effect was ineffective 30 min after tRNS. Importantly, the immediate analgesia induced by tRNS could be accounted for by tRNS effect on attenuating expected-pain ratings before certain painful stimuli. However, CPM efficacy was not significantly affected by tRNS. CONCLUSIONS: These results demonstrate analgesia immediately after applying tRNS over the left DLPFC. SIGNIFICANCE: This study provides evidence for analgesia of DLPFC-tRNS on an experimental pain model.