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Measured and estimated electric field magnitudes. a Field projections calculated as the difference in recorded voltages between neighboring electrodes divided by electrode distance for each subject (with four montage orientations shown for S10), b field magnitudes at electrode locations predicted by calibrated current-flow models, and c model-predicted field magnitude across the entire brain. Red lines indicate the medians, and boxes span from 5 to 95% of the data, with whiskers extending to the minima and maxima. All values shown here correspond to the maximal current intensity applied for each subject during stimulation (S1: 1 mA; S2: 0.75 mA; S3: 1 mA; S4: 1 mA; S5: 1 mA; S6: 1 mA; S7: 1.5 mA; S8: 2 mA; S9: 1.5 mA; S10A: 0.3 mA; S10B: 1 mA; S10C: 1 mA; S10D: 0.3 mA; S11: 0.3 mA; S12: 1 mA; S13: 1 mA). The difference in magnitude across subjects is primarily due to these varying stimulation intensities
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Transcranial electrical stimulation has widespread clinical and research applications, yet its effect on ongoing neural activity in humans is not well established. Previous reports argue that transcranial alternating current stimulation (tACS) can entrain and enhance neural rhythms related to memory, but the evidence from non-invasive recordings ha...
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Citations
... However, the effect is highly sensitive to the stimulus parameters (waveform, frequency), sleep status, and population characteristics, such as the elderly population or different stimulus waveforms [13], [20], [68]. It has been found that frequency matching alone may not be effective in entrainment of endogenous rhythm [69], and the reproducibility of the effect in real population experiments is limited. In contrast, our proposed IF-tACS protocol emphasizes the dynamic real-time synchronous matching of sleep state, spatial location and frequency, which can automatically track the frequent switching of individual sleep state, and select the best brain region and frequency for precise regulation. ...
Background: Insomnia, a common mental health issue, is characterized by brain hyperarousal and difficulties in transitioning between sleep stages. Pharmacological interventions often come with adverse effects and variable efficacy, while non-invasive brain stimulation holds potential but lacks in providing tailored, dynamic, and precisely targeted solutions. Method: A novel online closed-loop individualized frequency transcranial alternating current stimulation protocol (IF-tACS) was developed to dynamically adjust the stimulation sites and parameters in sync with sleep states. Specifically, the frequency of the stimulation signal is synchronized with the predominant individualized neural oscillation frequency specific to each state: the alpha rhythm in the parietal-occipital region during Wake, theta in the central parietal region during stage N1, and delta in the frontal region during the early stage N2. This approach was evaluated in 30 subjects with insomnia. Results: The application of IF-tACS showed preliminary improvements for those with insomnia, significantly reducing deep sleep latency by an average of 8.6 minutes. The stimulation also restore the cortical connectivity that is disrupted at sleep onset. Furthermore, IF-tACS decreased the instability in transitioning from N3 to N1 stages by approximately 46.4% and modulated spindle density towards healthier levels. Conclusion: The findings support the hypothesis that personalized, state-dependent, oscillation-synchronized tES can effectively normalize sleep in individuals with insomnia. This immediate intervention of may enhance sleep-promoting neural networks, thereby increasing excitatory inhibition, as well as stabilizing sleep homeostasis throughout the night.
... Indeed, several studies have highlighted the reduction of electric field magnitude due to the depth between scalp stimulation electrodes and the anatomical target. [19][20][21][22] Using multichannel tDCS, incorporating smaller electrode pairs and contrasting with conventional tDCS using two large rectangular electrodes, potentially enhances targeting precision while potentially reaching brain regions. 8,23 Incorporating multiple pairs of cathodal and anodal electrodes raises concerns about achieving precise targeting of the epileptogenic zone with an inhibitory electric field while minimizing unintended excitation of non-target areas. ...
... Previous studies have highlighted the potential difficulty in reaching deep brain regions with low-intensity stimulation due to the distance between the electrodes and the targeted area. [19][20][21][22]43 Our findings support this view, indicating a significant difference in the depth of the EZN in the brain in NR patients compared with R. These results diverge from computational studies developing epilepsy models to explore the spread of electric fields in the brain through various parameters of low-intensity stimulation application. ...
These authors contributed equally to this work. Transcranial direct current stimulation shows promise as a non-invasive therapeutic method for patients with focal drug-resistant epilepsy. However, there is considerable variability in individual responses to transcranial direct current stimulation, and the factors influencing treatment effectiveness in targeted regions are not well understood. We aimed to assess how the extent and depth of the epileptogenic zone and associated networks impact patient responses to transcranial direct current stimulation therapy. We conducted a retrospective analysis of stereoelectroencephalography data from 23 patients participating in a personalized multichannel transcra-nial direct current stimulation protocol. We evaluated the extent and depth of the epileptogenic zone network, propagation zone network , and the combined network of the entire epileptogenic and propagation zones, correlating these factors with clinical response measured by the reduction in seizure frequency following repeated transcranial direct current stimulation sessions. Among the patients, 10 (43.5%) were classified as responders (R), experiencing a significant (>50%) decrease in seizure frequency, while 13 were non-responders, showing minimal improvement or increased seizure frequency. Importantly, we found a significant positive correlation between the extent of the epileptogenic zone network and changes in seizure frequency. A smaller epileptogenic zone network extent was associated with better transcranial direct current stimulation efficacy, with responders demonstrating a significantly smaller epileptogenic and propagation zones compared with non-responders. Additionally, non-responders tended to have a significantly deeper epileptogenic zone network compared with responders. Our results highlight the significant impact of the extent and depth of the epileptogenic zone network on transcranial direct current stimulation efficacy in patients with refractory focal epilepsy. Responders typically exhibited a smaller and shallower epileptogenic zone network compared with non-responders. These findings suggest that utilizing individualized epileptogenic zone network characteristics could help refine patient selection for personalized transcranial direct current stimulation protocols, potentially improving therapeutic outcomes.
... However, this model neglects the involvement of endogenous oscillations of brain regions, and also the fact that the brain state is maintained through large-scale network-level interactions among many brain regions [17]. For instance, one study reported that low-frequency (0.75 Hz or 1 Hz) tACS over the frontal and occipital poles failed to enhance the intrinsic slow oscillations (~1 Hz) that dominate during non-rapid eye movement sleep [18]. Therefore, it is critical to obtain intracranial neurophysiological signals before and after noninvasive brain stimulation in order to understand the potential competition and synergy between exogenous and endogenous electrical fields. ...
Non-invasive brain stimulation is promising for treating many neuropsychiatric and neurological conditions. It could be optimized by understanding its intracranial responses in different brain regions. We implanted multi-site intracranial electrodes and systematically assessed the acute responses in these regions to transcranial alternating current stimulation (tACS) at different frequencies. We observed robust neural oscillation changes in the hippocampus and amygdala in response to non-invasive tACS procedures, and these effects were frequency-specific and state-dependent. Notably, the hippocampus responded most strongly and stably to 10 Hz stimulation, with pronounced changes across a wide frequency range, suggesting the potential of 10 Hz oscillatory stimulation to modulate a broad range of neural activity related to cognitive functions. Future work with increased sample sizes is required to determine the clinical implications of these findings for therapeutic efficiency.
... Therefore, for the TN-DCS experiments, DC stimulation was delivered once (no repetitions) for each amplitude at +0.5, +1, +2, and +3 mA as well as −0.5, −1, −2, and −3 mA in the NVsnpr, and +1, +2, and +3 mA as well as −1, −2, and −3 mA in the MeV. When a current of 1 mA is delivered to a tDCS scalp electrode in humans, it generates an electric field of below 1 V/m in the cortex [28,29]. The much thinner skull in rats means that to deliver an equivalent electric field (that is representative of human tDCS) we must use much lower amplitudes. ...
tDCS is widely assumed to cause neuromodulation via the electric field in the cortex acting directly on cortical neurons. However, recent evidence suggests that tDCS may indirectly influence brain activity through cranial nerve pathways, notably the trigeminal nerve, but these neuromodulatory pathways remain unexplored. To investigate the first stages in this potential pathway we developed an animal model to study the effect of trigeminal nerve direct current stimulation (TN-DCS) on neuronal activity in the principal sensory nucleus (NVsnpr) and the mesencephalic nucleus of the trigeminal nerve (MeV). We conducted experiments on twenty-four male Sprague Dawley rats (n = 10 NVsnpr, n = 10 MeV during anodic stimulation, and n = 4 MeV during cathodic stimulation). DC stimulation, ranging from 0.5 to 3 mA, targeted the trigeminal nerve’s marginal branch. Concurrently, single-unit electrophysiological recordings were obtained using a 32-channel silicon probe, encompassing three 1-min intervals: pre, during, and post-stimulation. Xylocaine trigeminal nerve blockage served as a control. TN-DCS increased neuronal spiking activity in both NVsnpr and MeV, returning to baseline during the post-stimulation phase. The 3 mA DC stimulation of the blocked trigeminal nerve failed to induce increased spiking activity in the trigeminal nuclei. These findings provide empirical support for trigeminal nuclei modulation via TN-DCS, suggesting the cranial nerve pathways could play a role in mediating the tDCS effects in humans.
... Alexander et al. showed that 10-Hz tACS, in fact, reduced alpha power in the frontal region [35]. In addition, Lafton et al. applied the intracranial recording and observed no sleep rhythm entrainment to tACS [36]. The contradictory findings cannot be resolved by entrainment theory alone but require a broader mechanism to reconcile them. ...
Transcranial alternating current stimulation (tACS) at 5-Hz to the right hemisphere can alleviate anxiety symptoms. We aimed to explore the connectivity changes following the treatment. We collected electroencephalography (EEG) data from 24 participants with anxiety disorders before and after the tACS treatment during a single session. Electric stimulation was applied over the right hemisphere, with 1.0 mA at F4, 1.0 mA at P4, and 2.0 mA at T8, following the 10-10 EEG convention. With eLORETA, the scalp signals were transformed into the cortex's current source density. We assessed the connectivity changes at theta frequency between the centers of Brodmann area (BA) 6/8 (frontal), BA 39/40 (parietal), and BA 21 (middle temporal). Functional connectivity was indicated by lagged coherences and lagged phase synchronization. Paired t-tests were used to quantify the differences statistically. We observed enhanced lagged phase synchronization at theta frequency between the frontal and parietal regions (P = 0.002) and between the parietal and temporal regions (P = 0.005) after Bonferroni correction. Applying tACS 5-Hz over the right hemisphere enhanced inter-regional interaction, which was spectrum-specific and mainly mediated by phase rather than power synchrony. The potential neural mechanisms are discussed.
... This was only across one-minute periods directly after stimulation however, and no change in time spent in different sleep stages was seen, both in the sixty minutes following stimulation, and the whole night succeeding, suggesting that this kind of intervention may not have longterm effects [31]. A study using intracranial recordings of neuronal activity failed to observe entrainment of neuronal activity using the SO-tDCS protocol, and they attribute this to the weak electric fields induced by the stimulation [37]. Perhaps due to these limitations and inconsistencies, few studies in the last five years have attempted to use this stimulation paradigm for sleep improvement. ...
Purpose of Review
In this review, we evaluate recent studies that employ neuromodulation, in the form of non-invasive brain stimulation, to improve sleep in both healthy participants, and patients with psychiatric disorders. We review studies using transcranial electrical stimulation, transcranial magnetic stimulation, and closed-loop auditory stimulation, and consider both subjective and objective measures of sleep improvement.
Recent Findings
Neuromodulation can alter neuronal activity underlying sleep. However, few studies utilizing neuromodulation report improvements in objective measures of sleep. Enhancements in subjective measures of sleep quality are replicable, however, many studies conducted in this field suffer from methodological limitations, and the placebo effect is robust.
Summary
Currently, evidence that neuromodulation can effectively enhance sleep is lacking. For the field to advance, methodological issues must be resolved, and the full range of objective measures of sleep architecture, alongside subjective measures of sleep quality, must be reported. Additionally, validation of effective modulation of neuronal activity should be done with neuroimaging.
... The few previous simultaneous tDCS-SEEG studies (Chhatbar et al., 2018;Huang et al., 2017;Lafon et al., 2017;Opitz et al., 2016) were exclusively designed to model the electric field propagation in the brain, lacking crucial information on epilepsy biomarkers and connectivity changes following tDCS application. Finally, despite the vast number of studies investigating the effects of tACS in cognitive functions, there is little account for tACS effects on epilepsy markers. ...
... iEEG has been used to delineate the temporal dynamics and spatial spread following intracranial electrical stimulation [10][11][12][13][14] and is a promising tool for providing similar resolution following noninvasive neuromodulatory techniques. Indeed, recent work with non-invasive transcranial direct and alternating current stimulation (tDCS & tACS) in humans has shown the utility of investigating these effects with iEEG [14][15][16][17][18]. These studies demonstrated that higher stimulation amplitude than is typically used may be needed to reliably induce intracranial effects [18]. ...
... These studies demonstrated that higher stimulation amplitude than is typically used may be needed to reliably induce intracranial effects [18]. Moreover, protocols that were presumed to drive specific oscillation frequencies did not find supporting evidence from iEEG [16]. To date these iEEG studies have not been extended to TMS, though studies of TMS with intracranial recordings have been highly informative in nonhuman primates [5,6]. ...
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.
... In violin plots representing estimated distributions of data (generated with violinplot, FieldTrip toolbox 92 , MATLAB, MathWorks), lines represent 5, 50 and 95 percentiles. No statistical methods were used to predetermine sample sizes but our sample sizes are similar to those generally used in previous publications 44, 73,95 . Data collection and analysis were not performed blind to the conditions of the experiments. ...
Memory consolidation during sleep is thought to depend on the coordinated interplay between cortical slow waves, thalamocortical sleep spindles and hippocampal ripples, but direct evidence is lacking. Here, we implemented real-time closed-loop deep brain stimulation in human prefrontal cortex during sleep and tested its effects on sleep electrophysiology and on overnight consolidation of declarative memory. Synchronizing the stimulation to the active phases of endogenous slow waves in the medial temporal lobe (MTL) enhanced sleep spindles, boosted locking of brain-wide neural spiking activity to MTL slow waves, and improved coupling between MTL ripples and thalamocortical oscillations. Furthermore, synchronized stimulation enhanced the accuracy of recognition memory. By contrast, identical stimulation without this precise time-locking was not associated with, and sometimes even degraded, these electrophysiological and behavioral effects. Notably, individual changes in memory accuracy were highly correlated with electrophysiological effects. Our results indicate that hippocampo–thalamocortical synchronization during sleep causally supports human memory consolidation.
... Transcranial alternating current stimulation (tACS) is a noninvasive technique that mediates frequency-specific entrainment of cortical activity (3). The rapidly growing number of publications assessing the state of the field (4-6), emergence of new rhythmic neuromodulation protocols (7)(8)(9), and conflicting evidence about the effectiveness of tACS (10) suggest the need for a systematic and quantitative examination of the existing literature. ...
Transcranial alternating current stimulation (tACS) has attracted interest as a technique for causal investigations into how rhythmic fluctuations in brain neural activity influence cognition and for promoting cognitive rehabilitation. We conducted a systematic review and meta-analysis of the effects of tACS on cognitive function across 102 published studies, which included 2893 individuals in healthy, aging, and neuropsychiatric populations. A total of 304 effects were extracted from these 102 studies. We found modest to moderate improvements in cognitive function with tACS treatment that were evident in several cognitive domains, including working memory, long-term memory, attention, executive control, and fluid intelligence. Improvements in cognitive function were generally stronger after completion of tACS ("offline" effects) than during tACS treatment ("online" effects). Improvements in cognitive function were greater in studies that used current flow models to optimize or confirm neuromodulation targets by stimulating electric fields generated in the brain by tACS protocols. In studies targeting multiple brain regions concurrently, cognitive function changed bidirectionally (improved or decreased) according to the relative phase, or alignment, of the alternating current in the two brain regions (in phase versus antiphase). We also noted improvements in cognitive function separately in older adults and in individuals with neuropsychiatric illnesses. Overall, our findings contribute to the debate surrounding the effectiveness of tACS for cognitive rehabilitation, quantitatively demonstrate its potential, and indicate further directions for optimal tACS clinical study design.
