Impact of Stimulation Duration in taVNS-Exploring Multiple Physiological and Cognitive Outcomes.

Transcutaneous auricular vagus nerve stimulation (taVNS) is a non-invasive neuromodulation technique that modulates the noradrenergic activity of the locus coeruleus (LC). Yet, there is still uncertainty about the most effective stimulation and reliable outcome parameters. In a double blind, sham-controlled study including a sample of healthy young individuals (N = 29), we compared a shorter (3.4 s) and a longer (30 s) stimulation duration and investigated the effects of taVNS (real vs. sham) on saliva samples (alpha amylase and cortisol concentration), pupil (pupillary light reflex and pupil size at rest) and EEG data (alpha and theta activity at rest, ERPs for No-Go signals), and cognitive tasks (Go/No-Go and Stop Signal Tasks). Salivary alpha amylase concentration was significantly increased in the real as compared to sham stimulation for the 30 s stimulation condition. In the 3.4 s stimulation condition, we found prolonged reaction times and increased error rates in the Go/No-Go task and increased maximum acceleration in the pupillary light reflex. For the other outcomes, no significant differences were found. Our results show that prolonged stimulation increases salivary alpha-amylase, which was expected from the functional properties of the LC. The finding of longer response times to short taVNS stimulation was not expected and cannot be explained by an increase in LC activity. We also discuss the difficulties in assessing pupil size as an expression of taVNS-mediated LC functional changes.

Differential online and offline effects of theta-tACS on memory encoding and retrieval.

Theta oscillations support memory formation, but their exact contribution to the communication between prefrontal cortex (PFC) and the hippocampus is unknown. We tested the functional relevance of theta oscillations as a communication link between both areas for memory formation using transcranial alternating current stimulation (tACS). Healthy, young participants learned two lists of Dutch-German word pairs and retrieved them immediately and with a 30-min delay. In the encoding group (N = 30), tACS was applied during the encoding of list 1. List 2 was used to test stimulation aftereffects. In the retrieval group (N = 23), we stimulated during the delayed recall. In both groups, we applied tACS bilaterally at prefrontal and tempo-parietal sites, using either individualized theta frequency or 15 Hz (as control), according to a within-subject design. Stimulation with theta-tACS did not alter overall learning performance. An exploratory analysis revealed that immediate recall improved when word-pairs were learned after theta-tACS (list 2). Applying theta-tACS during retrieval had detrimental effects on memory. No changes in the power of the respective frequency bands were observed. Our results do not support the notion that impacting the communication between PFC and the hippocampus during a task by bilateral tACS improves memory. However, we do find evidence that direct stimulation had a trend for negatively interfering effects during immediate and delayed recall. Hints for beneficial effects on memory only occurred with aftereffects of the stimulation. Future studies need to further examine the effects during and after stimulation on memory formation.

Illness perception in functional neurological disorder: low illness coherence and personal control.

Introduction: Illness perception refers to patients' subjective representations and appraisals of somatic and mental symptoms. These are relevant for self-management and outcome. In clinical practice, patients with functional neurological disorder (FND) often encounter a fragmented biomedical attitude, which leaves them without clear concepts. In this context, illness perception is relevant. Methods: Illness perception was assessed in FND patients and compared with samples of psychosomatic patients (PSM) as well as poststroke patients (STR). The three samples (FND, n=87; PSM, n=97 and STR, n=92) were almost all in inpatient treatment or rehabilitation. Illness perception was assessed with the revised German version of the Illness Perception Questionnaire (IPQ-R). For assessments of correlations, depressive symptoms were tested with the Patient Health Questionnaire-9, dissociative and functional neurological symptoms by the German adaption of the Dissociative Experiences Scale and biopsychosocial complexity by the INTERMED Self-Assessment questionnaire. Results: Apart from the chronicity subscale, all dimensions of the IPQ-R differed between groups. FND patients perceived lower illness coherence and personal control than both other groups and attributed their illness more to chance than to behavioural risk factors. PSM patients had the strongest emotional representations. There were only few correlations with dissociative scores and biopsychosocial complexity. Conclusion: Illness perception is an important issue in patients with FND with particular emphasis on low illness coherence and personal control. Missing associations with biopsychosocial complexity suggest that subjective illness perception is an important complementary but separate issue, which likely influences therapeutic alliance and self-management in FND. Future studies should assess its influences on outcome. Trial registration number: DRKS00024685; German Clinical Trials Register; www.drks.de.

Aligning Event-Related Potentials with Transcranial Alternating Current Stimulation for Modulation-a Review.

This review aims to demonstrate the connections between event-related potentials (ERPs), event-related oscillations (EROs), and non-invasive brain stimulation (NIBS), with a specific focus on transcranial alternating current stimulation (tACS). We begin with a short examination and discussion of the relation between ERPs and EROs. Then, we investigate the diverse fields of NIBS, highlighting tACS as a potent tool for modulating neural oscillations and influencing cognitive performance. Emphasizing the impact of tACS on individual ERP components, this article offers insights into the potential of conventional tACS for targeted stimulation of single ERP components. Furthermore, we review recent articles that explore a novel approach of tACS: ERP-aligned tACS. This innovative technique exploits the temporal precision of ERP components, aligning tACS with specific neural events to optimize stimulation effects and target the desired neural response. In conclusion, this review combines current knowledge to explore how ERPs, EROs, and NIBS interact, particularly highlighting the modulatory possibilities offered by tACS. The incorporation of ERP-aligned tACS introduces new opportunities for future research, advancing our understanding of the complex connection between neural oscillations and cognitive processes.

No Benefit in Memory Performance after Nocturnal Memory Reactivation Coupled with Theta-tACS.

Targeted memory reactivation (TMR) is an effective technique to enhance sleep-associated memory consolidation. The successful reactivation of memories by external reminder cues is typically accompanied by an event-related increase in theta oscillations, preceding better memory recall after sleep. However, it remains unclear whether the increase in theta oscillations is a causal factor or an epiphenomenon of successful TMR. Here, we used transcranial alternating current stimulation (tACS) to examine the causal role of theta oscillations for TMR during non-rapid eye movement (non-REM) sleep. Thirty-seven healthy participants learned Dutch-German word pairs before sleep. During non-REM sleep, we applied either theta-tACS or control-tACS (23 Hz) in blocks (9 min) in a randomised order, according to a within-subject design. One group of participants received tACS coupled with TMR time-locked two seconds after the reminder cue (time-locked group). Another group received tACS in a continuous manner while TMR cues were presented (continuous group). Contrary to our predictions, we observed no frequency-specific benefit of theta-tACS coupled with TMR during sleep on memory performance, neither for continuous nor time-locked stimulation. In fact, both stimulation protocols blocked the TMR-induced memory benefits during sleep, resulting in no memory enhancement by TMR in both the theta and control conditions. No frequency-specific effect was found on the power analyses of the electroencephalogram. We conclude that tACS might have an unspecific blocking effect on memory benefits typically observed after TMR during non-REM sleep.

Modulating the difficulty of a visual oddball-like task and P3m amplitude.

It is often necessary to modulate the difficulty of an experimental task without changing physical stimulus characteristics that are known to modulate event-related potentials. Here, we developed a new, oddball-like visual discrimination task with varying levels of difficulty despite using almost identical visual stimuli. Gabor patches of one orientation served as frequent standard stimuli with 75% probability. Gabor patches with a slightly different orientation served as infrequent target stimuli (25% probability). Analyzing the behavioral outcomes revealed a successful modulation of task difficulty, i.e. the hard condition revealed decreased d' values and longer reaction times for standard stimuli. In addition, we recorded MEG and computed event-related fields in response to the stimuli. In line with our expectation, the amplitude of the P3m was reduced in the hard condition. We localized the sources of the P3m with a focus on those that are modulated by changes in task difficulty. The sources of P3m modulation by difficulty were found primarily in the centro-parietal regions of both hemispheres. Additionally, we found significant differences in source activity between the easy and hard conditions in parts of the pre and post-central gyrus and inferior parietal lobe. Our findings are in line with previous research suggesting that the brain areas responsible for the conventional P3m generators also contribute to a modulation by task difficulty.

Cognitive-behavioral therapy for patients with post-COVID-19 condition (CBT-PCC): a feasibility trial.

BACKGROUND: The post-COVID-19 condition describes the persistence or onset of somatic symptoms (e.g. fatigue) after acute COVID-19. Based on an existing cognitive-behavioral treatment protocol, we developed a specialized group intervention for individuals with post-COVID-19 condition. The present study examines the feasibility, acceptance, and effectiveness of the program for inpatients in a neurological rehabilitation setting. METHODS: The treatment program comprises eight sessions and includes psychoeducational and experience-based interventions on common psychophysiological mechanisms of persistent somatic symptoms. A feasibility trial was conducted using a one-group design in a naturalistic setting. N = 64 inpatients with a history of mild COVID-19 that fulfilled WHO criteria for post-COVID-19 condition were enrolled. After each session, evaluation forms were completed and psychometric questionnaires on somatic and psychopathological symptom burden were collected pre- and post-intervention. RESULTS: The treatment program was well received by participants and therapists. Each session was rated as comprehensible and overall satisfaction with the sessions was high. Pre-post effect sizes (of standard rehabilitation incl. new treatment program; intention-to-treat) showed significantly reduced subjective fatigue (p < 0.05, dav = 0.33) and improved disease coping (ps < 0.05, dav = 0.33-0.49). CONCLUSIONS: Our results support the feasibility and acceptance of the newly developed cognitive-behavioral group intervention for individuals with post-COVID-19 condition. Yet, findings have to be interpreted cautiously due to the lack of a control group and follow-up measurement, the small sample size, and a relatively high drop-out rate.

Alpha transcranial alternating current stimulation modulates auditory perception.

BACKGROUND: Studies using transcranial alternating current stimulation (tACS), a type of non-invasive brain stimulation, have demonstrated a relationship between the positive versus negative phase of both alpha and delta/theta oscillations with variable near-threshold auditory perception. These findings have not been directly compared before. Furthermore, as perception was better in the positive versus negative phase of two different frequencies, it is unclear whether changes in polarity (independent of a specific frequency) could also modulate auditory perception. OBJECTIVE: We investigated whether auditory perception depends on the phase of alpha, delta/theta, or polarity alone. METHODS: We stimulated participants with alpha, delta, and positive and negative direct current (DC) over temporal and central scalp sites while they identified near-threshold tones-in-noise. A Sham condition without tACS served as a control condition. A repeated-measures analysis of variance was used to assess differences in proportions of hits between conditions and polarities. Permutation-based circular-logistic regressions were used to assess the relationship between circular-predictors and single-trial behavioral responses. An exploratory analysis compared the full circular-logistic regression model to the intercept-only model. RESULTS: Overall, there were a greater proportion of hits in the Alpha condition in comparison to Delta, DC, and Sham conditions. We also found an interaction between polarity and stimulation condition; post-hoc analyses revealed a greater proportion of hits in the positive versus negative phase of Alpha tACS. In contrast, no significant differences were found in the Delta, DC, or Sham conditions. The permutation-based circular-logistic regressions did not reveal a statistically significant difference between the obtained RMS of the sine and cosine coefficients and the mean of the surrogate distribution for any of the conditions. However, our exploratory analysis revealed that circular-predictors explained the behavioral data significantly better than an intercept-only model for the Alpha condition, and not the other three conditions. CONCLUSION: These findings suggest that alpha tACS, and not delta nor polarity alone, modulates auditory perception.

ERP-aligned delta transcranial alternating current stimulation modulates the P3 amplitude.

The underlying mechanisms of the event-related potential (ERP) generation are still under debate. One popular model considers the ERP as a superposition of phase-resets of ongoing endogenous oscillations of different frequencies. Brain oscillations have been shown to be modulated by transcranial alternating current stimulation (tACS). Thus, it seems feasible, that an ERP could be altered by modulating the contributing oscillations using tACS. One possible approach would be to target a frequency-matched stimulation signal to a specific ERP-component. One possible target for such an approach is the P3, which appears as delta/theta oscillations in the frequency-domain. Thus, an ERP-aligned stimulation in the delta/theta-range might be suitable to force synchronization in the stimulated frequency band and thus increase the amplitude of the P3 component. Building on an existing paradigm, in the present study 21 healthy participants received individualized ERP-aligned delta tACS and control stimulation while performing a visual task. The visual stimulation was matched to the continuous tACS in order to align the tACS peak with the P3 peak. Both the P3 amplitude and the evoked delta power were significantly increased after ERP-aligned tACS but not after control stimulation. The investigated behavioral parameter showed no stimulation dependent effect. Our results may provide new insights into the debate on the contribution of phase-reset mechanisms to the generation of ERPs and offer new opportunities for clinical trials.

Biopsychosocial complexity in functional neurological disorder.

BACKGROUND: Functional Neurological Disorder (FND) is considered a biopsychosocial disorder nowadays, with chronicity in >50% of cases. The INTERMED Self-Assessment Questionnaire (IMSA) assesses the various domains and indicates biopsychosocial complexity. OBJECTIVE: FND patients were compared with a sample of psychosomatic (PSM) patients as well as post-stroke patients. METHODS: The three samples (N = 287 altogether) were largely in inpatient and day clinic psychotherapeutic treatment or inpatient neurological rehabilitation. The IMSA covers all three biopsychosocial domains as well as health care utilisation in the time frame of the past, the present and the future. In addition, affective burden (GAD-7, PHQ-9), somatoform symptoms (PHQ-15), dissociation (FDS) and quality of life (SF-12) were evaluated. RESULTS: FND and PSM patients scored highly in the IMSA, with ≥70% regarded as complex, compared to 15% of post-stroke patients. Affective, somatoform and dissociation scores were high in FND and PSM patients. Mental and somatic quality of life were lower in these groups compared to post-stroke patients. DISCUSSION: FND patients showed high biopsychosocial strain, similar to a typical sample of inpatient and day clinic, i.e. severely affected, PSM patients, and they were more affected than post-stroke patients. These data emphasize that FND should be evaluated with a biopsychosocial perspective. The IMSA likely represents a valuable tool, which has to be assessed by further longitudinal studies.

Personalized alpha-tACS targeting left posterior parietal cortex modulates visuo-spatial attention and posterior evoked EEG activity.

BACKGROUND: Covert visuo-spatial attention is marked by the anticipatory lateralization of neuronal alpha activity in the posterior parietal cortex. Previous applications of transcranial alternating current stimulation (tACS) at the alpha frequency, however, were inconclusive regarding the causal contribution of oscillatory activity during visuo-spatial attention. OBJECTIVE: Attentional shifts of behavior and electroencephalography (EEG) after-effects were assessed in a cued visuo-spatial attention paradigm. We hypothesized that parietal alpha-tACS shifts attention relative to the ipsilateral visual hemifield. Furthermore, we assumed that modulations of behavior and neurophysiology are related to individual electric field simulations. METHODS: We applied personalized tACS at alpha and gamma frequencies to elucidate the role of oscillatory neuronal activity for visuo-spatial attention. Personalized tACS montages were algorithmically optimized to target individual left and right parietal regions that were defined by an EEG localizer. RESULTS: Behavioral performance in the left hemifield was specifically increased by alpha-tACS compared to gamma-tACS targeting the left parietal cortex. This hemisphere-specific effect was observed despite the symmetry of simulated electric fields. In addition, visual event-related potential (ERP) amplitudes showed a reduced lateralization over posterior sites induced by left alpha-tACS. Neuronal sources of this effect were localized in the left premotor cortex. Interestingly, accuracy modulations induced by left parietal alpha-tACS were directly related to electric field magnitudes in the left premotor cortex. CONCLUSION: Overall, results corroborate the notion that alpha lateralization plays a causal role in covert visuo-spatial attention and indicate an increased susceptibility of parietal and premotor brain regions of the left dorsal attention network to subtle tACS-neuromodulation.

Attempting to counteract vigilance decrement in older adults with brain stimulation.

Introduction: Against the background of demographic change and the need for enhancement techniques for an aging society, we set out to repeat a study that utilized 40-Hz transcranial alternating current stimulation (tACS) to counteract the slowdown of reaction times in a vigilance experiment but with participants aged 65 years and older. On an oscillatory level, vigilance decrement is linked to rising occipital alpha power, which has been shown to be downregulated using gamma-tACS. Method: We applied tACS on the visual cortex and compared reaction times, error rates, and alpha power of a group stimulated with 40 Hz to a sham and a 5-Hz-stimulated control group. All groups executed two 30-min-long blocks of a visual task and were stimulated according to group in the second block. We hypothesized that the expected increase in reaction times and alpha power would be reduced in the 40-Hz group compared to the control groups in the second block (INTERVENTION). Results: Statistical analysis with linear mixed models showed that reaction times increased significantly over time in the first block (BASELINE) with approximately 3 ms/min for the SHAM and 2 ms/min for the 5-Hz and 40-Hz groups, with no difference between the groups. The increase was less pronounced in the INTERVENTION block (1 ms/min for SHAM and 5-Hz groups, 3 ms/min for the 40-Hz group). Differences among groups in the INTERVENTION block were not significant if the 5-Hz or the 40-Hz group was used as the base group for the linear mixed model. Statistical analysis with a generalized linear mixed model showed that alpha power was significantly higher after the experiment (1.37 µV2) compared to before (1 µV2). No influence of stimulation (40 Hz, 5 Hz, or sham) could be detected. Discussion: Although the literature has shown that tACS offers potential for older adults, our results indicate that findings from general studies cannot simply be transferred to an old-aged group. We suggest adjusting stimulation parameters to the neurophysiological features expected in this group. Next to heterogeneity and cognitive fitness, the influence of motivation and medication should be considered.

Alpha modulation via transcranial alternating current stimulation in adults with attention-deficit hyperactivity disorder.

Background: One potential therapy treating attention-deficit/hyperactivity disorder (ADHD) is to modulate dysfunctional brain activations using brain stimulation techniques. While the number of studies investigating the effect of transcranial direct current stimulation on ADHD symptoms continues to increase, transcranial alternating current stimulation (tACS) is poorly examined. Previous studies reported impaired alpha brain oscillation (8-12 Hz) that may be associated with increased attention deficits in ADHD. Our aim was to enhance alpha power in adult ADHD patients via tACS, using different methods to explore potential therapeutic effects. Methods: Undergoing a crossover design, adults with ADHD received active and sham stimulation on distinct days. Before and after each intervention, mean alpha power, attention performance, subjective symptom ratings, as well as head and gaze movement were examined. Results: Frequency analyses revealed a significant power increase in the alpha band after both interventions. Despite a trend toward an interaction effect, this alpha power increase was, however, not significantly higher after active stimulation compared to sham stimulation. For the other measures, some additional pre-post effects were found, which were not intervention-related. Conclusion: Our study cannot provide clear evidence for a tACS-induced increase in alpha power in adult ADHD patients, and thus no stimulation related improvement of attention parameters. We provide further recommendations for the future investigation of tACS as a potential ADHD treatment.

The hidden brain-state dynamics of tACS aftereffects.

Non-invasive techniques to electrically stimulate the brain such as transcranial direct and alternating current stimulation (tDCS/tACS) are increasingly used in human neuroscience and offer potential new avenues to treat brain disorders. Previous research has shown that stimulation effects may depend on brain-states. However, this work mostly focused on experimentally induced brain-states over the course of several minutes. Besides such global, long-term changes in brain-states, previous research suggests, that the brain is likely to spontaneously alternate between states in sub-second ranges, which is much closer to the time scale at which it is generally believed to operate. Here, we utilized Hidden Markov Models (HMM) to decompose magnetoencephalography data obtained before and after tACS into spontaneous, transient brain-states with distinct spatial, spectral and connectivity profiles. Only one out of four spontaneous brain-states, likely reflecting default mode network activity, showed evidence for an effect of tACS on the power of spontaneous α-oscillations. The identified state appears to disproportionally drive the overall (non-state resolved) tACS effect. No or only marginal effects were found in the remaining states. We found no evidence that tACS influenced the time spent in each state. Although stimulation was applied continuously, our results indicate that spontaneous brain-states and their underlying functional networks differ in their susceptibility to tACS. Global stimulation aftereffects may be disproportionally driven by distinct time periods during which the susceptible state is active. Our results may pave the ground for future work to understand which features make a specific brain-state susceptible to electrical stimulation.

P300 Modulation via Transcranial Alternating Current Stimulation in Adult Attention-Deficit/Hyperactivity Disorder: A Crossover Study.

Objective: A repeated finding regarding event-related potentials (ERPs) is that patients with ADHD show a reduced P300 amplitude. This raises the question of whether the attention of ADHD patients can be increased by stabilizing the P300. Assuming that the P300 is generated by event-related oscillations (EROs) in the low frequency range (0-8 Hz), one approach to increase the P300 could be to stimulate the patient's P300 underlying ERO by means of transcranial alternating current stimulation (tACS). The aim of this follow-up study was to investigate this hypothesized mechanism of action in adult ADHD patients. Materials and Methods: Undergoing a crossover design, 20 adult ADHD patients (10 female) received an actual stimulation via tACS on one day and a sham stimulation on another day. Before and after each intervention, EEG characteristics (P300 amplitudes, low frequency power) and attention performances (d2 attention test, visual oddball task (VOT)) were recorded. Results: Electrophysiological analyses revealed no evidence for an enhanced P300 amplitude or low frequency power increase after actual stimulation compared to sham stimulation. Instead, a significant effect was found for a stronger N700 amplitude increase after actual stimulation compared to sham stimulation. Consistent with the P300 null results, none of the examined neuropsychological performance measures indicated a tACS-induced improvement in attentional ability. Conclusion: Contrary to a previous study using tACS to modulate the P300 in adult ADHD patients, the current study yields no evidence that tACS can increase the P300 amplitude in adult ADHD patients and that such P300 enhancement can directly improve neuropsychological parameters of attention.

Evidence of Neuroplastic Changes after Transcranial Magnetic, Electric, and Deep Brain Stimulation.

Electric and magnetic stimulation of the human brain can be used to excite or inhibit neurons. Numerous methods have been designed over the years for this purpose with various advantages and disadvantages that are the topic of this review. Deep brain stimulation (DBS) is the most direct and focal application of electric impulses to brain tissue. Electrodes are placed in the brain in order to modulate neural activity and to correct parameters of pathological oscillation in brain circuits such as their amplitude or frequency. Transcranial magnetic stimulation (TMS) is a non-invasive alternative with the stimulator generating a magnetic field in a coil over the scalp that induces an electric field in the brain which, in turn, interacts with ongoing brain activity. Depending upon stimulation parameters, excitation and inhibition can be achieved. Transcranial electric stimulation (tES) applies electric fields to the scalp that spread along the skull in order to reach the brain, thus, limiting current strength to avoid skin sensations and cranial muscle pain. Therefore, tES can only modulate brain activity and is considered subthreshold, i.e., it does not directly elicit neuronal action potentials. In this review, we collect hints for neuroplastic changes such as modulation of behavior, the electric activity of the brain, or the evolution of clinical signs and symptoms in response to stimulation. Possible mechanisms are discussed, and future paradigms are suggested.

Benchmarking the effects of transcranial temporal interference stimulation (tTIS) in humans.

Deep brain stimulation (DBS) provides clinical benefits for several neurological and psychiatric conditions. By overcoming the limitations and risks of conventional DBS, transcranial temporal interference stimulation (tTIS) has the potential to offer non-invasive stimulation of deep brain regions. However, research that investigates the efficacy of tTIS is limited to animal studies or computer simulations and its capability to modulate neural oscillations in humans has not been demonstrated so far. The method of tTIS is hypothesized to elicit its effects via neural entrainment, corresponding to the supposed mechanism of action underlying transcranial alternating current stimulation (tACS), another, more established non-invasive brain stimulation technique. Physiological effects of tACS are well established for cortical brain oscillations, but not for deep brain structures. In particular, aftereffects on the power of parieto-occipital alpha oscillations have been shown repeatedly. In a first attempt to test the efficacy of tTIS in the human brain, the current study thus seeks to compare the effects of tTIS to the well-studied aftereffect of tACS in the cortex. To investigate this research question, the current study compared MEG-recorded brain activity during a simple visual change detection task in 34 healthy subjects pre- and post-tTIS. Additionally, the effects of tTIS were contrasted to conventional tACS and a control stimulation. We expected that the parieto-occipital α-power will increase after tTIS and tACS, in contrast to the control stimulation. Overall, no difference between the experimental groups (tTIS, tACS and control stimulation) were found regarding the source-projected increase in α-power. Based on the results of the study two hypothesis can be made: tTIS, tACS and the control stimulation condition don't have an effect on human brain oscillations in the α-band, or, any experimental conditions of the current study can modulate brain oscillations in the α-band. Both hypotheses emphasize the importance of further studies investigating different carrier frequencies, and the comparison to sham stimulation.

Non-invasive brain stimulation and neuroenhancement.

Attempts to enhance human memory and learning ability have a long tradition in science. This topic has recently gained substantial attention because of the increasing percentage of older individuals worldwide and the predicted rise of age-associated cognitive decline in brain functions. Transcranial brain stimulation methods, such as transcranial magnetic (TMS) and transcranial electric (tES) stimulation, have been extensively used in an effort to improve cognitive functions in humans. Here we summarize the available data on low-intensity tES for this purpose, in comparison to repetitive TMS and some pharmacological agents, such as caffeine and nicotine. There is no single area in the brain stimulation field in which only positive outcomes have been reported. For self-directed tES devices, how to restrict variability with regard to efficacy is an essential aspect of device design and function. As with any technique, reproducible outcomes depend on the equipment and how well this is matched to the experience and skill of the operator. For self-administered non-invasive brain stimulation, this requires device designs that rigorously incorporate human operator factors. The wide parameter space of non-invasive brain stimulation, including dose (e.g., duration, intensity (current density), number of repetitions), inclusion/exclusion (e.g., subject's age), and homeostatic effects, administration of tasks before and during stimulation, and, most importantly, placebo or nocebo effects, have to be taken into account. The outcomes of stimulation are expected to depend on these parameters and should be strictly controlled. The consensus among experts is that low-intensity tES is safe as long as tested and accepted protocols (including, for example, dose, inclusion/exclusion) are followed and devices are used which follow established engineering risk-management procedures. Devices and protocols that allow stimulation outside these parameters cannot claim to be "safe" where they are applying stimulation beyond that examined in published studies that also investigated potential side effects. Brain stimulation devices marketed for consumer use are distinct from medical devices because they do not make medical claims and are therefore not necessarily subject to the same level of regulation as medical devices (i.e., by government agencies tasked with regulating medical devices). Manufacturers must follow ethical and best practices in marketing tES stimulators, including not misleading users by referencing effects from human trials using devices and protocols not similar to theirs.

The Influence of the Modulation Index on Frequency-Modulated Steady-State Visual Evoked Potentials.

Based on increased user experience during stimulation, frequency-modulated steady-state visual evoked potentials (FM-SSVEPs) have been suggested as an improved stimulation method for brain-computer interfaces. Adapting such a novel stimulation paradigm requires in-depth analyses of all different stimulation parameters and their influence on brain responses as well as the user experience during the stimulation. In the current manuscript, we assess the influence of different values for the modulation index, which determine the spectral distribution in the stimulation signal on FM-SSVEPs. We visually stimulated 14 participants at different target frequencies with four different values for the modulation index. Our results reveal that changing the modulation index in a way that elevates the stimulation power in the targeted sideband leads to increased FM-SSVEP responses. There is, however, a tradeoff with user experience as increased modulation indices also lead to increased perceived flicker intensity as well as decreased stimulation comfort in our participants. Our results can guide the choice of parameters in future FM-SSVEP implementations.