Phasic, Event-Related Transcutaneous Auricular Vagus Nerve Stimulation Modifies Behavioral, Pupillary, and Low-Frequency Oscillatory Power Responses.

Transcutaneous auricular vagus nerve stimulation (taVNS) has been proposed to activate the locus ceruleus-noradrenaline (LC-NA) system. However, previous studies failed to find consistent modulatory effects of taVNS on LC-NA biomarkers. Previous studies suggest that phasic taVNS may be capable of modulating LC-NA biomarkers such as pupil dilation and alpha oscillations. However, it is unclear whether these effects extend beyond pure sensory vagal nerve responses. Critically, the potential of the pupillary light reflex as an additional taVNS biomarker has not been explored so far. Here, we applied phasic active and sham taVNS in 29 subjects (16 female, 13 male) while they performed an emotional Stroop task (EST) and a passive pupil light reflex task (PLRT). We recorded pupil size and brain activity dynamics using a combined Magnetoencephalography (MEG) and pupillometry design. Our results show that phasic taVNS significantly increased pupil dilation and performance during the EST. During the PLRT, active taVNS reduced and delayed pupil constriction. In the MEG, taVNS increased frontal-midline theta and alpha power during the EST, whereas occipital alpha power was reduced during both the EST and PLRT. Our findings provide evidence that phasic taVNS systematically modulates behavioral, pupillary, and electrophysiological parameters of LC-NA activity during cognitive processing. Moreover, we demonstrate for the first time that the pupillary light reflex can be used as a simple and effective proxy of taVNS efficacy. These findings have important implications for the development of noninvasive neuromodulation interventions for various cognitive and clinical applications.SIGNIFICANCE STATEMENT taVNS has gained increasing attention as a noninvasive neuromodulation technique and is widely used in clinical and nonclinical research. Nevertheless, the exact mechanism of action of taVNS is not yet fully understood. By assessing physiology and behavior in a response conflict task in healthy humans, we demonstrate the first successful application of a phasic, noninvasive vagus nerve stimulation to improve cognitive control and to systematically modulate pupillary and electrophysiological markers of the noradrenergic system. Understanding the mechanisms of action of taVNS could optimize future clinical applications and lead to better treatments for mental disorders associated with noradrenergic dysfunction. In addition, we present a new taVNS-sensitive pupillary measure representing an easy-to-use biomarker for future taVNS studies.

Effects of transcutaneous auricular vagus nerve stimulation paired with tones on electrophysiological markers of auditory perception.

BACKGROUND: Transcutaneous auricular vagus nerve stimulation (taVNS) has been introduced as a non-invasive alternative to invasive vagus nerve stimulation (iVNS). While iVNS paired with tones has been highlighted as a potential effective therapy for the treatment of auditory disorders such as tinnitus, there is still scarce data available confirming the efficacy of non-invasive taVNS. Here, we assessed the effect of taVNS paired with acoustic stimuli on sensory-related electrophysiological responses. METHODS: A total of 22 healthy participants were investigated with a taVNS tone-pairing paradigm using a within-subjects design. In a single session pure tones paired with either active taVNS or sham taVNS were repeatedly presented. Novel tones without electrical stimulation served as control condition. Auditory event related potentials and auditory cortex oscillations were compared before and after the tone pairing procedure between stimulation conditions. RESULTS: From pre to post pairing, we observed a decrease in the N1 amplitude and in theta power to tones paired with sham taVNS while these electrophysiological measures remained stable for tones paired with active taVNS a pattern mirroring auditory sensory processing of novel, unpaired control tones. CONCLUSION: Our results demonstrate the efficacy of a short-term application of non-invasive taVNS to modulate auditory processing in healthy individuals and, thereby, have potential implications for interventions in auditory processing deficits.

Rhythmic interactions between the mediodorsal thalamus and prefrontal cortex precede human visual perception.

The thalamus is much more than a simple sensory relay. High-order thalamic nuclei, such as the mediodorsal thalamus, exert a profound influence over animal cognition. However, given the difficulty of directly recording from the thalamus in humans, next-to-nothing is known about thalamic and thalamocortical contributions to human cognition. To address this, we analysed simultaneously-recorded thalamic iEEG and whole-head MEG in six patients (plus MEG recordings from twelve healthy controls) as they completed a visual detection task. We observed that the phase of both ongoing mediodorsal thalamic and prefrontal low-frequency activity was predictive of perceptual performance. Critically however, mediodorsal thalamic activity mediated prefrontal contributions to perceptual performance. These results suggest that it is thalamocortical interactions, rather than cortical activity alone, that is predictive of upcoming perceptual performance and, more generally, highlights the importance of accounting for the thalamus when theorising about cortical contributions to human cognition.

The LC-NE system as a potential target for neuromodulation to ameliorate non-motor symptoms in Parkinson's disease.

Parkinson's disease (PD) is associated with severe motor symptoms but also with several non-motor symptoms (NMS). A substantial reduction of norepinephrine (NE) levels in various brain regions reflecting an extensive loss of innervation from the LC has been assumed as causal for the development of NMS and specifically of attentional impairments in PD. Transcutaneous auricular vagus nerve stimulation (taVNS) is a new, non-invasive neurostimulation method supposed to modulate the LC-NE system in humans. In the current opinion paper, we introduce taVNS as a systemic approach to directly affect NE neurotransmission in healthy as well as clinical populations and discuss its potential as therapeutic option for the treatment of NMS, specifically attentional deficits, in patients with PD. Here, we first describe the LC-NE system and discuss how LC-NE dysfunction might affects cognition in PD before detailing the mode of action of taVNS and proposing its use to modulate cognitive deficits in these patients.

Current challenges in reliably targeting the noradrenergic locus coeruleus using transcutaneous auricular vagus nerve stimulation (taVNS).

Transcutaneous auricular vagus nerve stimulation (taVNS), as a non-invasive brain stimulation technique may influence the locus coeruleus-norepinephrine system (LC-NE system) via modulation of the Vagus Nerve (VN) which projects to the LC. Few human studies exist examining the effects of taVNS on the LC-NE system and studies to date assessing the ability of taVNS to target the LC yield heterogeneous results. The aim of this review is to present an overview of the current challenges in assessing effects of taVNS on LC function and how translational approaches spanning animal and human research can help in this regard. A particular emphasis of the review discusses how the effects of taVNS may be influenced by changes in structure and function of the LC-NE system across the human lifespan and in disease.

Amplitude modulated transcranial alternating current stimulation (AM-TACS) efficacy evaluation via phosphene induction.

Amplitude modulated transcranial alternating current stimulation (AM-tACS) is a novel method of electrostimulation which enables the recording of electrophysiological signals during stimulation, thanks to an easier removable stimulation artefact compared to classical electrostimulation methods. To gauge the neuromodulatory potential of AM-tACS, we tested its capacity to induce phosphenes as an indicator of stimulation efficacy. AM-tACS was applied via a two-electrode setup, attached on FpZ and below the right eye. AM-tACS waveforms comprised of different carrier (50 Hz, 200 Hz, 1000 Hz) and modulation frequencies (8 Hz, 16 Hz, 28 Hz) were administered with at maximum 2 mA peak-to-peak stimulation strength. TACS conditions in the same frequencies were used as a benchmark for phosphene induction. AM-tACS conditions using a 50 Hz carrier frequency were able to induce phosphenes, but with no difference in phosphene thresholds between modulation frequencies. AM-tACS using a 200 Hz or 1000 Hz carrier frequency did not induce phosphenes. TACS conditions induced phosphenes in line with previous studies. Stimulation effects of AM-tACS conditions were independent of amplitude modulation and instead relied solely on the carrier frequency. A possible explanation may be that AM-tACS needs higher stimulation intensities for its amplitude modulation to have a neuromodulatory effect.

Transcutaneous vagus nerve stimulation in patients with attention-deficit/hyperactivity disorder: A viable option?

Individuals with attention-deficit/hyperactivity disorder (ADHD) suffer from a range of cognitive and behavioral problems that severely impair their educational and occupational attainment. ADHD symptoms have been linked to structural and functional changes within and between different brain regions, particularly the prefrontal cortex. At the system level, reduced availability of the neurotransmitters dopamine (DA) and norepinephrine (NE) but also γ-aminobutyric acid (GABA) have been repeatedly demonstrated. Recently, non-invasive brain stimulation (NIBS) techniques have been explored as treatment alternatives to alter dysfunctional activation patterns in specified brain areas or networks. In the current paper, we introduce transcutaneous vagus nerve stimulation (tVNS) as a systemic approach to directly affect NE and GABA neurotransmission. TVNS is a non-drug intervention with low risk and proven efficacy in improving cognitive particularly executive functions. It is easy to apply and therefore well-suited to provide home-based or mobile treatment options allowing a significant increase in treatment intensity and providing easier access to medical care for individuals who are unable to regularly visit a clinician. We describe in detail the underlying mechanisms of tVNS and current fields of application and discuss its potential as an adjuvant treatment for ADHD.

Effects of transcutaneous vagus nerve stimulation (tVNS) on beta and gamma brain oscillations.

Physiological and behavioral effects induced through transcutaneous vagus nerve stimulation (tVNS) are under scrutiny in a growing number of studies, yet its mechanisms of action remain poorly understood. One candidate mechanism is a modulation of γ-aminobutyric acid (GABA) transmission through tVNS. Two recent behavioral studies suggest that such a GABAergic effect might occur in a lateralized fashion, i.e., the GABA modulation might be stronger in the left than in the right brain hemisphere after tVNS applied to the left ear. Using magnetoencephalography (MEG), we tested for GABA-associated modulations in resting and event-related brain oscillations and for a lateralization of those effects in a sample of 41 healthy young adults. Our data provide substantial evidence against all hypotheses, i.e., we neither find effects of tVNS on oscillatory power nor a lateralization of effects.

Pulsed transcranial electric brain stimulation enhances speech comprehension.

BACKGROUND: One key mechanism thought to underlie speech processing is the alignment of cortical brain rhythms to the acoustic input, a mechanism termed entrainment. Recent work showed that transcranial electrical stimulation (tES) in speech relevant frequencies or adapted to the speech envelope can in fact enhance speech processing. However, it is unclear whether an oscillatory tES is necessary, or if transients in the stimulation (e.g., peaks in the tES signal) at relevant times are sufficient. OBJECTIVE: In this study we used a novel pulsed-tES-protocol and tested behaviorally if a transiently pulsed - instead of a persistently oscillating - tES signal, can improve speech processing. METHODS: While subjects listened to spoken sentences embedded in noise, brief electric direct current pulses aligned to speech transients (syllable onsets) were applied to auditory cortex regions to modulate comprehension. Additionally, we modulated the temporal delay between tES-pulses and speech transients to test for periodic modulations of behavior, indicative of entrainment by tES. RESULTS: Speech comprehension was improved when tES-pulses were applied with a delay of 100 ms in respect to the speech transients. Contradictory to previous reports we find no periodic modulation of behavior. However, we find indications that periodic modulations can be spurious results of sampling behavioral data too coarsely. CONCLUSIONS: Subject's speech comprehension benefits from pulsed-tES, yet behavior is not modulated periodically. Thus, pulsed-tES can aid cortical entrainment to speech input, which is especially relevant in a noisy environment. Yet, pulsed-tES does not seem to entrain brain oscillations by itself.

Inconsistent effects of stochastic resonance on human auditory processing.

It has been demonstrated that, while otherwise detrimental, noise can improve sensory perception under optimal conditions. The mechanism underlying this improvement is stochastic resonance. An inverted U-shaped relationship between noise level and task performance is considered as the signature of stochastic resonance. Previous studies have proposed the existence of stochastic resonance also in the human auditory system. However, the reported beneficial effects of noise are small, based on a small sample, and do not confirm the proposed inverted U-shaped function. Here, we investigated in two separate studies whether stochastic resonance may be present in the human auditory system by applying noise of different levels, either acoustically or electrically via transcranial random noise stimulation, while participants had to detect acoustic stimuli adjusted to their individual hearing threshold. We find no evidence for behaviorally relevant effects of stochastic resonance. Although detection rate for near-threshold acoustic stimuli appears to vary in an inverted U-shaped manner for some subjects, it varies in a U-shaped manner or in other manners for other subjects. Our results show that subjects do not benefit from noise, irrespective of its modality. In conclusion, our results question the existence of stochastic resonance in the human auditory system.

Transcranial Static Magnetic Field Stimulation Over the Temporal Cortex Modulating the Right Ear Advantage in Dichotic Listening.

OBJECTIVE: Transcranial static magnetic field stimulation (tSMS) has proposed a new, promising, and simple non-invasive brain stimulation method. While several studies gained certain evidence about tSMS effects in the motor, somatosensory, and visual domains, there is still a controversial debate about its general effectiveness. In the present study, we investigated potential tSMS effects on auditory speech processing as measured by a dichotic listening (DL) task. MATERIALS AND METHODS: Fifteen healthy participants received in randomized order on three different days one session of either sham, tSMS over the left, or tSMS over the right auditory cortex (AC). Under stimulation, participants performed a standard DL task with consonant-vowel syllables. Simultaneously, we recorded electroencephalogram from central sites (Fz, Cz, Pz). RESULTS: TSMS over the left AC changed the behavioral performance and modulated auditory evoked potentials. Stimulation of the left AC significantly reduced the right ear advantage during the DL task and the N1 component of auditory evoked potentials in response to these syllables. CONCLUSIONS: The preliminary results of the present exploratory study demonstrate the ability of tSMS to modulate human brain activity on a behavioral as well as physiologic level. Furthermore, tSMS effects on acoustic processing may have clinical implications by fostering potential approaches for a treatment of speech-related pathologies associated with hyperexcitability in the AC.

No modulation of pupil size and event-related pupil response by transcutaneous auricular vagus nerve stimulation (taVNS).

Transcutaneous auricular vagus nerve stimulation (taVNS) bears therapeutic potential for a wide range of medical conditions. However, previous studies have found substantial interindividual variability in responsiveness to taVNS, and no reliable predictive biomarker for stimulation success has been developed so far. In this study, we investigate pupil size and event-related pupil response as candidate biomarkers. Both measures have a direct physiological link to the activity of the locus coeruleus (LC), a brainstem structure and the main source of norepinephrine in the brain. LC activation is considered one of the key mechanisms of action of taVNS, therefore, we expected a clear increase of the pupillary measures under taVNS compared to sham (placebo) stimulation, such that it could serve as a prospective predictor for individual clinical and physiological taVNS effects in future studies. We studied resting pupil size and pupillary responses to target stimuli in an auditory oddball task in 33 healthy young volunteers. We observed stronger pupil responses to target than to standard stimuli. However, and contrary to our hypothesis, neither pupil size nor the event-related pupil response nor behavioral performance were modulated by taVNS. We discuss potential explanations for this negative finding and its implications for future clinical investigation and development of taVNS.

Transcranial electrical stimulation improves phoneme processing in developmental dyslexia.

BACKGROUND: About 10% of the western population suffers from a specific disability in the acquisition of reading and writing skills, known as developmental dyslexia (DD). Even though DD starts in childhood it frequently continuous throughout lifetime. Impaired processing of acoustic features at the phonematic scale based on dysfunctional auditory temporal resolution is considered as one core deficit underlying DD. Recently, the efficacy of transcranial electrical stimulation (tES) to modulate auditory temporal resolution and phoneme processing in healthy individuals has been demonstrated. OBJECTIVE: The present work aims to investigate online effects of tES on phoneme processing in individuals with DD. METHOD: Using an established phoneme-categorization task, we assessed the immediate behavioral and electrophysiological effects of transcranial alternating current stimulation (tACS) and transcranial random noise stimulation (tRNS) over bilateral auditory cortex in children and adolescents with DD (study 1) and adults with DD (study 2) on auditory phoneme processing acuity. RESULTS: Our data revealed that tACS improved phoneme categorization in children and adolescents with DD, an effect that was paralleled by an increase in evoked brain response patterns representing low-level sensory processing. In the adult sample we replicated these findings and additionally showed a more pronounced impact of tRNS on phoneme-categorization acuity. CONCLUSION: These results provide compelling evidence for the potential of both tACS and tRNS to increase temporal precision of the auditory system in DD and suggest transcranial electrical stimulation as potential intervention in DD to foster the effect of standard phonology-based training.

Modulating auditory selective attention by non-invasive brain stimulation: Differential effects of transcutaneous vagal nerve stimulation and transcranial random noise stimulation.

Selective attention is a basic process required to maintain goal-directed behavior by appropriately responding to target stimuli and suppressing reactions to non-target stimuli. It has been proposed that auditory selective attention is linked to the activity of the locus coeruleus-norepinergic (LC-NE) system and a large-scale fronto-parietal cortical network, but there is still sparse causal evidence for these assumptions. By applying transcutaneous vagal nerve stimulation (tVNS) and transcranial random noise stimulation (tRNS) over the frontal cortex, we systematically assessed the involvement of these subcortical and cortical components in the regulation of auditory selective attention. Using a single-blinded, sham-controlled, within-subject design we analyzed online effects of tVNS and tRNS in 20 healthy participants during an auditory oddball paradigm. We show significant stimulation-dependent modulations of auditory selective attention on the behavioral and electrophysiological level. Compared to sham, tVNS increased the P3 amplitude, while tRNS reduced the reaction time to target stimuli. Moreover, both techniques reduced the P3 latency. Our data provide evidence for the functional relevance of the subcortical NE system in the regulation of neural resources that allows a phasic response to incoming target stimuli. They indicate that frontal cortex structures are crucially involved in the successful evaluation of the respective information. Moreover, our results are in favor of the LC-P3 hypothesis claiming the vital role of the NE system in auditory selective attention and in the generation of the P3. Of note, the effects of tVNS on auditory selective attention are comparable with those evoked by pharmacological interventions and invasive vagal nerve stimulation.

Behavioral and electrophysiological evidence for GABAergic modulation through transcutaneous vagus nerve stimulation.

OBJECTIVE: Transcutaneous vagus nerve stimulation (tVNS) has been hypothesized to modulate γ-aminobutyric (GABA) transmission in the human brain. GABA in the motor cortex is highly correlated to measures of automatic motor inhibition that can be obtained in simple response priming paradigms. To test the effects of tVNS on GABA transmission, we measured tVNS-induced alterations in behavioral and electrophysiology during automatic motor inhibition. METHODS: Participants were 16 young, healthy adults (8 female). We combined a subliminal response priming paradigm with tVNS and EEG measurement. In this paradigm, automatic motor inhibition leads to a reversal of the priming effect, a phenomenon referred to as the negative compatibility effect (NCE). We compute the NCE separated by response hands, hypothesizing a modulation of the left-hand NCE. Using EEG we measured readiness potentials, an established electrophysiological index of cortical motor preparation. RESULTS: As hypothesized, for the ipsilateral hand/contralateral hemisphere, compared to sham stimulation, tVNS increased the NCE and modulated the electrophysiological readiness potentials. CONCLUSION: Our results indicate that tVNS is selectively affecting the GABAergic system in the motor system contralateral to the stimulated ear as reflected in a behavioral and electrophysiological modulation. SIGNIFICANCE: We provide first combined behavioral and electrophysiological evidence for direct GABAergic neuromodulation through tVNS.

Thalamic interictal epileptiform discharges in deep brain stimulated epilepsy patients.

The relationships between interictal epileptiform discharges (IEDs) in the anterior (ANT) and dorsomedial nuclei (DMNT) of the thalamus and electro-clinical parameters in pharmacoresistant focal epilepsy patients receiving intrathalamic electrodes for deep brain stimulation (DBS) were investigated. Thalamus-localized IEDs (LIEDs) and surface EEG (sEEG)-IEDs were evaluated in eight patients who underwent ANT-DBS. Occurrence and frequency of ANT- and DMNT-LIEDs and pre-operative sEEG-IEDs were examined with respect to seizure onset location and seizure outcome following ANT-DBS. LIEDs were identified in all eight patients, in the ANT, DMNT, or both. ANT-LIEDs were observed in all patients with an unequivocal temporal seizure onset zone. The ANT-LIED frequency correlated with pre-surgical sEEG-IED frequency (ρ = 0.76, p = 0.033) and predicted ANT-DBS responsiveness (T = -2.6; p = 0.0428). Of the five patients with bilateral sEEG-IEDs, all had ANT-LIEDs, but only one patient had DMNT-LIEDs. All patients with no or unilateral sEEG-IEDs had DMNT-LIEDs. Observation of LIEDS in the ANT and DMNT supports the hypothesis that these nuclei are involved in propagation of focal epileptic activity. Their correspondence with differing electro-clinical features suggests that these nuclei are functionally distinguishable nodes within the epileptic networks of individual patients.

Changed categorical perception of consonant-vowel syllables induced by transcranial direct current stimulation (tDCS).

BACKGROUND: Speech-related disorders may refer to impairment of temporal analysis in the human auditory system. By the advance of non-invasive brain stimulation new forms of therapy arise. In the present study, we examined the neuromodulatory effect of auditory tDCS on the perception of temporal modulated speech syllables. In three experimental sessions we assessed phonetic categorization of consonant-vowels (CV)-syllables (/da/,/ta/) with varying voice onset times (VOT) during sham, anodal, and cathodal tDCS delivered bilateral to the auditory cortex (AC). Subsequently, we recorded auditory evoked potentials (AEP) in response to voiced (/ba/,/da/,/ga/) and voiceless (/pa/,/ta/,/ka/) CV-syllables. RESULTS: In result, we demonstrate that bilateral tDCS of the AC can modulate CV-syllable perception. Behaviorally, cathodal tDCS improved phonetic categorization abilities in a VOT continuum accompanied by an elevation of the P50 amplitude of the AEP to CV-syllables during the anodal tDCS after effect. CONCLUSIONS: The present study demonstrates the ability of bilateral tDCS over the AC to ameliorate speech perception. The results may have clinical implications by fostering potential approaches for a treatment of speech-related pathologies with a deficit of temporal processing.

40Hz-Transcranial alternating current stimulation (tACS) selectively modulates speech perception.

The present study investigated the functional relevance of gamma oscillations for the processing of rapidly changing acoustic features in speech signals. For this purpose we analyzed repetition-induced perceptual learning effects in 18 healthy adult participants. The participants received either 6Hz or 40Hz tACS over the bilateral auditory cortex, while repeatedly performing a phoneme categorization task. In result, we found that 40Hz tACS led to a specific alteration in repetition-induced perceptual learning. While participants in the non-stimulated control group as well as those in the experimental group receiving 6Hz tACS considerably improved their perceptual performance, the application of 40Hz tACS selectively attenuated the repetition-induced improvement in phoneme categorization abilities. Our data provide causal evidence for a functional relevance of gamma oscillations during the perceptual learning of acoustic speech features. Moreover, we demonstrate that even less than twenty minutes of alternating current stimulation below the individual perceptual threshold is sufficient to affect speech perception. This finding is relevant in that this novel approach might have implications with respect to impaired speech processing in dyslexics and older adults.

Sensory Deviancy Detection Measured Directly Within the Human Nucleus Accumbens.

Rapid changes in the environment evoke a comparison between expectancy and actual outcome to inform optimal subsequent behavior. The nucleus accumbens (NAcc), a key interface between the hippocampus and neocortical regions, is a candidate region for mediating this comparison. Here, we report event-related potentials obtained from the NAcc using direct intracranial recordings in 5 human participants while they listened to trains of auditory stimuli differing in their degree of deviation from repetitive background stimuli. NAcc recordings revealed an early mismatch signal (50-220 ms) in response to all deviants. NAcc activity in this time window was also sensitive to the statistics of stimulus deviancy, with larger amplitudes as a function of the level of deviancy. Importantly, this NAcc mismatch signal also predicted generation of longer latency scalp potentials (300-400 ms). The results provide direct human evidence that the NAcc is a key component of a network engaged in encoding statistics of the sensory environmental.