Fatigue is one of the most common and debilitating symptoms affecting patients with multiple sclerosis (MS). Sustained cognitive effort induces cognitive fatigue, operationalized as subjective exhaustion and fatigue-related objective alertness decrements with time-on-task. During prolonged cognitive testing, MS patients show increased simple reaction times (RT) accompanied by lower amplitudes and prolonged latencies of the P300 event-related potential. Previous studies suggested a major role of structural and functional abnormalities in the frontal cortex including a frontal hypo-activation in fatigue pathogenesis. In the present study we investigated the neuromodulatory effect of transcranial direct current stimulation (tDCS) over the left dorsolateral prefrontal cortex (DLPFC) on objective measures of fatigue-related decrements in cognitive performance in MS patients. P300 during an auditory oddball task and simple reaction times in an alertness test were recorded at baseline, during and after stimulation. Compared to sham, anodal tDCS caused an increase in P300 amplitude that persisted after the end of stimulation and eliminated the fatigue-related increase in RT over the course of a testing session. Our findings demonstrate that anodal tDCS over the left DLPFC can counteract performance decrements associated with fatigue thereby leading to an improvement in the patient's ability to cope with sustained cognitive demands. This provides causal evidence for the functional relevance of the left DLPFC in fatigue pathophysiology. The results indicate that tDCS-induced modulations of frontal activity can be an effective therapeutic option for the treatment of fatigue-related declines in cognitive performance in MS patients.

Cognitive fatigue is one of the most frequent symptoms in multiple sclerosis (MS), associated with significant impairment in daily functioning and quality of life. Despite its clinical significance, progress in understanding and treating fatigue is still limited. This limitation is already caused by an inconsistent and heterogeneous terminology and assessment of fatigue. In this review, we integrate previous literature on fatigue and propose a unified schema aiming to clarify the fatigue taxonomy. With special focus on cognitive fatigue, we survey the significance of objective behavioral and electrophysiological fatigue parameters and discuss the controversial literature on the relationship between subjective and objective fatigue assessment. As MS-related cognitive fatigue drastically affects quality of life, the development of efficient therapeutic approaches for overcoming cognitive fatigue is of high clinical relevance. In this regard, the reliable and valid assessment of the individual fatigue level by objective parameters is essential for systematic treatment evaluation and optimization. Transcranial electrical stimulation (tES) may offer a unique opportunity to manipulate maladaptive neural activity underlying MS fatigue. Therefore, we discuss evidence for the therapeutic potential of tES on cognitive fatigue in people with MS.

Background: Oscillatory phase has been proposed as a key parameter defining the spatiotemporal structure of neural activity. To enhance our understanding of brain rhythms and improve clinical outcomes in pathological conditions, modulation of neural activity by transcranial alternating current stimulation (tACS) emerged as a promising approach. However, the phase-specificity of tACS effects in humans is still critically debated. Objective: Here, we investigated the phase-specificity of tACS on visually evoked steady state responses (SSRs) in 24 healthy human participants. Methods: We used an intermittent electrical stimulation protocol and assessed the influence of tACS on SSR amplitude in the interval immediately following tACS. A neural network model served to validate the plausibility of experimental findings. Results: We observed a modulation of SSR amplitudes dependent on the phase shift between flicker and tACS. The tACS effect size was negatively correlated with the strength of flicker-evoked activity. Supported by simulations, data suggest that strong network synchronization limits further neuromodulation by tACS. Neural sources of phase-specific effects were localized in the parieto-occipital cortex within flicker-entrained regions. Importantly, the optimal phase shift between flicker and tACS associated with strongest SSRs was correlated with SSR phase delays in the tACS target region. Conclusions: Overall, our data provide electrophysiological evidence for phase-specific modulations of rhythmic brain activity by tACS in humans. As the optimal timing of tACS application was dependent on cortical SSR phase delays, our data suggest that tACS effects were not mediated by retinal co-stimulation. These findings highlight the potential of tACS for controlled, phase-specific modulations of neural activity.

Transcranial electrical stimulation (tES) has become a valuable research tool for the investigation of neurophysiological processes underlying human action and cognition. In recent years, striking evidence for the neuromodulatory effects of transcranial direct current stimulation, transcranial alternating current stimulation, and transcranial random noise stimulation has emerged. While the wealth of knowledge has been gained about tES in the motor domain and, to a lesser extent, about its ability to modulate human cognition, surprisingly little is known about its impact on perceptual processing, particularly in the auditory domain. Moreover, while only a few studies systematically investigated the impact of auditory tES, it has already been applied in a large number of clinical trials, leading to a remarkable imbalance between basic and clinical research on auditory tES. Here, we review the state of the art of tES application in the auditory domain focussing on the impact of neuromodulation on acoustic perception and its potential for clinical application in the treatment of auditory related disorders.

Zur Sicherung valider Testprofile in der neuropsychologischen Begutachtung ist die Beurteilung der Plausibilität vorgebrachter Defizite unerlässlich. In der vorliegenden Studie wurde die Sensibilität für Täuschungsverhalten des Alertness-Tests der Testbatterie zur Aufmerksamkeitsprüfung (TAP) untersucht. Der Vergleich der Testleistungen von 17 Probanden unter (i) normaler Anstrengungsbereitschaft, (ii) Simulationsvorsatz und (iii) Simulation mit vorheriger Information über glaubhafte Täuschungsstrategien zeigte, dass informierte Probanden geringere Reaktionszeiten und Standardabweichungen als unter der naiven Simulationsbedingung aufweisen, aber weiterhin langsamere und inkonsistentere Reaktionen als unter optimaler Anstrengungsbereitschaft zeigen. Selbst unter willentlicher Anstrengung waren sie nicht fähig, normgerechte Standardabweichungen ihrer simulierten Minderleistung zu erreichen. Demnach deuten konstante Reaktionszeiten auf authentisches Leistungsverhalten hin. Im Vergleich zu Testdaten von Patienten zeigte sich, dass die Simulationsabsicht informierter Probanden mittels einzelner Testparameter nicht identifiziert werden kann. Unter Berücksichtigung mehrerer Testparameter ist es allerdings auch bei Kenntnis glaubhafter Täuschungsstrategien möglich, eine valide Beurteilung der Plausibilität der individuellen Leistung zu gewährleisten.

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Oscillatory phase has been proposed as key parameter defining the spatiotemporal structure of neural activity. Phase alignment of oscillations by transcranial alternating current stimulation (tACS) may offer a unique opportunity to enhance our understanding of brain rhythms and to alter brain function. However, the precise mechanism and effectiveness of tACS are still critically debated. Here, we investigated the phase-specificity of tACS effects on visually evoked steady state responses (SSR) measured by electroencephalography (EEG). Using an intermittent electrical stimulation protocol, we assessed the influence of tACS on SSR amplitude as a function of phase shift between rhythmic sensory and electrical stimulation in the interval immediately following tACS. Visual flicker was delivered at six different phase angles relative to the tACS cycle. Participants were presented with flicker and high-definition tACS over the occipital cortex at 10 Hz in two sessions using active or sham stimulation. We observed that the phase shift between flicker and tACS modulates evoked SSR amplitudes. The amplitude change over phase shift conditions was significant for both general and sinusoidal modulation measures. Neural sources of phase-specific effects were localized in the parietooccipital cortex within flicker-aligned regions. Importantly, tACS effects were stronger in subjects with lower phase locking between EEG and flicker. Overall, our data provide evidence for phase alignment of brain activity by tACS, since the change in SSR amplitude can only result from phase-specific interactions with the applied electric fields. This finding corroborates the physiological efficacy of tACS and highlights its potential for controlled modulation of brain signals. Keywordstranscranial alternating current stimulation (tACS), EEG, phase, alpha oscillations, visual flicker Significance StatementThe lacking proof of phase-specific effects of transcranial alternating current stimulation (tACS) on neural activity in humans still restricts its potential to advance knowledge on the functional significance of brain oscillations. We show that the phase shift between concurrent 10 Hz tACS and precisely controlled oscillatory activity via visual flicker modulated the amplitude of evoked neural oscillations. Interindividual differences in tACS effect size were dependent on the current brain state. Our findings provide electrophysiological evidence for the capability of tACS to phase-align intrinsic neural activity. These mechanistic insights emphasize the value of tACS to advance research on the causal role of brain rhythms and offer important implications for the treatment of disturbed oscillatory patterns and cortical connectivity in brain disorders.

No abstract