Double-blind, randomized pilot clinical trial targeting alpha oscillations with transcranial alternating current stimulation (tACS) for the treatment of major depressive disorder (MDD).

Major depressive disorder (MDD) is one of the most common psychiatric disorders, but pharmacological treatments are ineffective in a substantial fraction of patients and are accompanied by unwanted side effects. Here we evaluated the feasibility and efficacy of transcranial alternating current stimulation (tACS) at 10 Hz, which we hypothesized would improve clinical symptoms by renormalizing alpha oscillations in the left dorsolateral prefrontal cortex (dlPFC). To this end, 32 participants with MDD were randomized to 1 of 3 arms and received daily 40 min sessions of either 10 Hz-tACS, 40 Hz-tACS, or active sham stimulation for 5 consecutive days. Symptom improvement was assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS) as the primary outcome. High-density electroencephalograms (hdEEGs) were recorded to measure changes in alpha oscillations as the secondary outcome. For the primary outcome, we did not observe a significant interaction between treatment condition (10 Hz-tACS, 40 Hz-tACS, sham) and session (baseline to 4 weeks after completion of treatment); however, exploratory analyses show that 2 weeks after completion of the intervention, the 10 Hz-tACS group had more responders (MADRS and HDRS) compared with 40 Hz-tACS and sham groups (n = 30, p = 0.026). Concurrently, we found a significant reduction in alpha power over the left frontal regions in EEG after completion of the intervention for the group that received per-protocol 10 Hz-tACS (n = 26, p < 0.05). Our data suggest that targeting oscillations with tACS has potential as a therapeutic intervention for treatment of MDD.

Targeting reduced neural oscillations in patients with schizophrenia by transcranial alternating current stimulation.

Transcranial alternating current stimulation (tACS) modulates endogenous neural oscillations in healthy human participants by the application of a low-amplitude electrical current with a periodic stimulation waveform. Yet, it is unclear if tACS can modulate and restore neural oscillations that are reduced in patients with psychiatric illnesses such as schizophrenia. Here, we asked if tACS modulates network oscillations in schizophrenia. We performed a randomized, double-blind, sham-controlled clinical trial to contrast tACS with transcranial direct current stimulation (tDCS) and sham stimulation in 22 schizophrenia patients with auditory hallucinations. We used high-density electroencephalography to investigate if a five-day, twice-daily 10Hz-tACS protocol enhances alpha oscillations and modulates network dynamics that are reduced in schizophrenia. We found that 10Hz-tACS enhanced alpha oscillations and modulated functional connectivity in the alpha frequency band. In addition, 10Hz-tACS enhanced the 40Hz auditory steady-state response (ASSR), which is reduced in patients with schizophrenia. Importantly, clinical improvement of auditory hallucinations correlated with enhancement of alpha oscillations and the 40Hz-ASSR. Together, our findings suggest that tACS has potential as a network-level approach to modulate reduced neural oscillations related to clinical symptoms in patients with schizophrenia.

Randomized trial of transcranial alternating current stimulation for treatment of auditory hallucinations in schizophrenia.

BACKGROUND: Approximately 30% of patients with schizophrenia experience auditory hallucinations that are refractory to antipsychotic medications. Here, we evaluated the feasibility and efficacy of transcranial alternating current stimulation (tACS) that we hypothesized would improve auditory hallucination symptoms by enhancing synchronization between the frontal and temporo-parietal areas of the left hemisphere. METHOD: 22 participants were randomized to one of three arms and received twice daily, 20 min sessions of sham, 10 Hz 2 mA peak-to-peak tACS, or 2 mA tDCS over the course of 5 consecutive days. Symptom improvement was assessed using the Auditory Hallucination Rating Scale (AHRS) as the primary outcome measure. The Positive and Negative Syndrome Scale (PANSS) and the Brief Assessment of Cognition in Schizophrenia (BACS) were secondary outcomes. RESULTS: Primary and secondary behavioral outcomes were not significantly different between the three arms. However, effect size analyses show that tACS had the greatest effect based on the auditory hallucinations scale for the week of stimulation (1.31 for tACS; 1.06 and 0.17, for sham and tDCS, respectively). Effect size analysis for the secondary outcomes revealed heterogeneous results across measures and stimulation conditions. CONCLUSIONS: To our knowledge, this is the first clinical trial of tACS for the treatment of symptoms of a psychiatric condition. Further studies with larger sample sizes are needed to better understand the effect of tACS on auditory hallucinations.

Feedback-Controlled Transcranial Alternating Current Stimulation Reveals a Functional Role of Sleep Spindles in Motor Memory Consolidation.

Transient episodes of brain oscillations are a common feature of both the waking and the sleeping brain. Sleep spindles represent a prominent example of a poorly understood transient brain oscillation that is impaired in disorders such as Alzheimer's disease and schizophrenia. However, the causal role of these bouts of thalamo-cortical oscillations remains unknown. Demonstrating a functional role of sleep spindles in cognitive processes has, so far, been hindered by the lack of a tool to target transient brain oscillations in real time. Here, we show, for the first time, selective enhancement of sleep spindles with non-invasive brain stimulation in humans. We developed a system that detects sleep spindles in real time and applies oscillatory stimulation. Our stimulation selectively enhanced spindle activity as determined by increased sigma activity after transcranial alternating current stimulation (tACS) application. This targeted modulation caused significant enhancement of motor memory consolidation that correlated with the stimulation-induced change in fast spindle activity. Strikingly, we found a similar correlation between motor memory and spindle characteristics during the sham night for the same spindle frequencies and electrode locations. Therefore, our results directly demonstrate a functional relationship between oscillatory spindle activity and cognition.

Transcranial direct current stimulation (tDCS) of frontal cortex decreases performance on the WAIS-IV intelligence test.

Transcranial direct current stimulation (tDCS) modulates excitability of motor cortex. However, there is conflicting evidence about the efficacy of this non-invasive brain stimulation modality to modulate performance on cognitive tasks. Previous work has tested the effect of tDCS on specific facets of cognition and executive processing. However, no randomized, double-blind, sham-controlled study has looked at the effects of tDCS on a comprehensive battery of cognitive processes. The objective of this study was to test if tDCS had an effect on performance on a comprehensive assay of cognitive processes, a standardized intelligence quotient (IQ) test. The study consisted of two substudies and followed a double-blind, between-subjects, sham-controlled design. In total, 41 healthy adult participants were included in the final analysis. These participants completed the Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV) as a baseline measure. At least one week later, participants in substudy 1 received either bilateral tDCS (anodes over both F4 and F3, cathode over Cz, 2 mA at each anode for 20 min) or active sham tDCS (2 mA for 40 s), and participants in substudy 2 received either right or left tDCS (anode over either F4 or F3, cathode over Cz, 2 mA for 20 min). In both studies, the WAIS-IV was immediately administered following stimulation to assess for performance differences induced by bilateral and unilateral tDCS. Compared to sham stimulation, right, left, and bilateral tDCS reduced improvement between sessions on Full Scale IQ and the Perceptual Reasoning Index. This demonstration that frontal tDCS selectively degraded improvement on specific metrics of the WAIS-IV raises important questions about the often proposed role of tDCS in cognitive enhancement.

Functional role of frontal alpha oscillations in creativity.

Creativity, the ability to produce innovative ideas, is a key higher-order cognitive function that is poorly understood. At the level of macroscopic cortical network dynamics, recent electroencephalography (EEG) data suggests that cortical oscillations in the alpha frequency band (8-12 Hz) are correlated with creative thinking. However, whether alpha oscillations play a functional role in creativity has remained unknown. Here we show that creativity is increased by enhancing alpha power using 10 Hz transcranial alternating current stimulation (10 Hz-tACS) of the frontal cortex. In a study of 20 healthy participants with a randomized, balanced cross-over design, we found a significant improvement of 7.4% in the Creativity Index measured by the Torrance Test of Creative Thinking (TTCT), a comprehensive and most frequently used assay of creative potential and strengths. In a second similar study with 20 subjects, 40 Hz-tACS was used instead of 10 Hz-tACS to rule out a general "electrical stimulation" effect. No significant change in the Creativity Index was found for such frontal 40 Hz stimulation. Our results suggest that alpha activity in frontal brain areas is selectively involved in creativity; this enhancement represents the first demonstration of specific neuronal dynamics that drive creativity and can be modulated by non-invasive brain stimulation. Our findings agree with the model that alpha recruitment increases with internal processing demands and is involved in inhibitory top-down control, which is an important requirement for creative ideation.