Neurocognitive, physiological, and biophysical effects of transcranial alternating current stimulation

Abstract

Transcranial alternating current stimulation (tACS) can modulate human neural activity and behavior. Accordingly, tACS has vast potential for cognitive research and brain disorder therapies. The stimulation generates oscillating electric fields in the brain that can bias neural spike timing, causing changes in local neural oscillatory power and cross-frequency and cross-area coherence. tACS affects cognitive performance by modulating underlying single or nested brain rhythms, local or distal synchronization, and metabolic activity. Clinically, stimulation tailored to abnormal neural oscillations shows promising results in alleviating psychiatric and neurological symptoms. We summarize the findings of tACS mechanisms, its use for cognitive applications, and novel developments for personalized stimulation.

Keywords: cognitive performance; neural oscillations; neuromodulation; non-invasive brain stimulation; transcranial alternating current stimulation; transcranial brain stimulation.

Figure 1.. Biophysics of transcranial alternating current stimulation (tACS).

[Top left] During tACS, an alternating current (AC) is applied between two or more electrodes placed on the scalp. Current flows between electrodes of opposing phase (indicated here with red and blue). The sum of electric currents at all stimulation electrodes needs to be zero (Kirchhoff’s circuit rule). For multi-electrode montages, the stimulation intensity per electrode should be adjusted accordingly. AC passes through the scalp, skull, and cerebrospinal fluid and penetrates the brain. [Bottom left] The resulting electric current in the head depends on the stimulation “montage” (electrode locations and current intensity per electrode) and the conductivity of the biological tissues. Due to the low conductivity of the skull, shunting in the scalp can occur if electrodes are placed too close to each other (approx. <3 cm), resulting in close-to-zero electric field intensity in the brain [149]. While we can control the montage, conductivity is a biophysical property. It is noteworthy that conductivity values differ between individuals, meaning that computational modeling of electric field intensities should be viewed as an estimate [143,144]. [Top right] The AC creates an electric field (in mV/mm), which is the acting force (i.e., “dose”) of neuromodulation. Electric fields generally become weaker in deeper cortical structures. [Bottom right] When the electric field strength in the brain is sufficient, it biases the timing of neural action potentials (i.e., neural spikes) [2,3]. The total spike count per time most often remains constant at effective doses reached in human research, namely, ~0.3 to ~1 mV/mm, corresponding to a total external current intensity of 1 to 4 mA.

Figure 2.. Physiological mechanisms of action.

TACS electric fields in the brain can affect information flow, and thus cognition, through various neural mechanisms. [Left] Reaching sufficient electric field strength is crucial for a successful intervention. A recent meta-analysis [28] on awake rodent and non-human primate data has shown that a dose of ~0.3 mV/mm has an 80% probability to modulate brain activity. A 95% probability corresponds to ~0.4 mV/mm across the whole region of interest. These levels form an estimate of the minimum effective dose of tACS. [Middle] With sufficient dosage, tACS can affect brain physiology in three ways: First, tACS can modulate neural spike-timing, causing biased neural spiking and local neural entrainment [2,3]. This effect primarily occurs online, during the stimulation. Second, tACS can induce NMDA-mediated synaptic plasticity with long-lasting effects [53]. Third, tACS over two or more regions can strengthen or weaken long-range connectivity by synchronizing affected areas to the same or different AC phases [6,60,107]. Multiple mechanisms can be engaged at the same time. [Right] By modulating oscillations, tACS can affect the brain’s communication through coherence [58]. That is, tACS can synchronize the time windows of neural depolarization when cells are more likely to generate action potentials, promoting information flow. Specifically, the effects of tACS on neural entrainment and synaptic plasticity can promote communication within local networks and regional task-related processes. Enhancing long-range connectivity through phase-dependent tACS can strengthen communication between distant networks and task-specific network activity. Choices of tACS parameters (electrode locations, waveforms, dose) and concurrent brain state influence the involvement of different mechanisms, which will determine effects on cognition and behavior.

Figure 3.. Effects of tACS on cognitive performance.

How tACS modulates behavior depends on the stimulation parameters, target brain area, and cognitive domain. Here, we present four non-mutually exclusive hypotheses on tACS mechanisms. [Left upper] Certain cognitive domains underlie a trade-off between competing processes, e.g., speed vs. accuracy or stability vs. flexibility in decision making [4,93]. If distinct neural oscillatory generators drive these competing processes, single-frequency tACS may improve one dimension and shift the balance between them. [Right upper] Phase-amplitude coupling or nesting of multiple oscillations reflects the integration of global and local processes in brain networks [102,103]. Canonically, high-frequency oscillations characterize local information processing, whereas low-frequency oscillations involve inter-regional communication. Cross-frequency tACS can modulate nested oscillatory activity towards an optimal ratio, which improves cognitive performance [5,7,66]. [Left lower] Long-range synchronization is crucial for information exchange between distal brain regions. Hypo- or hyper-synchronization yields suboptimal behavioral performance. Multi-area tACS can modulate the phase of several oscillatory generators, driving them in-phase, anti-phase, or with a phase shift [6,60,107]. [Right lower] Enhanced brain activity can demand higher metabolic activity, including glucose and oxygen uptake. Early-stage evidence suggests that tACS may affect metabolic activity [112,113]. As such, changes in metabolic rate through tACS could drive cognitive performance.