Non-invasive brain stimulation (NIBS) has been gaining increased popularity in human neuroscience research during the last years. Among the emerging NIBS tools is transcranial electrical stimulation (tES), whose main modalities are transcranial direct, and alternating current stimulation (tDCS, tACS). In tES, a small current (usually less than 3mA) is delivered through the scalp. Depending on its shape, density, and duration, the applied current induces acute or long-lasting effects on excitability and activity of cerebral regions, and brain networks. tES is increasingly applied in different domains to (a) explore human brain physiology with regard to plasticity, and brain oscillations, (b) explore the impact of brain physiology on cognitive processes, and (c) treat clinical symptoms in neurological and psychiatric diseases. In this review, we give a broad overview of the main mechanisms and applications of these brain stimulation tools.

Neural oscillations in the cerebral cortex are associated with a range of cognitive processes and neuropsychiatric disorders. However, non-invasively modulating oscillatory activity remains technically challenging, due to limited strength, duration, or non-synchronization of stimulation waveforms with endogenous rhythms. We hypothesized that applying controllable phase-synchronized repetitive transcranial magnetic stimulation pulses (rTMS) with alternating currents (tACS) may induce and stabilize neuro-oscillatory resting-state activity at targeted frequencies. Using a novel circuit to precisely synchronize rTMS pulses with phase of tACS, we empirically tested whether combined, 10-Hz prefrontal bilateral stimulation could induce and stabilize 10-Hz oscillations in the bilateral prefrontal cortex (PFC). 25 healthy participants took part in a repeated-measures design. Whole-brain resting-state EEG in eyes-open (EO) and eyes-closed (EC) was recorded before (baseline), immediately (1-min), and 15- and 30-min after stimulation. Bilateral, phase-synchronized rTMS aligned to the positive tACS peak was compared with rTMS at tACS trough, with bilateral tACS or rTMS on its own, and to sham. 10-Hz resting-state PFC power increased significantly with peak-synchronized rTMS + tACS (EO: 44.64%, EC: 46.30%, p < 0.05) compared to each stimulation protocol on its own, and sham, with effects spanning between prefrontal and parietal regions and sustaining throughout 30-min. No effects were observed with the sham protocol. Moreover, rTMS timed to the negative tACS trough did not induce local or global changes in oscillations. Phase-synchronizing rTMS with tACS may be a viable approach for inducing and stabilizing neuro-oscillatory activity, particularly in scenarios where endogenous oscillatory tone is attenuated, such as disorders of consciousness or major depression.

During recent years, non-invasive brain stimulation, including transcranial electrical stimulation (tES) in general, and transcranial direct current stimulation (tDCS) in particular, have created new hopes for treatment of neurological and psychiatric diseases. Despite promising primary results in some brain disorders, a more widespread application of tES is hindered by the unsolved question of determining optimum stimulation protocols to receive meaningful therapeutic effects. tES has a large parameter space including various montages and stimulation parameters. Moreover, inter- and intra-individual differences in responding to stimulation protocols have to be taken into account. These factors contribute to the complexity of selecting potentially effective protocols for each disorder, different clusters of each disorder, and even each single patient. Expanding knowledge in different dimensions of basic and clinical neuroscience could help researchers and clinicians to select potentially effective protocols based on tES modulatory mechanisms for future clinical studies. In this paper, we propose a heuristic spatiomechanistic framework which contains nine levels to address tES effects on brain functions. Three levels refer to the spatial resolution (local, small-scale networks, and large-scale networks) and three levels of tES modulatory effects based on its mechanisms of action (neurochemical, neuroelectrical, and oscillatory modulations). At the group level, this framework could be helpful to enable an informed and systematic exploration of various possible protocols for targeting a brain disorder or its neuroscience-based clusters. Considering recent advances in exploration of neurodiversity at the individual level with different brain mapping technologies, the proposed framework might also be used in combination with personal data to design individualized protocols for tES in the context of precision medicine in the future.

Fear extinction is a fundamental component of exposure-based therapies for anxiety-related disorders. The renewal of fear in a different context after extinction highlights the importance of contextual factors. In this study, we aimed to investigate the causal role of the left inferior frontal gyrus (LiFG) in the context-dependency of fear extinction learning via administration of transcranial direct current stimulation (tDCS) over this area. 180 healthy subjects were assigned to 9 groups: 3 tDCS conditions (anodal, cathodal, and sham) × 3 context combinations (AAA, ABA, and ABB). The fear conditioning/extinction task was conducted over three consecutive days: acquisition, extinction learning, and extinction recall. tDCS (2mA, 10min) was administered during the extinction learning phase over the LiFG via a 4-electrode montage. Skin conductance response (SCR) data and self-report assessments were collected. During the extinction learning phase, groups with excitability-enhancing anodal tDCS showed a significantly higher fear response to the threat cues compared to cathodal and sham stimulation conditions, irrespective of contextual factors. This effect was stable until the extinction recall phase. Additionally, excitability-reducing cathodal tDCS caused a significant decrease of the response difference between the threat and safety cues during the extinction recall phase. The self-report assessments showed no significant differences between the conditions throughout the experiment. Independent of the context, excitability enhancement of the LiFG did impair fear extinction, and led to preservation of fear memory. In contrast, excitability reduction of this area enhanced fear extinction retention. These findings imply that the LiFG plays a role in the fear extinction network, which seems to be however context-independent.

Fear extinction is the foundation of exposure therapy for anxiety and phobias. However, the stability of extinction memory diminishes over time, coinciding with fear recovery. To augment long-term extinction retention, the temporal distribution of extinction learning sessions is critical. This study investigated the effects of massed and spaced training (with short and long intervals) on extinction retention compared to a classic protocol. 120 healthy participants were recruited and randomly divided to massed training, spaced training with 20-minutes or 3-hours intervals, and a control group. The control group completed half the number of extinction trials compared to the other groups. The fear conditioning/extinction paradigm consisted of three consecutive days of fear acquisition, extinction, and recall, followed by a second recall one week later. Skin conductance response (SCR) and self-rating questionnaires (ratings of valence, arousal, and fear) were recorded and analyzed using mixed model ANOVAs. The results revealed that during the extinction phase, both massed and spaced protocols showed significantly lower SCRs compared to the control group, with massed training resulting in the largest effects. In the second recall, only the massed extinction group showed no significant difference in SCRs between threat and safety cues. The self-report assessments indicated that the massed extinction group showed furthermore lower arousal than the control group in the first recall. These results suggest that both massed and spaced training promote fear extinction learning, but only massed training improves long-term extinction retention. This study highlights the impact of the temporal distribution and trial number of extinction learning on extinction retention, offering insights for future research on improving fear extinction efficacy.

A growing body of research highlights the fear extinction model as a key framework for understanding the pathology of anxiety disorders and developing therapeutic interventions. Functional imaging studies link successful extinction recall and reduced amygdala reactivity with ventromedial prefrontal cortex (vmPFC) activity, while dysfunctional vmPFC activity is associated with anxiety pathology. Enhancing vmPFC activity through transcranial direct current stimulation (tDCS) has thus emerged as a promising approach to augment cognitive behavioral therapy (CBT) and therapeutic exposure therapies for anxiety disorders. In this study, anodal tDCS was applied over the vmPFC during the extinction learning phase of a 3-day fear acquisition/extinction paradigm (anodal tDCS: 21, sham tDCS: 23 participants). Skin conductance response (SCR) and Blood Oxygenation Level Dependent (BOLD) brain activity were recorded simultaneously. Healthy participants who received real tDCS showed significantly improved extinction recall compared to the sham tDCS group, as indicated by the SCR. Fear acquisition activated core regions of the fear network, including the anterior cingulate cortex, amygdala, orbitofrontal cortex, and insular cortex. During extinction learning, real tDCS activated both fear and safety networks (particularly the posterior cingulate and middle temporal cortex) during early extinction, while the sham tDCS group showed activity only in the fear network. Furthermore, a decoupling of the vmPFC with fear network regions with real tDCS during extinction was observed, indicating strengthened inhibitory control. These findings suggest that anodal tDCS over the vmPFC promotes early activation of the safety network, enhancing extinction learning and consolidation. This suggests its translational potential as an adjunctive intervention for anxiety disorders.