Schizophrenia is a severe mental disorder character-ised by delusions, hallucinations, disorganisation, negative symptoms, cognitive symptoms, and significant impairment in multiple domains of one’s life. Schizophrenia affects around one in every hundred in the general population [1] and ranks among the leading causes of disability between the age group of 25−49 years [2]. Since the fortuitous discovery of chlorpromazine, antipsychotic medications continue to remain the primary treatment modality for schizophrenia. The current guidelines recommend the long-term use of antipsychotic medications in treating schizophrenia in conjugation with psychosocial interventions [3]. However, the current antipsychotic medications possess significant limitations. Firstly, despite treatment, around 10−30% of the patients show no response, and another 30% show residual positive symptoms [4,5]. Secondly, antipsychotic medications do not optimally ameliorate the negative and cognitive symptoms; the persistence of these symptoms leads to significant dysfunction and poor quality of life [6,7]. Thirdly, antipsychotic medications are associated with the risk of various adverse effects such as extrapyramidal side effects, hyperprolactinemia, weight gain, and metabolic abnormalities [8,9].

The limitations of antipsychotic medications kindled investigation into other treatment modalities for treating patients with schizophrenia. Neuromodulation is one of them. Among the various methods of neuromodulation, transcranial alternating current stimulation (tACS) has been recently explored in the treatment of psychiatric disorders, especially in the treatment of schizophrenia.

tACS is a non-invasive brain stimulation technique involving the application of alternating electric currents, sinusoidal in nature, through the scalp using electrodes to the specific brain regions to modulate their activity. The current amplitude, frequency, phase difference and duration of stimulation, along with the site of stimulation, are the major parameters involved in the application of tACS [10,11]. The intensity of the alternating current is generally administered within the range of 0.5−2 mA using metal or rubber electrodes with a skin-electrolyte contact area of 25−35 cm². Unlike transcranial direct current sti-mulation (tDCS), the amplitude here is measured from peak-to-peak of the positive and negative phases of the cycle. The alternating current mimics the rhythmic electrophysiological brain activity and helps to modulate the brain functions associated with them [12]. Hence, the stimulation involves sinusoidal waves of a frequency that matches the frequency of the intrinsic neural oscillations, ranging from 0.5−80 Hz. The electric current has to have one or more entry points as well as one or more exit points on the scalp through electrodes. Conventional montage involves 2-electrode, and the fluctuations in the polarity of the current maintain the electrodes in fluctuating states of anode/cathode. Adding a DC offset can keep these fluctuations within a single polarity. The offsets are generally kept zero in tACS. But when non-zero offsets with/without overlapping to other polarity are used, the stimulation will be termed “oscillatory transcranial direct current stimulation” (otDCS) [10].

The difference in the phase of the oscillating current is usually kept similar when the current is told to be “in- phase”. Whereas the electrodes can be kept “out-of- phase” where the phase difference will be at 180°. The studies may use the whole range of phase differences between 0−360°; the physiological/clinical implications of these are yet to be ascertained. Novel high-definition tACS applications with single-entry and multiple-exit or vice-versa are also being utilised in clinical studies [13] aiming to achieve focused stimulation.

The exact mechanism of action of tACS is an area of immense research interest. The current evidence points toward the possible effect of tACS on neural oscillations. The neural oscillations are synchronized rhythmic patterns of electrophysiological activity produced by neurons in the brain. These neural oscillations are associated with multiple perceptual, behavioural and cognitive functions as well as different brain states [14]. Also, the connectivity between various cortical brain regions is mediated by synchronizing brain oscillations across these regions [15]. Various psychiatric disorders, such as schizophrenia, have been implicated to have abnormalities in these neural oscillations [16].

tACS is thought to have online effects, i.e., effects noticed during the stimulation period, as well as after-effects that outlast the stimulation period [17,18]. The online effects and after-effects are attributed to entrainment and neuroplasticity, respectively [18,19]. Entrainment is a phenomenon wherein the rhythmicity of 2 systems synchronizes with each other [19,20]. In tACS, it is hypothesised that an externally applied sinusoidal current of a specific frequency can modulate the endogenous neural oscillations in the brain either by synchronizing or desynchronising the oscillatory activities in the specific region of the brain leading to ameliorating the abnormalities in neural oscillations, which translates into an improvement in clinical symptoms [18,19,21]. For entrainment to be possible, an endogenous oscillation should be present in the range of the frequency of the applied alternating current [18,19,21]. This entrainment can also happen at harmonic frequencies, which are integral multiple of the stimulating frequency (resonant frequency), such as twice or half of the stimulation frequency [19,21,22]. There will be an enhancement of the power of these frequency-specific oscillations contributing to the psychophysiological effects. Entrainment also depends on the amplitude of the stimulation, as described by the Arnold’s Tongue [18,19]. This property of tACS describes the ability of higher amplitude current to entrain wider frequencies of endogenous oscillations with peak entrainment at the stimulation frequency. In contrast, lower amplitude stimulation will be able to entrain among the narrower frequency range [19]. Also, it is known that during cognitive processes, it is not the oscillation of a single frequency (frequency range) that is involved, but the waves of different frequency ranges interact with each other, i.e., cross-frequency coupling [22,23]. The coupling could be at the inter-frequency domains, inter amplitudes or, more commonly, amplitude-frequency coupling [24]. Hence, the application of tACS at one specific frequency may also affect the properties of other endogenous frequencies leading to improvement in symptoms [18,19]. The effects of entrainment last for the stimulation period. However, tACS may have a long-lasting effect due to neuroplastic changes. The synapses are strengthened or weakened based on the timing of input and output activity, a mechanism referred to as spike-timing-dependent plasticity (STDP) [21,22]. Thus, synapses with a resonance frequency similar to repetitive input are strengthened, leading to long-lasting effects [25].

In patients with schizophrenia, specific abnormalities in brain oscillations have been noted. These abnormalities are frequency, brain region and state specific. A consistent finding in patients with schizophrenia is a decrease in alpha rhythm in the prefrontal and parietal regions of the brain [26-30]. The alpha is an inhibitory waveform, and its deficits suggest dysregulation in top-down processing [28,31]. Alpha tACS has been used in studies targeting positive symptoms (hallucinations and delusions) of schizophrenia. The idea behind this is to regulate top- down processing by inhibiting the activity of targeted areas. Aberrant activity in the temporoparietal junction (TPJ) (the site of auditory processing) and medial prefrontal cortex (the site of self-referential processing) [28] were targeted to be regulated using alpha tACS.

Theta waves and the amplitude-modulated gamma within the phase of theta waves are found to be crucial in the flow of information packages across short- and long- range brain networks, respectively. Deficit theta oscillations in the frontal lobe are associated with working memory impairment in patients with schizophrenia [32, 33]. Aberrant gamma oscillations have been linked to an imbalance between excitatory and inhibitory networks due to impaired GABAergic inter-neuronal activity [34]. In patients with schizophrenia, there is a reduction of task-related gamma oscillation and associated synchronization [33-38] that correlated with deficit symptoms, including negative symptoms [39]. tACS attempting to enhance the theta and gamma oscillations in the frontoparietal network is thus shown to improve the cognitive and negative symptoms of schizophrenia. A novel tACS approach by combining these 2 frequencies termed theta-gamma tACS is attempted in healthy controls showing its superiority over theta tACS [40]. It would be interesting to see its translational application in schizophrenia pa-tients.

Given the advancing conceptualization of schizophrenia as a disorder of abnormal oscillatory activity, the application of tACS exploring its utility and safety in this population is imperative. This article provides an up-to-date review of the clinical utility, including the clinical effect and safety, as well as any research application of tACS in schizophrenia.

This is a scoping review of the literature on the utility of tACS in Schizophrenia. A systematic literature search on the MEDLINE and Scopus databases as well as in the WHO International Clinical Trials Registry Platform (ICTRP) was conducted based on combination of keywords: ((tACS [Title/Abstract]) OR (transcranial alternating current stimulation [Title/Abstract])) AND (schizophrenia [Title/Ab-stract]). The search process was last performed on 15th October 2022. All the original studies investigating the effect of the administration of tACS in patients with schizophrenia with published results in the English language till date were included.

The search resulted in 59 publications after the removal of duplicates. Screening of the study was done by 2 authors (HP and VSS), and a final consensus was taken for the inclusion/exclusion of a study. Overall, 45 studies were excluded as they were review articles/they did not involve studying patients with schizophrenia/they were unrelated to tACS/trials in the registries without published results. The remaining studies were reviewed in full text to assess for eligibility and were included. One trial result was found unpublished in a peer-reviewed journal and has been included in the review. The studies included 2 conference abstract papers investigating the effect of tACS in schizophrenia, one of them being an unpublished Master’s thesis work where we could find the full thesis [41]. We reviewed the protocols used in these studies, their clinical/ neurobiological outcomes and their safety profile. See Figure 1.

In total, 14 articles studied the role of tACS in patients with schizophrenia [41-54]. Out of 14 publications, 8 articles were clinical trials, including 4 double-blind, ran-domized controlled trials (RCT). Four case reports and 2 case series were also reported. The 2 RCTs [45,46] among these were of the same set of subjects evaluating the clinical and biological outcomes in separate articles. The findings are summarized in Table 1.

Sample profile: The number and the clinical profile of participants differed across the studies based on the design and objectives of the studies. The number of participants in the studies ranged from 1 [44,47,52] to 36 [53]. The participants included were diagnosed with schizo-phrenia. However, 4 studies also included participants diagnosed with schizoaffective disorder [43,45,46,53,54]. Most studies included a specific subgroup of schizophrenia targeting specific symptom domains, such as those having treatment-resistant negative symptoms [42,50], treat-ment-resistant delusions [48], treatment-resistant auditory hallucinations [45,46,52,54], or those with cognitive deficits [41,44,47]. But few studies seemed to have heterogeneous samples without specific symptom profiles.

Stimulation parameters: In studies investigating the effect of tACS on positive symptoms, 4 studies [45,46,52,54] examined the effect on auditory hallucinations. In these studies, an alternating current of 2 mA intensity and 10 Hz frequency (alpha frequency) was applied using electrodes (5 × 5 cm) at the left dorsolateral prefrontal cortex (DLPFC) and left TPJ with a reference electrode (5 × 7 cm) at the central region. While another study in patients with persistent delusions [48] applied electrodes (5 × 7 cm) at the medial prefrontal cortex and vertex region with alternating currents of similar intensity and frequency. All these studies administered alpha tACS for 20 minutes twice daily sessions for 5 days [45,46,48,52,54]. Few patients in one study were continued for 10 days [27], and 2 other studies evaluated the continuation therapy by administering a 40 minutes weekly session for up to 20 sessions [52, 54].

One RCT [53], 2 case series [42,49] and one case report [50] investigated the tACS effect on negative symp-toms. All studies applied 2 mA alternating current over bilateral DLPFC except the RCT, wherein the frontoparietal area was stimulated. However, other parameters varied among the studies. The electrode size ranged from 25 cm² [42] to 35 cm² [49,50]. However, for the RCT, 2 sets of 4 electrodes of 1 cm² size in the left frontal and left parietal regions referenced to the frontoparietal midline electrodes were used. Theta frequency (4.5 Hz and 6 Hz respectively) alternating current was applied in one case series and RCT [42,53], while the other 2 studies [49,50] applied gamma frequency alternating current (40 Hz). The number and frequency of sessions varied from 10 sessions (once daily for 10 days) to 20 sessions (once daily for 20 days or twice daily for 10 days), with the duration of sessions ranging between 10−20 minutes.

The studies [41,43,44,47,51] investigating the effect of tACS on working memory applied the stimulation, using electrodes of 35 cm², mainly on the left DLPFC with the other electrode either on the left posterior parietal region or right supraorbital region. Theta frequency stimulation was applied in 2 studies, while gamma frequency stimulation was used in 3 studies [43,44,51]. Three studies piloted with single session tACS administration crossing- over from theta-tACS to gamma-tACS, sham-tACS or tDCS stimulation on different days [43,44,51]. The 2 reports [41,47] of therapeutic applications involved the administration of 20 minutes sessions for 5 days (once/twice daily sessions).

All studies that reported phase differences between the electrodes had administered tACS in-phase (zero phase difference). At the same time, most studies had no mention of phase difference [42,43,51,54]. None of the studies on schizophrenia had used any DC offset (otDCS).

Five of the studies [43,44,47,51,53] involved the application of tACS while participants engaged in certain working memory tasks, including online n-back task, dual back task, and computerized digit symbol substitution task. These studies mostly looked at cognitive symptoms or negative symptoms as the primary outcome measure. In 2 of the studies [48,52] involving positive symptoms and 1 study [41] involving cognitive symptoms, participants were in a resting wakeful state. However, in 2 studies [45,54] with persistent auditory hallucinations, participants were in a relaxed state watching “reefscapes” videos.

Outcome and findings: tACS have shown promising results in patients with schizophrenia. In studies assessing effects on auditory hallucinations, a study [23] reported improvement in auditory hallucinations, which was later shown to be associated with enhancement of alpha oscillations, connectivity and auditory steady-state response (ASSR) in another paper [24]. Though this RCT had shown a good effect size in reducing hallucinations, the difference between sham stimulation or tDCS group could not be established, probably due to the small sample size. A case study [52], reported improvement in the duration and controllability of auditory hallucinations with weekly tACS, but this could not be replicated in the original RCT by the same group [33]. The open-labelled study targeting the medial prefrontal cortex [48] reported significant improvement in the severity of delusions with the persistence of improvement for at least a month following tACS.

With regards to negative symptoms of schizophrenia, one RCT [53], 2 case series [42,49], and a report [50] noted a reduction in negative symptoms as well as an improvement in cognitive symptoms. Though 2 studies [43, 51] reported no change in working memory with tACS, 3 other studies [41,44,47] reported improvement in working memory along with processing speed.

Adverse effects: Most studies used structured question-naires to systematically assess the associated adverse effects [41,42,44,45,47-50,52-54]. Nine of the studies used standardised questionnaires to evaluate the adverse effects, and the other 2 used a comfort rating questionnaire [49,50]. The studies suggested good tolerance of tACS by schizophrenia patients, with a few reporting of mild and transient adverse effects like scalp pain, itching and burning sensations, tingling sensation, phosphenes, and increased depth of sleep. Additionally, diarrhoea and muscular pain were noted in one study in 2 participants [54]. Across all studies, approximately 1,180 sessions of tACS were administered with no reports of serious side effects or drop-outs due to intolerability.

tACS is a novel non-invasive technique that applies a low-intensity alternating current stimulation leading to modulation of the neuronal oscillations, which in turn affects the cortical processes [55]. Though the role of tACS in modulating cognitive processes has been known for the past decade, its use in psychiatric disorders, especially schizophrenia, began in the last 5 years. Here in this review, we have tried to summarize the protocols used and outcomes of tACS in patients with schizophrenia and it adds on to the earlier review on tACS [56]. There is a paucity of rigorous studies assessing the effects of tACS in patients with schizophrenia, with only 4 sham controlled trials [21,23,32,33] to date. Most of the published studies were either case reports, case series or open-labelled trials. All of these open-label studies showed promising results. In a case study [52], with weekly alpha tACS over left DLPFC and left TPJ reported improvement in auditory hallucinations. An open-labelled study reported signifi-cant improvement in delusions following alpha tACS targeting the medial prefrontal cortex [48]. A reduction in negative symptoms along with cognitive symptoms was noted in 2 case series [42,49], and a case report [50] was noted using theta tACS [42] and gamma tACS [49,50]. Moreover, 3 studies [41,44,47] reported improvement in working memory along with processing speed using theta tACS. For RCTs, except for one RCT, which used HD- tACS targeting working memory [53], all others could not demonstrate the superiority of tACS [43,45,54]. The RCT that targeted hallucinations in schizophrenia had a higher effect size with true tACS than the sham with respect to improvement [45] and showed associated changes in neural oscillatory markers [46]. However, this clinical effect could not be replicated in a recent larger study [54]. The current findings do support the notion that abnormal neural oscillations are associated with symptoms of schizophrenia (Table 2) [21,26,29,31,32,57-63]. The positive symptoms are associated with dysfunctional alpha [57- 59], gamma [21,57] and beta oscillations [57], negative symptoms mainly with gamma oscillations [21,57], and cognitive symptoms mainly with theta [32] and gamma oscillations [21,57]. As noted, targeting these abnormal oscillations may lead to the amelioration of symptoms associated with schizophrenia, thus suggesting a potential role of tACS in schizophrenia.

The stimulation parameters for tACS in patients with schizophrenia are still evolving compared to other neuromodulation modalities such as tDCS [64]. The studies in schizophrenia have generally used 2 mA peak-to-peak (−1 mA to +1 mA) intensity current and were found to be tolerable without major adverse effects. Tolerability acts as a decisive factor in determining the current intensity. As tACS involves the transcutaneous application of alternating current, it would become intolerable at higher inten-sities. A burning sensation is common above ± 1 mA with higher reporting of dizziness, phosphenes, and metallic taste [65]. Thus, balancing effectiveness and safety, a current amplitude of 2 mA is used as optimal stimulation intensity in schizophrenia.

Conventional conductible latex-rubber electrodes (25−35 cm²) were applied in all except 1 study. These electrodes lack focality but have high tolerability, and the electric field distribution over the brain surface is simpler to predict. To further improve the current density and spatial focality of stimulation, a high-definition montage using multi-electrode configurations was devised for tDCS [66]. Recently high-definition montage has been applied in studies using tACS [13,67]. The only study that used smaller electrodes in schizophrenia had 2 sets of 4 ring-electrodes was designed to provide stimulation in frontoparietal regions with current directed towards each other. This distribution and direction of current flow in high-definition tACS [32] was demonstrated using computer simulation over the modelled brain from neuroimaging data. How-ever, more studies investigating HD-tACS in schizophrenia would assist in exploring the neurobiological basis of schizophrenia. Though HD-tACS optimises the focality of stimulation, it may be less tolerable with a potential of higher current shunting due to decreased inter-electrode distance [65].

The electrodes, as noted in the studies, were in the same phase of the cycle of alternating current with zero phase difference between them leading to synchronization of neuronal activity in the targeted brain area in the studies. However, if electrodes are in the opposite phase, it can lead to desynchronisation [12,68] and the clinical /neurobiological effects of this desynchronisation would be of research interest.

Stimulation in the range of 10−20 minutes duration is required to produce after-effects following tACS [69]. Multiple sessions are known to enhance the plasticity, thereby bringing a longer-lasting effect. In studies investigating the effect of tDCS in schizophrenia, higher frequency (2 sessions per day) and a greater number of sessions (> 10 sessions) were associated with better outcomes [64]. Although currently, data is lacking, a similar result may be anticipated with tACS [12]. Thus, most studies with the therapeutic application of tACS have used twice daily sessions. But the exact effects of session duration, number and frequency of sessions of tACS in schizophrenia need systematic evaluation.

Also, the effect of tACS is noted to be state-dependent [70] with effects known to be enhanced with the targeted region in an activated state. As noted, in most of the studies involving cognitive or negative symptoms wherein a working memory task (online) was performed during stimulation to activate the region of interest. However, in studies involving positive symptoms, the participants were mainly in a resting state, as the targeted region was already in an activated state. Thus, based on the symptom domain to be targeted, online or offline stimulation can be planned.

The tACS is well tolerated, with adverse effects being transient. The adverse effects could be linearly related to intensity and stimulus frequency [71]. However, no serious adverse effects have been reported in any single/ multi-session tACS study in either healthy volunteers or patients. The common side effects in schizophrenia patients have been phosphene perception, dizziness, skin sensation, pressure perception and increased depth of sleep similar to that of healthy volunteers based studies [71,72]. The phosphene perception is commonly reported with anterior montages and at a higher frequency, while dizziness is associated with posterior montages. Higher frequency and intensity of stimulation may lead to skin sensations (burning and tingling). Phosphene experience can be minimised by watching videos on a television screen during stimulation [45], but it may affect the tACS effect, which may be brain state-dependent. None of the patients discontinued tACS secondary to the adverse side effects. Thus, in patients with schizophrenia, the application of tACS appears to be safe in the short-term, even with multiple sessions, though long-term safety needs further evaluation. The adverse effects were well-documented in the studies using structured adverse effect questionnaires. Given that tACS research is in its early phase, it is advisable to use structured questionnaires to assess the adverse side effects [72].

In summary, we can note that very few studies have assessed the effect of tACS in patients with schizophrenia. Most of the studies had sub-optimal evidence and smaller sample sizes. The studies were heterogeneous, using varied protocols and targeting different symptom domains of schizophrenia. As a result, no robust inference can be drawn regarding the clinical, biological or therapeutic effects of tACS in patients with schizophrenia. Further, it is unclear whether tACS can be used as a stand-alone therapeutic modality or as an add-on option to target residual symptoms. Also, most studies examined only the short- term tolerability of tACS in patients with schizophrenia.

Further research is needed with well-structured double-blind RCTs with a larger sample size to replicate the findings. Drug-naïve/drug-free patients could be recruited to rule out the effects of pharmacological treatment in investigative applications of tACS. Inter-individual variability in response to tACS may happen secondary to differences in neuroanatomy and resultant difference in the electric field inside the brain. Individualisation of stimulation protocol based on dysfunctional neuronal oscillation and neuroimaging-based computational modelling would be advisable. Also, to optimise the effect of tACS various methods have been investigated such as HD-tACS wherein by using smaller electrodes, more focal effects can be provided. Multi-site stimulation brings in complexity but also much scope to understand the neuro-biology. Recent studies in healthy individuals using travelling wave tACS have immense potential for investigational and translational applications in schizophrenia [73].

Temporal interferential stimulation is a modification of tACS where high frequency-low amplitude waves are focused onto the deeper brain regions to provide stimulation with frequencies in the range of endogenous oscillations. Early experiments on safety and applicability in human subjects have been promising [74]. This would overcome the major drawback of the transcranial electrical stimulation related to the depth of penetration. We will be able to target the deep-seated brain regions enhancing the applicability of tACS in schizophrenia. Special waveforms of tACS such as amplitude-modulated tACS as described earlier could replicate the intrinsic interactions among different frequencies of neural oscillations and may provide evidence of neuropathology by direct manipu-lations. Intersectional short pulse stimulations are being attempted to enhance the tolerance to higher intensity of current targeting deeper brain regions. Here multi-electrode montage will be used but targeting a common specific brain region through short pulses of alternating currents administered from different electrodes sets placed at multiple scalp locations shifting from one set to the other. Additionally, methods like transcranial electrical theta burst stimulation (te-TBS) is another promising development in this field and awaits application in neuropsychiatric conditions [75]. These advancements in the methods need to be investigated further to improve the effect of tACS. Additionally, clinical studies should target long-duration follow-ups to assess the long-term effects and safety of multi-session tACS.

tACS, a novel neuromodulation technique, modulates neuronal oscillations as well as causes long-term neuroplastic changes. It is a safe technique with minimal side effects. The initial studies have shown improvement in aberrant brain oscillations associated with schizophrenia with associated improvement in clinical symptoms. Though the current findings are promising, further studies are required to confirm these findings.

HP is supported by the Department of Biotechnology (DBT) - Wellcome Trust India Alliance (IA/CRC/19/1/ 610005). V.S.S. acknowledges the support of India-Korea joint program cooperation of science and technology by the National Research Foundation (NRF) Korea (2020K1A3A1A68093469), the Ministry of Science and ICT (MSIT) Korea, and the Department of Biotechnol-ogy (India) (DBT/IC-12031(22)-ICD-DBT). G.V. acknowledges the support of and Department of Biotechnology, Govern-ment of India (BT/HRD-NBA-NWB/38/2019-20(6)).

This work is supported by the Department of Biotech-nology (DBT) - Wellcome Trust India Alliance (IA/CRC/ 19/1/610005).

No potential conflict of interest relevant to this article was reported.

Conceptualization: Harsh Pathak, Vanteemar S Sreeraj, Ganesan Venkatasubramanian. Review: Harsh Pathak, Vanteemar S Sreeraj. Funding: Ganesan Venkatasubram-anian. Supervision: Vanteemar S Sreeraj, Ganesan Ven-katasubramanian. Writing—original draft: Harsh Pathak. Writing—review & editing: Vanteemar S Sreeraj, Ganesan Venkatasubramanian.