{"doi":"10.1016/j.brs.2022.08.018","title":"A minimum effective dose for (transcranial) alternating current stimulation","abstract":"The question of adequate dosing is fundamental to non-invasive brain stimulation. Selecting stimulation intensity that results in an electric field leading to a desired physiological response is crucial. For transcranial alternating current stimulation (tACS), the concept of dose refers to the induced electric fields in the brain [1Anastassiou C.A. Perin R. Markram H. Koch C. Ephaptic coupling of cortical neurons.Nat Neurosci. 2011; 14: 217-223https://doi.org/10.1038/nn.2727Crossref PubMed Scopus (353) Google Scholar, 2Opitz A. Falchier A. Yan C. Yeagle E.M. Linn G.S. Megevand P. et al.Spatiotemporal structure of intracranial electric fields induced by transcranial electric stimulation in humans and nonhuman primates.Sci Rep. 2016; 631236https://doi.org/10.1038/srep31236Crossref Scopus (193) Google Scholar, 3Huang Y. Liu A.A. Lafon B. Friedman D. Dayan M. Wang X. et al.Measurements and models of electric fields in the in vivo human brain during transcranial electric stimulation.Elife. 2017; 6e18834https://doi.org/10.7554/eLife.18834Crossref Scopus (326) Google Scholar]. Thus, we can ask: What minimum electric field strength causes detectable changes in neural activity? This question is vital for understanding tACS dosing in humans necessary to modulate mental states and behavior. Many in-vitro and animal studies have investigated how intrinsic and induced oscillating electric fields modulate neural activity. However, a clear consensus on an adequate electric field strength for physiological effects is still lacking. Here, we use a meta-analytic probabilistic approach to determine the minimum effective dose (MED) at which alternating current (AC) modulates neural spiking. To identify effective stimulation parameters, we manually collected data from 16 papers identified in a PubMed® search (see Supplementary Table S1). We included experimental mechanistic studies in brain slices and animals that applied AC stimulation at 0.1–100 Hz with simultaneous direct neural recordings. In addition, we only considered papers that measured the AC electric field. Our analysis summarized 11 experiments in rodent brain slices and deeply anesthetized rodents (study group I) and 5 experiments in awake or behaving nonhuman primates and rodents (group II). From them, we extracted the lowest electric field strength values at which neural changes were detected, which constitutes the upper MED boundary (a certainly effective dose per experiment). The highest electric field values at which no changes occurred defined the lower MED boundary (a certainly ineffective dose per experiment). Here we define the \"minimum effect\" as significant changes in at least one observed unit in the sample. See Supplementary Methods for more details. We assumed that the MED lies between these boundaries and follows a Beta distribution, commonly used in uncertainty analyses. The meta-analytical distribution is a Gaussian function, satisfying the Central Limit Theorem, truncated to avoid negative values. Moreover, we estimated 99% confidence intervals (CI99) of the meta-analytical fit, assuming that each underlying study has a statistical power of 80%. Finally, study groups were statistically compared using the nonparametric two-sample Kolmogorov-Smirnov (KS) test. Meta-analytic results show the mean probabilistic MED of 0.49 mV/mm (CI99: 0.39–0.58 mV/mm) and standard deviation of 0.21 mV/mm for AC stimulation in brain slices and anesthetized rodents (Fig. 1). This mean dose corresponds to the cumulative probability of 50% to elicit minimum significant neural changes. Results in brain slices and anesthetized animals separately are given in Supplementary Materials (Fig. S1). For awake/behaving mammals, the MED's mean = 0.23 mV/mm (CI99: 0.15–0.31 mV/mm) and SD = 0.10 mV/mm. By extension, the 80% probability of eliciting a significant neural response corresponds to 0.67 mV/mm (CI99: 0.57–0.76 mV/mm) in the slices and anesthetized rodents and 0.31 mV/mm (CI99: 0.23–0.40 mV/mm)","journal":"Brain stimulation","year":2022,"id":235851,"datarank":0.6515708132780527,"base_score":4.343805421853684,"endowment":4.343805421853684,"self_citation_contribution":0.6515708132780527,"citation_network_contribution":0.0,"self_endowment_contribution":0.6515708132780527,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":76,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9697,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":642995,"name":"Miles Wischnewski","orcid":"0000-0002-0056-6464","position":1,"is_corresponding":false},{"id":240702,"name":"Alexander Opitz","orcid":"0000-0002-4851-1243","position":2,"is_corresponding":false},{"id":240697,"name":"Ivan Alekseichuk","orcid":"0000-0002-2205-4910","position":0,"is_corresponding":true}],"reference_count":12,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:21:53.333008Z","pmid":"36044976","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}