The Effects of Prefrontal Transcranial Electrical Stimulation on Brain Function and Connectivity in Normal Aging: A Systematic Review
DOI: Pending DOI
Synopsis
Behavioral effects of prefrontal transcranial electrical stimulation (tES) in older adults are mixed. We asked whether mixed behavioral findings were due to heterogeneous neural responses to tES. We also investigated how baseline brain state and individually delivered current impacted neural change. Following PRISMA 2020 (PROSPERO CRD420251084451), we reviewed tES studies targeting the prefrontal cortex with fMRI or fNIRS in cognitively normal older adults. From 5199 records, 21 studies met inclusion. Hemispheric and inhibitory predictions made by aging theories were not consistent, but prefrontal tES often increased within-network frontoparietal coupling. Working memory was the clearest beneficiary. Effects tracked cognitive trajectory and modeled current density in the prefrontal cortex.
Background
Normal aging is accompanied by changes in cognition and in the brain systems that support it. Transcranial electrical stimulation (tES) has been proposed as a way to modulate age-related neural change, yet the older adult literature remains mixed at the behavioral level1,2. The present study had two primary questions: (a) do mixed behavioral findings reflect true null effects or depend on reliable neural changes that are not always successfully modulated, and (b) which neurocognitive aging accounts best fit the observed pattern of neural responses. Heterogeneous behavioral results might reflect differences in baseline brain state, anatomy-driven differences in the delivered electric field, and the assumption that one protocol produces one effect across older adults3,4. Major neurocognitive aging theories make different predictions about whether stimulation should strengthen compensatory neural recruitment, restore more youth-like network organization, or reduce inefficient hyperactivation5. Behavioral data alone cannot adjudicate among these accounts. Combining tES with functional magnetic resonance imaging (fMRI) or functional near-infrared spectroscopy (fNIRS) is therefore needed to identify which neural changes occur, which networks are modulated, and whether reported behavioral outcomes track those changes6,7. No prior systematic review had synthesized prefrontal tES-imaging evidence specifically in cognitively normal older adults. The present review was designed to address that gap.
Methods
This systematic review followed PRISMA 2020 guidelines8, and the protocol was registered in PROSPERO (CRD420251084451). Searches covered PubMed, Embase, Web of Science, APA PsycInfo, APA PsycArticles, and Google Scholar (first 49 records), with no start-date restriction and a final search date of July 9, 2025. The strategy combined three concept blocks: aging-related terms, tES-related terms (tDCS, tACS, tRNS), and neuroimaging-related terms (fMRI, fNIRS, functional connectivity, network terms). Three seed papers were used to validate the search syntax. Records were imported into Rayyan and screened by two independent reviewers, with conflicts resolved by discussion. Eligible studies enrolled cognitively normal older adults and combined prefrontal tDCS, tACS, or tRNS with fMRI or fNIRS. Studies of younger adults, individuals with mild or major neurocognitive disorders, non-tES techniques, reviews, and animal studies were excluded. Sham-controlled, pre/post, and concurrent-stimulation designs were eligible. Primary outcomes were stimulation-related changes in brain activity and functional connectivity; cognitive outcomes were extracted when reported alongside neural endpoints. Findings were synthesized along two axes: theory-driven hypotheses and additional patterns that emerged across studies but were not captured by those predictions. For each the included studies, we asked under what conditions the brain changed and whether behavioral change needed a brain change first.
Results
Searches yielded 5,199 records across six databases. After 1,055 duplicates were removed, 4,144 records were screened, 87 full texts were assessed, and 21 studies met inclusion criteria. Common exclusion reasons were non-healthy older-adult samples, no tES, no fMRI/fNIRS, or non-prefrontal targets. Montages included left-anodal, right-anodal, bifrontal, and multifocal prefrontal configurations. Imaging endpoints included task/resting-state fMRI and fNIRS; endpoints spanned working memory, episodic memory, attention, dual-task walking, and sleep.
Hemispheric models predict that excitatory stimulation of one prefrontal hemisphere should increase activity in that hemisphere and reduce it in the contralateral hemisphere because there would no longer be a need to recruit the other hemisphere, especially for difficult tasks. The included studies did not consistently show this full pattern. Some left-prefrontal or bifrontal protocols produced left-prefrontal increases, including left DLPFC-VLPFC coupling and left middle frontal/anterior cingulate activation during item retrieval9–11. Other studies showed bilateral or right-hemisphere increases or reductions in left prefrontal activation, with one study reporting fewer task errors despite reduced left prefrontal activity12.
Right-anodal or right-targeted stimulation did not produce a consistent increase in right prefrontal activity, and several studies reported null effects or decreases in right-hemisphere connectivity10,13,14. Inhibitory hypotheses could not be tested cleanly because most cathodal evidence was embedded within bifrontal or multifocal montages. Posterior compensation predicted by the Posterior-Anterior Shift in Aging (PASA)5 account was largely absent. The only directly relevant finding was a study that classified older adults as cognitive decliners or stable based on a 4-year longitudinal working-memory trajectory. Decliners receiving a multifocal montage designed to reproduce a frontoparietal pattern previously linked to high working memory in older adults showed reduced posterior activity rather than the predicted increase15.
The clearest signal emerged at the network level. Several studies reported increased within-network connectivity in frontal or frontoparietal systems after left-anodal or bifrontal stimulation targeting the left prefrontal cortex 9–11,16–18. This pattern was true in both task-based and resting-state designs. Working memory was the clearest behavioral beneficiary, with the most consistent gains on the 2-back and near-transfer N-back, often when stimulation was paired with cognitive training. A smaller subset reported reduced coupling between default-mode regions and other networks, and one study linked default-mode-subcortical connectivity change to improve sleep quality 12,19,20. Stand-alone default-mode suppression as the mechanism predicted by the Default-Executive Coupling Hypothesis of Aging (DECHA)5 was not directly demonstrated. Two studies clarified response variability: Indahlastari et al. showed that modeled current density in the left dorsolateral prefrontal cortex predicted change in left dorsolateral-ventrolateral prefrontal connectivity, while current density in the left ventrolateral prefrontal cortex did not. Vaqué-Alcázar et al. showed the neural response depended on cognitive trajectory, with effects appearing only in decliners15,18. Many studies reported null or trend-level behavioral effects despite reliable neural change, but no included study reported stimulation-related decline.
Discussion
We investigated whether mixed behavioral findings reflect true null effects or depend on reliable neural changes that are not always successfully modulated, and whether neural change tracks predictions of major neurocognitive aging theories. Neural change was often found even when behavior did not move. Hemispheric predictions from neurocognitive theories of aging5 received only partial support. Inhibitory and PASA-consistent posterior compensation predictions could not be tested fully because most cathodal evidence was embedded within bifrontal or multifocal montages and few studies included a young-adult comparison group. The most consistent pattern emerged at the network level: left-anodal or bifrontal stimulation targeting the left dorsolateral prefrontal cortex increased within-network frontoparietal connectivity, and a smaller subset of studies reported reduced coupling between default-mode regions and other networks. This pattern fits with neurocognitive theories of brain-maintenance that suggest tES can restore a more segregated, youth-like network architecture. Behavioral gains were clearest for working memory, on the N-back, when the left dorsolateral prefrontal cortex was stimulated and paired with cognitive training across multiple sessions. The role of dose was regionally specific: modeled current density in the left dorsolateral prefrontal cortex, but not the left ventrolateral prefrontal cortex, predicted working-memory connectivity change.
Disclosures
Nothing to disclose by any authors.
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