Research Article Local and Distributed fMRI Changes Induced by 40Hz Gamma tACS of the Bilateral Dorsolateral Prefrontal Cortex: A Pilot Study Lucia Mencarelli , 1,2 Lucia Monti , 3 Sara Romanella , 1 Francesco Neri , 1 Giacomo Koch , 2 Ricardo Salvador , 4,5 Giulio Ruffini , 4,5 Giulia Sprugnoli , 1 Simone Rossi , 1,6 and Emiliano Santarnecchi 7 1 Siena Brain Investigation & Neuromodulation Lab (Si-BIN Lab), Department of Medicine, Surgery and Neuroscience, Neurology and Clinical Neurophysiology Section, University of Siena, Italy 2 Non-invasive Brain Stimulation Unit, Department of Behavioral and Clinical Neurology, Santa Lucia Foundation IRCCS, Rome, Italy 3 Unit of Neuroimaging and Neurointervention, “Santa Maria Alle Scotte” Medical Center, Siena, Italy 4 Neuroelectrics, Cambridge, MA, USA 5 Neuroelectrics, Barcelona, Spain 6 Human Physiology Section, Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy 7 Precision Neuromodulation Program & Network Control Laboratory, Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA Correspondence should be addressed to Emiliano Santarnecchi; esantarnecchi@mgh.harvard.edu Received 14 December 2021; Revised 6 May 2022; Accepted 21 June 2022; Published 16 July 2022 Academic Editor: nicoletta berardi Copyright © 2022 Lucia Mencarelli et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Over the past few years, the possibility of modulating fast brain oscillatory activity in the gamma (γ) band through transcranial alternating current stimulation (tACS) has been discussed in the context of both cognitive enhancement and therapeutic scenarios. However, the effects of tACS targeting regions outside the motor cortex, as well as its spatial specificity, are still unclear. Here, we present a concurrent tACS-fMRI block design study to characterize the impact of 40 Hz tACS applied over the left and right dorsolateral prefrontal cortex (DLPFC) in healthy subjects. Results suggest an increase in blood oxygenation level-dependent (BOLD) activity in the targeted bilateral DLPFCs, as well as in surrounding brain areas affected by stimulation according to biophysical modeling, i.e., the premotor cortex and anterior cingulate cortex (ACC). However, off-target effects were also observed, primarily involving the visual cortices, with further effects on the supplementary motor areas (SMA), left subgenual cingulate, and right superior temporal gyrus. The specificity of 40 Hz tACS over bilateral DLPFC and the possibility for network-level effects should be considered in future studies, especially in the context of recently promoted gamma- induction therapeutic protocols for neurodegenerative disorders. 1. Introduction Endogenous gamma (γ) oscillations encompass rhythmic brain activity within the range of 35 to 100 Hz. So far, loco-regional increases in γ frequency have been observed in tasks such as reading and subtraction expectancy [1], as well as during memory encoding in humans and mice [2, 3], working memory [4], and chess playing [5]. However, the exact role and contribution of γ frequency oscillations in neural activity has been debated for a long time, with evidence supporting γ as a clock-like temporal framework of brain function [6, 7]. Prediction of cognitive performance looking at γ spectral power changes obtained through intracranial recordings—mainly in temporal and prefrontal cortices in epileptic patients—has helped to highlight the functional role of γ in cognition [8, 9]. Nevertheless, the Hindawi Neural Plasticity Volume 2022, Article ID 6197505, 14 pages https://doi.org/10.1155/2022/6197505