Evidence of a large current of transcranial alternating current stimulation directly to deep brain regions

Abstract

Deep brain regions such as hippocampus, insula, and amygdala are involved in neuropsychiatric disorders, including chronic insomnia and depression. Our recent reports showed that transcranial alternating current stimulation (tACS) with a current of 15 mA and a frequency of 77.5 Hz, delivered through a montage of the forehead and both mastoids was safe and effective in intervening chronic insomnia and depression over 8 weeks. However, there is no physical evidence to support whether a large alternating current of 15 mA in tACS can send electrical currents to deep brain tissue in awake humans. Here, we directly recorded local field potentials (LFPs) in the hippocampus, insula and amygdala at different current strengths (1 to 15 mA) in 11 adult patients with drug-resistant epilepsy implanted with stereoelectroencephalography (SEEG) electrodes who received tACS at 77.5 Hz from 1 mA to 15 mA at 77.5 Hz for five minutes at each current for a total of 40 min. For the current of 15 mA at 77.5 Hz, additional 55 min were applied to add up a total of 60 min. Linear regression analysis revealed that the average LFPs for the remaining contacts on both sides of the hippocampus, insula, and amygdala of each patient were statistically associated with the given currents in each patient (p < 0.05-0.01), except for the left insula of one subject (p = 0.053). Alternating currents greater than 7 mA were required to produce significant differences in LFPs in the three brain regions compared to LFPs at 0 mA (p < 0.05). The differences remained significant after adjusting for multiple comparisons (p < 0.05). Our study provides direct evidence that the specific tACS procedures are capable of delivering electrical currents to deep brain tissues, opening a realistic avenue for modulating or treating neuropsychiatric disorders associated with hippocampus, insula, and amygdala.

Fig. 1. Study procedure overview.

a Summary of study flow. 45 patients with drug-resistant epilepsy (DRE) were verified and entered the comprehensive evaluation of their treatments. Of them, 11 patients with DRE signed the informed content and experienced the tACS procedure, then received the corresponding interventions and followed up. b Structure of the tACS protocol. Each patient was presented with a set of alternating currents, beginning at 1 mA and stepwise increasing by 2 mA until reaching 15 mA. 15 mA persisted for 60 min. c Stimulating placements. An electrode was put on the forehead, and two electrodes were placed on the mastoid region of each side. d Sample of 9 mA stimulating waveform. Each stimulating waveform is composed of ramp-up (Tu), stable period (Ts), and ramp down (Td). e Details on ramp-up (Tu), stable period (Ts), and ramp down (Td) of various stimulating currents. f Sample of 9 mA stimulating model. The stimulation was a 1 s duration and 5 s stop. g Sample of 9 mA stimulating pulses. Each circle of the stimulating pulse was 12.9 ms with a square wave. SEEG stereoelectroencephalography, tACS transcranial alternating current stimulation.

Fig. 2. Depth electrodes and the average local field potentials in hippocampus (left, n = 8; right, n = 7), insula (left, n = 6; right, n = 4), and amygdala (left, n = 6; right, n = 4).

a, e, i Total intracranial electrodes in the hippocampus, insula, and amygdala, respectively. b, f, j The average local field potentials, represented as median and interquartile range, were significantly linearly correlated with the increasing extracranial currents (all p < 0.05) in hippocampus, insula, and amygdala, respectively. c, g, k Positive correlations of the average local field potentials, expressed as the mean and standard deviation, with the increased stimulation currents were found in hippocampus, insula, and amygdala, respectively (all p < 0.05). d, h, and l The observable variations of local field potentials of the deepest contacts in hippocampus, insula, and amygdala within 180 seconds after the tACS intervention, respectively. All illustrations were standardized based on their raw SEEG signals. A anterior, AMY Amygdala, HIP Hippocampus, INS Insula, L left, MTG middle temporal gyrus, P posterior, PoAMY post-amygdala, PreAMY pre-amygdala, PreCG precentral gyrus, PreHIP pre-hippocampus, R right, Sub subject.