Noninvasive modulation of the hippocampal-entorhinal complex during spatial navigation in humans

Abstract

Because of the depth of the hippocampal-entorhinal complex (HC-EC) in the brain, understanding of its role in spatial navigation via neuromodulation was limited in humans. Here, we aimed to better elucidate this relationship in healthy volunteers, using transcranial temporal interference electric stimulation (tTIS), a noninvasive technique allowing to selectively neuromodulate deep brain structures. We applied tTIS to the right HC-EC in either continuous or intermittent theta-burst stimulation patterns (cTBS or iTBS), compared to a control condition, during a virtual reality-based spatial navigation task and concomitant functional magnetic resonance imaging. iTBS improved spatial navigation performance, correlated with hippocampal activity modulation, and decreased grid cell-like activity in EC. Collectively, these data provide the evidence that human HC-EC activity can be directly and noninvasively modulated leading to changes of spatial navigation behavior. These findings suggest promising perspectives for patients suffering from cognitive impairment such as following traumatic brain injury or dementia.

Fig. 1.. Set-up of the experiment.

(A) Spatial navigation task. Each block started with an encoding period during which participants were consecutively presented with three objects at specific locations and asked to memorize their position. After encoding each object multiple times, a cue was shown during the retrieval phase with the image of one of the objects and the participant had to navigate to the location of the object. (B) Temporal interference stimulation concept. Two pairs of electrodes are placed on the head and deliver two HF currents I1 and I2 at a frequency f1 and f2 = f1 + Δf, respectively. On the bottom of the panel, the combination of the two fields is shown with high envelope modulation inside the target region and low envelope modulation outside. (C) Theta burst protocols. A specific shift in frequency between the two signals was applied with a specific timing to mimic either iTBS or cTBS. During iTBS, central panel, trains of 2 s are applied every 10 s, each one composed of 10 bursts at 5 Hz. Each burst is composed of three pulses at 100 Hz. In the 8-s break, no shift is applied between the two sources, leading to a flat envelope. During cTBS, bursts at 5 Hz are applied continuously without breaks. The bursts are composed of three pulses at 100 Hz as for the iTBS protocol.

Fig. 2.. Changes in the behavioral performance associated with tTIS targeted on the right HC-EC.

For the visualization of the behavioral performance, the participant-wise mean per active TBS conditions was normalized with respect to the data in the control condition to better depict within-participant effects of the active stimulations. Normalization was performed using the Z score with the mean and standard deviation (SD) of the control data, i.e., (X - mean_ctrl) / sd_ctrl. Hence, a value of “0” on the y axis represents the control level (mean_ctrl). However, the statistical assessment was performed using the dedicated mixed-effect models with the trial-wise data points before normalization, and showed a significant difference for the trial time and departure time. N = 30. Barplots height indicates the mean and black lines show the standard error (SE). Asterisks represent significant differences with a P threshold of 0.05. (A) The time the participants spent per trial was shorter in iTBS than cTBS (P = 0.04). (B) Further analysis on departure time (i.e., time duration until a participant started actively moving) revealed that shorter retrieval trial time in iTBS than cTBS stemmed from the shorter departure time in iTBS (compared to cTBS, P < 0.001; compared to control, P = 0.04). There was no significant difference between conditions in (C) navigated distance per trial (possibly reflecting an efficiency of the navigation path) nor in (D) distance error (i.e., distance between the correct and recalled location, inversely indexing a precision of spatial memory).

Fig. 3.. Changes in the GCLR associated with the tTIS targeted on the right HC-EC.

N = 28. Barplot height indicates the mean, and black lines show the SE. Asterisks represent significant differences with a P threshold of 0.05. (A) GCLR was significantly greater than 0 in the control condition (P = 0.009). Contrarily, GCLR was not greater than 0 in iTBS (P = 0.99) and in cTBS (P = 0.40). GCLR during the control was greater than GCLR during both iTBS (P < 0.001) and cTBS (P = 0.019). GCLR in iTBS condition was even lower than GCLR in cTBS condition (P = 0.030). (B) As a control analysis, we assessed other multifold symmetries (four, five, and sevenfold) than sixfold [i.e., GCLR results in (A)]. We found that only sixfold symmetry in the control condition was significant, confirming the validity of our GCLR data. (C) Correlation analysis between departure time and GCLR for each stimulation condition. No significant correlation was found.

Fig. 4.. Extracted BOLD activity in target areas.

N = 30. Barplot height indicates the mean and black lines show the 95% confidence interval. (A) Average BOLD activity within the right hippocampus (left barplots) and the right entorhinal cortex (right barplots) during each stimulation session. In the top and bottom panels, activity associated with active navigation periods and with Cue + Retrieval periods are plotted, respectively. (B) Correlation between the difference in departure time versus the difference in averaged BOLD activity within the right hippocampus between iTBS and cTBS. A significant correlation was found during Cue + Retrieval (bottom, r = −0.55, P = 0.01), indicating that the higher the BOLD activity during iTBS versus cTBS is, the faster the participants were recalling the position of the object to start navigation. No significant correlation was found during active navigation (top, r = 0.06, P = 0.75). a.u., arbitrary unit.

Fig. 5.. Sham versus HF control stimulation.

N = 30. Comparison of the differences between active and control conditions, HF versus sham, in behavioral performance (distance error and departure time, respectively). On the left (A), the iTBS versus control conditions is shown, while on the right (B), cTBS versus control conditions is plotted. No significant difference was observed between the two controls. In all box plots, the middle horizontal line represents the median value, while the red dot represents the mean value, colored areas represent the interquartile range, and the whiskers represent the 1.5 interquartile range.

Fig. 6.. Protocol of the experiment.

During the single session, each participant performed six blocks of the spatial navigation task with stimulation applied during the whole duration of the task. Stimulation conditions were applied twice in a pseudo-randomized order A-B-C-C-B-A.