Direct electrical stimulation of the amygdala enhances declarative memory in humans

Abstract

Emotional events are often remembered better than neutral events, a benefit that many studies have hypothesized to depend on the amygdala's interactions with memory systems. These studies have indicated that the amygdala can modulate memory-consolidation processes in other brain regions such as the hippocampus and perirhinal cortex. Indeed, rodent studies have demonstrated that direct activation of the amygdala can enhance memory consolidation even during nonemotional events. However, the premise that the amygdala causally enhances declarative memory has not been directly tested in humans. Here we tested whether brief electrical stimulation to the amygdala could enhance declarative memory for specific images of neutral objects without eliciting a subjective emotional response. Fourteen epilepsy patients undergoing monitoring of seizures via intracranial depth electrodes viewed a series of neutral object images, half of which were immediately followed by brief, low-amplitude electrical stimulation to the amygdala. Amygdala stimulation elicited no subjective emotional response but led to reliably improved memory compared with control images when patients were given a recognition-memory test the next day. Neuronal oscillations in the amygdala, hippocampus, and perirhinal cortex during this next-day memory test indicated that a neural correlate of the memory enhancement was increased theta and gamma oscillatory interactions between these regions, consistent with the idea that the amygdala prioritizes consolidation by engaging other memory regions. These results show that the amygdala can initiate endogenous memory prioritization processes in the absence of emotional input, addressing a fundamental question and opening a path to future therapies.

Keywords: amygdala; brain stimulation; hippocampus; memory consolidation; memory enhancement.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

The procedure used to stimulate the human amygdala and to test recognition memory. (A) A representative postoperative coronal MRI showing electrode contacts in the amygdala (white square). (B) Illustration of left amygdala (coronal slice) with black circles indicating estimated centroids of bipolar stimulation in or near the BLA in all 14 patients. (See Fig. S1 for more precise localizations.) White borders denote right-sided stimulation. All patients had at least one bipolar stimulation contact in the BLA. AC, anterior commissure; CM, centromedial complex of the amygdala; EC, entorhinal cortex; Hipp, head of the hippocampus; LV, lateral ventricle (temporal horn). Adapted with permission from ref. , copyright Elsevier 2007. (C) Schematic of the 1-s stimulation pulse sequence (each pulse = 500 μs biphasic square wave; pulse frequency = 50 Hz; train frequency = 8 Hz). (D) Schematic of the recognition-memory task in which the amygdala was stimulated after the presentation of half of the objects in the study phase and recognition memory was tested on unique subsets of images immediately and one day after the study phase.

Fig. 2.

Brief electrical stimulation to the amygdala in humans enhanced subsequent declarative memory without eliciting an emotional response. (A) Recognition-memory performance for each patient plotted as discriminability index (d′). All data were normally distributed without statistical outliers (Materials and Methods). The one-day memory-enhancement effect is significant even with the largest individual positive effect removed, and the memory-enhancement effect in the immediate test remained nonsignificant with the largest negative individual effect removed. (B) Recognition-memory test performance plotted for each patient as the difference in d′ in the stimulation and no-stimulation conditions (scatter plots). Overlaid box-and-whisker plots show the median, range, and interquartile range for each condition. (C) Reported responses of patients when they were asked in subsequent testing whether they felt any sensation of stimulation. All patients responded “No” to every trial regardless of whether actual or sham stimulation had been delivered. Additionally, no patient indicated subjective awareness of stimulation during the study. **P < 0.005 (see text).

Fig. 3.

Recognition of specific object images one day following amygdala stimulation evokes increases in perirhinal gamma power and perirhinal–hippocampal theta coherence. (A) Illustration of the BLA (cyan), hippocampus (HIPP, orange), and perirhinal cortex (PERI, magenta) and a representative LFP from each region during a recognition test trial (black triangle indicates image onset). The 3D brain model was adapted with permission from the Albany Medical College Virtual Brain Model (www.amc.edu/academic/software). (B and C) Average overall power (B) and coherence (C) for the hippocampus, BLA, and perirhinal cortex electrodes during the one-day test (n = 5 subjects). The artifact at 18 Hz in the power spectra resulted from different multitaper parameters used for low-frequency and higher frequency ranges (Materials and Methods). (D and E) Difference in power (D) and coherence (stimulation − no-stimulation conditions) (E) for the theta (5–7 Hz) and gamma (30–55 Hz) bands. All error bars represent the SEM. *P < 0.05; **P < 0.01 after correcting for multiple comparisons; see Materials and Methods. (F and G) Spectral plot of differences in perirhinal gamma power (F) and perirhinal–hippocampal theta coherence (G) in the stimulation and no-stimulation conditions.

Fig. 4.

Increased modulation of perirhinal gamma power by amygdala theta phase during accurate recognition of objects from the stimulation condition. (A) A phase–amplitude modulation index (MI) is plotted for interactions between BLA theta phase (5–7 Hz) and perirhinal cortex gamma amplitude for remembered objects in the stimulation and no-stimulation conditions at the immediate and one-day recognition tests. (B) MI differences in the stimulation and no-stimulation conditions by spectral frequency in the perirhinal cortex. The shaded region denotes the gamma band between 30–55 Hz. (C) Cumulative MI difference between stimulation and no-stimulation conditions for the gamma range in the perirhinal cortex. During the one-day test, the MI was increased for remembered images in the stimulation condition relative to remembered images in the no-stimulation condition, *P < 0.05 (D) Schematic representation of oscillatory activity during the one-day recognition test in the BLA, hippocampus (HIPP), and perirhinal cortex (PERI) for objects in the stimulation condition. The oscillations depict increased theta interactions between the three regions and gamma power in perirhinal cortex modulated by those theta oscillations. Im, immediate test. All error bars and bands represent the SEM.