Integrative roles of human amygdala subdivisions: Insight from direct intracerebral stimulations via stereotactic EEG

Abstract

Substantial studies of human amygdala function have revealed its importance in processing emotional experience, autonomic regulation, and sensory information; however, the neural substrates and circuitry subserving functions have not been directly mapped at the level of the subnuclei in humans. We provide a useful overview of amygdala functional characterization by using direct electrical stimulation to various amygdala regions in 48 patients with drug-resistant epilepsy undergoing stereoelectroencephalography recordings. This stimulation extends beyond the anticipated emotional, neurovegetative, olfactory, and somatosensory responses to include visual, auditory, and vestibular sensations, which may be explained by the functional connectivity with cortical and subcortical regions due to evoked amygdala-cortical potentials. Among the physiological symptom categories for each subnucleus, the most frequently evoked neurovegetative symptoms were distributed in almost every subnucleus. Laterobasal subnuclei are mainly associated with emotional responses, somatosensory responses, and vestibular sensations. Superficial subnuclei are mainly associated with emotional responses and olfactory and visual hallucinations. Our findings contribute to a better understanding of the functional architecture of the human amygdala at the subnuclei level and as a mechanistic basis for the clinical practice of amygdala stimulation in treating patients with neuropsychiatric disorders.

Keywords: SEEG; electrical stimulation; function; human amygdala; subnuclei.

FIGURE 1

Parcellation of the amygdala overlaid in slices with MNI space and reconstruction of stereoelectroencephalography (SEEG) electrodes in all patients. (a) The amygdala was divided into the centromedial group (CM), medial fiber (MF), intermediate fiber (IF), superficial group (SF), laterobasal group (LB), and ventromedial part (VTM) according to the cytoarchitecture (Julich‐Brain, Science, 2020). (b) The trajectories of SEEG electrodes into the amygdala overlaid with all patients in MNI space. (c) Location of some sample contacts of the amygdala subnuclei in the MNI space (red arrow) and the personal space (green arrow). The first row (1–3) shows the contacts within the LB. The second row (4–6) shows the contacts within the SF. The last two rows show the contacts within IF (left column, 7 and 10), VTM (middle column, 8 and 11), and CM (right column, 9 and 12).

FIGURE 2

Spatial distribution of contacts within the amygdala (left) and the relative frequencies distribution (right) of elicited responses. In the left column, dots represent stimulation sites in the amygdala. The color of the dots was coordinated with the evoked response distributions in the right column. (a) The distribution of evoked physiological responses without electrical post‐discharge. (b) The distribution of evoked responses related to the usual symptoms but without pathological electric activity. (c) The distribution of evoked responses with electrical after discharge.

FIGURE 3

Precise localization of stimulation sites and the evoked emotional responses. (a) The reconstruction of electrodes with postoperative CT images registered in preoperative MRI images. The black triangles indicate the stimulation site. The masks with different colors show the amygdala subnuclei. (b) The emotion wheel of the evoked emotional experiences. (c) The three‐dimensional distribution of stimulation sites of the amygdala with either positive or negative emotions (left) and the emotion distribution in the level of subnuclei (right).

FIGURE 4

Neurovegetative symptoms evoked by the amygdala subnuclei stimulation. (a) Subnuclei distribution of different neurovegetative symptoms in the MNI space. (b) Subnuclei distribution of evoked symptoms related to the autonomic nervous system. (c) Distribution of stimulation sites within the amygdala subnuclei. (d) The reconstruction of stereoelectroencephalography (SEEG) electrodes with the hemisphere (left) and electrode implanted in the amygdala and hippocampus. (e) Contact numbers of amygdala subnuclei inducing bradycardia in each hemisphere. (f,g) The amygdala stimulation decreased heart rate, displayed with raw data (f) and the temporal heartbeats (g).

FIGURE 5

Visual, olfactory, somatosensory, auditory, and vestibular symptoms evoked by the amygdala subnuclei stimulation. The colors of each row correspond to categories of the symptoms on the vertical axis. The circles with colors indicate stimulation sites within the amygdala subnuclei, which are demonstrated on the horizontal axis.

FIGURE 6

Categories of responses and the distribution of amygdala stimulation sites with different responses. (a) Contact numbers of each category in physiological responses, usual symptoms without pathological electrical activity, and electrical after discharge. (b) The distribution of stimulation sites with different physiological responses across the amygdala subnuclei. (c) The distribution of stimulation sites with responses related to habitual aura symptoms.

FIGURE 7

Overall circuits revealed by amygdala‐cortical evoked potential responses in 10 patients who have received amygdala‐cortical evoked investigation. Each dot over the slices represents a site with significant response potential evoked by amygdala stimulation. A different color identifies the evoked response of each patient consistent with the color shown in the dot. The red and blue arrows indicate information flows.