Recognizing motivationally salient information is critical to guiding behaviour. The amygdala and hippocampus are thought to support this operation, but the circuit-level mechanism of this interaction is unclear. We used direct recordings in the amygdala and hippocampus from human epilepsy patients to examine oscillatory activity during processing of fearful faces compared with neutral landscapes. We report high gamma (70–180 Hz) activation for fearful faces with earlier stimulus evoked onset in the amygdala compared with the hippocampus. Attending to fearful faces compared with neutral landscape stimuli enhances low-frequency coupling between the amygdala and the hippocampus.
Similar to the hippocampus, the amygdala is a paired structure, with one located in each hemisphere of the brain. The amygdala is part of the.
The interaction between the amygdala and hippocampus is largely unidirectional, with theta/alpha oscillations in the amygdala modulating hippocampal gamma activity. Granger prediction, phase slope index and phase lag analysis corroborate this directional coupling. These results demonstrate that processing emotionally salient events in humans engages an amygdala-hippocampal network, with the amygdala influencing hippocampal dynamics during fear processing. Swift detection of social, emotional or threatening stimuli is critical for adaptive fitness in humans. When we interact with each other, emotionally salient stimuli, such as fearful facial expressions, provide ecologically relevant signals that focus our attention towards perceptually relevant information. Thus, recognizing motivationally salient information constitutes an important social and biologically meaningful incentive and plays a key role in guiding our interpersonal behaviour.Successful detection of and response to motivationally important stimuli have been shown to rely on activity within two brain structures—the amygdala and hippocampus.
In particular, the amygdala is critical for prioritizing salient information such as emotion, valence and motivation. The hippocampus is thought to be important for contextual modulation of fear, emotion judgment and emotional memory —all operations that are critical for remembering motivationally salient stimuli.It is commonly assumed that the amygdala exerts directional influence onto the hippocampus during processing of salient information. This network model of salience processing is primarily based on rodent data. For example, the amygdala receives direct subcortical inputs thought to facilitate rapid detection of salient information, consistent with a proposed role of the amygdala in early cognitive engagement that may influence subsequent hippocampal mnemonic processing. Several studies also indicate that manipulating amygdala function alters hippocampal processing of salient information.
Evidence for this directional influence in humans has only been indirectly inferred from behaviour and neuroimaging studies showing that memory enhancement for emotionally arousing stimuli is positively associated with markers of endogenous norepinephrine release from the basolateral amygdala (BLA). However, there is no direct electrophysiological evidence for amygdala-hippocampal connectivity in humans and thus their directional relationship is unknown.We addressed this question by presenting salient (dynamic fearful faces) and neutral (landscapes) stimuli to patients with medication resistant epilepsy in whom stereotactic electrodes had been implanted in the amygdala and hippocampus for pre-surgical evaluation. First, we hypothesized that high gamma (HG; 70–180 Hz) band activity (a spatially precise measure of neuronal spiking ) will occur earlier in the amygdala than in the hippocampus, consistent with a directional relationship. Codecombat teacher login.
We next examined the electrophysiological evidence for connectivity between the amygdala and hippocampus. Low-frequency oscillations (theta=4–7 Hz and alpha=8–12 Hz) are ubiquitous in the human hippocampus and amygdala; fear conditioning studies in rodents suggest that they provide a temporal window for inter-regional communication.
Therefore, we hypothesized that low-frequency oscillations mediate functional connectivity between the amygdala and hippocampus by coupling spiking activity in the hippocampus (as indexed by the HG signal) to low-frequency oscillations in the amygdala. Finally, consistent with the model of detection/prioritization by the amygdala and post-detection processing by the hippocampus, we hypothesized that the synchronous activity in these two regions would be biased such that it is more likely that the amygdala exerts directional influence on the hippocampus rather than the reverse.In this study, we show that the amygdala and hippocampus are both engaged in the early stages of salience processing with increased intraregional HG activity and enhanced inter-regional low-frequency synchrony when attending to aversive compared with neutral stimuli. The coupling between these two regions is predominantly unidirectional, with low-frequency oscillations in the amygdala entraining hippocampal HG activity. Overall, these results provide evidence for a directional influence from the amygdala to the hippocampus during processing of motivationally salient stimuli. Experiment design and electrode localizationWe recorded oscillatory activity in local field potentials (LFPs) from nine human participants with intracranial depth electrodes implanted into the amygdala and the hippocampus. Electro-oculogram (EOG) electrodes and an eye tracker were used for one subject to evaluate the potential influence of saccadic muscle movements on neural signals.
We examined neuronal responses while individuals watched aversive movie clips containing blocks of dynamic fearful faces and neutral movie clips of landscapes. We employed dynamic fearful faces as a form of aversive stimuli, rather than static facial expressions, to provide participants with temporal cues that mimic real-life social exchanges. The localization of depth electrodes was determined based on co-registered pre- and post-implantation magnetic resonance imaging (MRI), as well as registration to a high-resolution anatomical atlas, labelled with medial temporal lobe regions of interest.
Localization of each electrode was performed in a semi-automated manner, guided by the anatomical atlas and visually checked by an experienced rater (S.L.L.). In all subjects, there were two to three depth electrodes located in the BLA and one to three electrodes located in the hippocampus (dentate gyrus (DG)/CA3 or CA1, and ). A three-dimensional rendering of the amygdala and hippocampus showed that for all subjects, the electrodes were located in the basal aspects of the amygdala and the anterior hippocampus. ( a) Participants watched silent movie clips consisting of alternating blocks of neutral (landscapes) and aversive stimuli (fearful faces). ( b) Example MRI and template for a single subject. Electrodes were localized in each participant using co-registered pre-implantation and post-implantation structural T1-weighted MRI scans. A high-resolution template of the hippocampal subfields and amygdala nuclei was aligned to each participant’s pre-implantation scan to visualize electrode locations in subject-specific anatomical space.
Regions of interest (ROIs) in the medial temporal lobe included the DG/CA3, CA1, subiculum (Sub), perirhinal cortex (PrC), lateral and medial entorhinal cortex (LEC, MEC), parahippocampal cortex (PhC), BLA, CeA and the CORT. Each electrode location was determined by selecting the centre of the electrode (indicated by cross-hairs) and determining which ROI best encompassed the centre of the electrode. ( c) Electrode localization of all subjects, rendered onto a three-dimensional amygdala and hippocampus model based on the high-resolution template.
Red dots indicate electrodes in the amygdala; blue dots denote electrodes in the hippocampus. ( d) Power spectral density (PSD) in log scale for the amygdala (upper panel) and hippocampus (lower panel). Peaks within theta (4–7 Hz)/alpha (8–12 Hz) and high gamma range (70–180 Hz) were consistently observed in all subjects. The black arrow denotes the power peak in the high gamma range, which is also shown for each individual subject on a linear scale (30–250 Hz) in the small plots. ( e) High gamma amplitude (70–180 Hz), averaged across participants (± s.e.m.
Shown as shading around the mean trace) and locked to stimulus onset, is shown for electrodes located in the amygdala and hippocampus (DG/CA3+CA1). Dotted lines represent significant differences between the aversive and neutral condition.
(permutation test, see methods). L, left; R, right. Local power and event-related potentialsNeuronal networks typically demonstrate activity in several oscillatory bands that cover both low- and high-frequency spectra with distinct roles in neuronal communication. Whereas high gamma band activity is a spatially precise measure of local neuronal population spiking, temporal synchronization of low-frequency phase is thought to mediate inter-regional communication. Therefore, we first determined the spectral specificity of low- and high-frequency oscillations in LFP. The power spectral density (PSD) plots revealed that each subject had a specific frequency peak in the theta/alpha and high gamma frequency ranges.
These peaks are thought to reflect coherent oscillatory processes. We then band passed the raw LFP signal to extract separate frequency components. These analyses showed that the low frequency of the amygdala and high gamma band power envelope of the hippocampus tended to co-occur in time during the aversive condition. Additional analyses demonstrated that event-related potentials (ERP; ) and ocular muscle activity ( and ) did not contaminate the neural signals used in subsequent analyses. Amygdala and hippocampus high gamma tracks salient stimuliWe explored the temporal profile of the oscillatory response to fearful faces versus landscapes.
Electrodes localized in the amygdala (BLA) and hippocampus (DG/CA3+CA1) with high-resolution MRIs as shown in were included in the analysis. We then focused on the temporally resolved changes in HG amplitude and examined the coordinated timing of amygdala and hippocampus neuronal responses during the processing of aversive compared with neutral stimuli.
The onset time was defined as the earliest time point at which two conditions showed a significant difference in HG amplitudes; the peak time was defined as the latency of the maximum magnitude of differences in HG amplitudes between the conditions. The average HG amplitude across trials was higher for the aversive relative to the neutral condition after 123±18 ms (mean±s.e.m.) in the amygdala and after 241±22 ms in the hippocampus post-stimulus onset (onset time, t-test, P. Low-frequency phase coupling differences (aversive—landscapes) for pairs of electrodes targeting the amygdala (red dots) and hippocampal subfields (blue dots), depicted with hive plots. Differences in the PLV between aversive and neutral conditions are presented in colour, with warmer colours indicating a greater magnitude of the contrast. Significance levels derived from permutation testing are indicated by the thickness of lines connecting each electrode pair. Asterisks represent electrode pairs with the most significant PLV that were used for directional coupling analyses in. To validate the role of low-frequency phase coupling in coordinating amygdala-hippocampal network communication during processing of motivationally salient information, we examined the PLV spectra between the most significant phase coupling electrode pairs (denoted by asterisks in ).
Across all subjects, the PLV increased when viewing aversive fearful faces compared with neutral stimuli (main effect: F (1,67)=8.88, P=0.004) and peaked in the low-frequency band for BLA-CA1 and BLA-CA3 compared with BLA- parahippocampal and BLA- subiculum electrode pairs. Further, the magnitude of low-frequency PLV varied among hippocampal sub-regions (F (3,67)=2.88, P=0.042) with the highest PLV observed for the BLA-CA1 electrode pairs. The phase coupling between BLA and CA1/CA3 were significantly greater than the other hippocampal sub-regions ( t-test, P. ( a) PAC comodulogram for differences between the aversive and the neutral conditions is shown, with warmer colours denoting higher z-scores. The high gamma amplitude in the hippocampus was phase-locked to the phase of amygdala low-frequency (theta and alpha) rhythms (all P.
We also examined whether the PAC varied as a function of the time lag between low-frequency and HG signals. We posited that an amygdala to hippocampus directionality would result in a conduction delay, which would translate to a relative phase shift between low-frequency and HG oscillations. Specifically, an earlier phase of amygdala low-frequency oscillations entraining hippocampal HG would result in the strongest PAC. We found that in the aversive condition, PAC between low frequency of the amygdala and HG of the hippocampus peaked around zero time lag (−13.15±2.92 ms versus hippocampus to amygdala directionality 13.52±22.83 ms), with 7 out of 9 subjects demonstrating that the amygdala low-frequency was leading the hippocampal HG (, denoted by+near the red line, Pearson’s χ 2-test=6.73, P=0.035).
In contrast, PAC between amygdala HG and hippocampus low-frequency was lower and failed to demonstrate a consistent peak at any time lag.Since spectrally broad transients such as evoked activity can produce spurious PAC results, we examined the spectral specificity of the modulated HG activity from the PAC results. To identify the rhythmic low-frequency fluctuation of the higher-frequency power time series, we determined the centre frequency of the HG signal from the PAC and filtered the raw signal within the HG band to extract the analytic amplitude of the signal (that is, envelope), which was then subjected to the PSD analysis. All subjects showed individual narrow-band low-frequency (4–12 Hz) peaks in the gamma envelope, thus supporting oscillatory properties of a separate low-frequency modulating signal in the HG band.
To examine potential influence of eye movements on the PAC results, we ran an independent component analysis (ICA) on the EOG combined with white matter referenced amygdala and hippocampal activity in one participant (subject 9). Components composed of EOG activity (three components, based on mixing weights, ) were removed from the raw intracranial data and all analyses were re-run with this ‘cleaned’ data. The observed PAC effect remained significant after ICA correction. Further, there was no significant PAC between EOG channels and the amygdala as well as the hippocampus. These findings indicate that eye movement contamination did not contribute to the original results.
Granger causality and phase slope indexTo further examine the directionality of the amygdala-hippocampal circuit, we utilized two complementary measures that rely on frequency and phase respectively: spectral Granger causality and phase slope index (PSI). The Granger causality measure quantifies the strength of directional influences between LFPs in the frequency domain by testing whether the LFP from one structure (for example, hippocampus) can be better predicted by incorporating information from the LFP from the other structure (for example, amygdala) and vice versa. PSI quantifies phase difference as a function of frequency, with a positive phase slope indicating that the signal from the first structure is leading the signal from the second structure. In low-frequency bands, we found significant Granger causal influence from the amygdala to hippocampus but not in the reciprocal direction (all P. ( a) Granger causality analyses demonstrated consistently stronger influence for the amygdala-to-hippocampus direction (top left) than for the hippocampus-to-amygdala direction (top right) when contrasting the aversive to the neutral condition. The red and blue solid lines represent the real data from aversive and neutral conditions±s.e.m., respectively. Dotted lines denote 99% confidence intervals for the null distribution.
( b) PSI between the aversive and the neutral conditions calculated point-by-point across time using the low-frequency signal from the modulating channel (coloured in red) and high gamma signal from the modulated channel (coloured in blue). Dotted lines above the graph denote significant differences between the two signals (all P. Here, we demonstrate that processing of motivationally salient stimuli depends on coordinated neural oscillations between the amygdala and hippocampus, two critical nodes in the emotion processing circuit.
Prior works have suggested that the amygdala rapidly detects salient stimuli, whereas the hippocampus engages in contextual and mnemonic processing,; however, the nature of their interaction and timing remains unclear. The current findings show that the interaction between the two structures is mediated by low-frequency phase coherence and that this relationship is directional, with amygdala low-frequency oscillations entraining hippocampal gamma. Our results are robust across individual subjects and provide a mechanism by which the amygdala influences hippocampal activity during recognition and emotional memory of salient information.
We were able to disentangle the temporal dynamics of the interaction between the amygdala and hippocampus during processing of aversive stimuli by demonstrating an earlier post-stimulus onset of HG activity in the amygdala (as early as 120 ms post-stimulus) relative to the hippocampus ( ∼240 ms post-stimulus). Overall, these findings showed that salient stimuli are processed with distinct temporal windows in the amygdala and hippocampus. The early amygdala activity observed in this study may reflect the fast automatic detection of motivational salience of information, while the later hippocampal onset may indicate formation or reactivation of emotional memory.Previous research in affective processing using intracranial electroencephalogram (EEG) recordings in humans has focused on either the amygdala or hippocampus, but the oscillatory mechanism mediating communication across the two structures has remained unclear.
Using retrograde tracing techniques in monkeys’ hippocampal formation, Amaral and Cowan demonstrated that labelled neurons were found predominately in the anterior amygdaloid area, basolateral nucleus and periamygdaloid cortex. The perirhinal and parahippocampal cortices have connections with the basolateral and accessory nuclei. Although the primate tracing study could not provide anatomical specificity at the level of hippocampal subfields, rodent studies have shown that the ventral CA1 region and, to a lesser extent, CA3 receive the most robust amygdalar inputs. Our findings are consistent with these known anatomical connections.We further demonstrate that amygdala-hippocampal interactions were predominantly mediated through low-frequency coherence. Specifically, the PLV between the amygdala and hippocampus was enhanced when participants viewed fearful faces compared with landscapes. Given the long temporal window afforded by low-frequency rhythms, phase–phase coupling between different brain regions has been extensively studied in animal emotional research to understand regulation of inter-regional communication. In rodent models, the degree of fearful memory retrieval.
BackgroundEarly life stress (ELS) can compromise development, with higher amounts of adversity linked to behavioral problems. To understand this linkage, a growing body of research has examined two brain regions involved with socioemotional functioning—amygdala and hippocampus. Yet empirical studies have reported increases, decreases, and no differences within human and nonhuman animal samples exposed to different forms of ELS. This divergence in findings may stem from methodological factors, nonlinear effects of ELS, or both.