Noradrenaline tracks emotional modulation of attention in human amygdala

Abstract

The noradrenaline (NA) system is one of the brain's major neuromodulatory systems; it originates in a small midbrain nucleus, the locus coeruleus (LC), and projects widely throughout the brain.^1,2 The LC-NA system is believed to regulate arousal and attention^3,4 and is a pharmacological target in multiple clinical conditions.^5,6,7 Yet our understanding of its role in health and disease has been impeded by a lack of direct recordings in humans. Here, we address this problem by showing that electrochemical estimates of sub-second NA dynamics can be obtained using clinical depth electrodes implanted for epilepsy monitoring. We made these recordings in the amygdala, an evolutionarily ancient structure that supports emotional processing^8,9 and receives dense LC-NA projections,¹⁰ while patients (n = 3) performed a visual affective oddball task. The task was designed to induce different cognitive states, with the oddball stimuli involving emotionally evocative images,¹¹ which varied in terms of arousal (low versus high) and valence (negative versus positive). Consistent with theory, the NA estimates tracked the emotional modulation of attention, with a stronger oddball response in a high-arousal state. Parallel estimates of pupil dilation, a common behavioral proxy for LC-NA activity,¹² supported a hypothesis that pupil-NA coupling changes with cognitive state,^13,14 with the pupil and NA estimates being positively correlated for oddball stimuli in a high-arousal but not a low-arousal state. Our study provides proof of concept that neuromodulator monitoring is now possible using depth electrodes in standard clinical use.

Keywords: amygdala; arousal; attention; electrochemistry; emotion; human brain; noradrenaline; pupil; pupillometry.

Figure 1

Electrochemistry on clinical depth electrodes (A) Sketch of electrochemical approach. (B) We made electrochemical recordings in the amygdala of three patients while they performed the task shown in Figure 2A. (C) In vitro evaluation of electrochemical approach. The macro-micro electrodes were explanted from the three patients who performed the task in Figure 2A. The Behnke-Fried electrodes were explanted from the amygdala of three patients at another hospital and were included to demonstrate generalizability. Dots indicate the average predicted NA concentration (nanomoles, nM) for single-analyte solutions that only contained NA (green), DA (blue), or 5-HT (red). Green diamonds indicate mixture solutions that contained DA and/or 5-HT in addition to NA. Predictions were from a 10-fold cross-validation and pooled across patients. R² values were obtained by regressing the predicted NA concentration against the true NA, DA, or 5-HT concentration. Error bars represent 95% confidence intervals but are not visible at this scale. See Figure S1 for in vitro evaluations for DA and 5-HT.

Figure 2

Experimental framework and behavioral results (A) Patients performed a visual affective oddball task while we simultaneously measured NA in the amygdala and pupil dilation with sub-second temporal resolution. The task was divided into six blocks of 100 images; the images were shown for 1 s and separated by 1 s blank intervals. Within each block, 80% of the images were a checkerboard image (standard) and the remaining 20% were unique IAPS images (oddball). See Figure S2A for IAPS content ratings and measured illuminance for the different image sets. (B) Oddball PDR for (top) patients and (bottom) controls across all trials. (C) Oddball PDR for (top) patients and (bottom) controls within each condition. (B and C) For each trial, we smoothed the time series using a 0.5 s causal filter, Z scored the smoothed data and removed any linear drift. Lines indicate the difference between the average time series for oddball and standard trials. Triangles indicate the significance (p < 0.050) of a predictor and their direction indicates the sign of the effect (down, negative; up, positive). Only significant predictors are shown. See Figure S2B for an analysis in raw units, which also considers image illuminance and trial history.

Figure 3

NA estimates track the emotional modulation of attention (A) Regression coefficients ± SE from linear mixed-effects regression described in main text. ^∗p < 0.050; ^∗∗p < 0.010; ^∗∗∗p < 0.001. (B) Single-trial NA estimates (mean ± SE) separated by emotional arousal and stimulus type. (A and B) Single-trial NA estimates were calculated as the mean NA estimate over a 1 s window centered on stimulus onset minus the mean NA estimate over the preceding 0.5 s and Z scored across trials for each patient. See Figure S3 for analysis of DA and 5-HT estimates.

Figure 4

Coupling between pupil and NA estimates varies with emotional arousal The panels show (top) the average estimated pupil and NA time series with simple correlation statistics reported and (bottom) the HMM estimate of pupil-NA coupling for (left) all trials irrespective of stimulus type, (middle) oddball stimuli in low-arousal blocks, and (right) oddball stimuli in high-arousal blocks. We first smoothed the time series using a 0.5 s causal filter and Z scored the smoothed data for each trial. We then averaged the time series for each condition, removed any linear drift, and scaled the average time series to have unit variance, by dividing each time point by the average of the condition-specific standard deviations over the average time series. The last step helps ensure that estimated correlations, which are sensitive to the variance of the data, are comparable across conditions. Shaded area for the HMM estimate of pupil-NA coupling indicates 95% credible interval. See Figure S4 for simple correlations for oddball stimuli in each block.