Human amygdala engagement moderated by early life stress exposure is a biobehavioral target for predicting recovery on antidepressants

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Abstract

<p id="d16020806e315">Amygdala reactivity and early life stress (ELS) are both strongly implicated in the mechanisms of depression in animal and human models. Despite these mechanistic foundations, amygdala reactivity and ELS have not been investigated as biobehavioral targets for predicting functional remission in depression. We addressed this issue by integrating human imaging and ELS measures within a controlled trial of antidepressant outcomes. We demonstrate that the interaction between ELS and amygdala engagement predicts functional remission on antidepressants with a greater than 80% cross-validated accuracy. In depressed people exposed to high ELS, a greater likelihood of remission was predicted by amygdala hyperreactivity to socially rewarding stimuli, whereas for those with low-ELS exposure, amygdala hyporeactivity to both rewarding and threat-related stimuli predicted remission. </p><p class="first" id="d16020806e318">Amygdala circuitry and early life stress (ELS) are both strongly and independently implicated in the neurobiology of depression. Importantly, animal models have revealed that the contribution of ELS to the development and maintenance of depression is likely a consequence of structural and physiological changes in amygdala circuitry in response to stress hormones. Despite these mechanistic foundations, amygdala engagement and ELS have not been investigated as biobehavioral targets for predicting functional remission in translational human studies of depression. Addressing this question, we integrated human neuroimaging and measurement of ELS within a controlled trial of antidepressant outcomes. Here we demonstrate that the interaction between amygdala activation engaged by emotional stimuli and ELS predicts functional remission on antidepressants with a greater than 80% cross-validated accuracy. Our model suggests that in depressed people with high ELS, the likelihood of remission is highest with greater amygdala reactivity to socially rewarding stimuli, whereas for those with low-ELS exposure, remission is associated with lower amygdala reactivity to both rewarding and threat-related stimuli. This full model predicted functional remission over and above the contribution of demographics, symptom severity, ELS, and amygdala reactivity alone. These findings identify a human target for elucidating the mechanisms of antidepressant functional remission and offer a target for developing novel therapeutics. The results also offer a proof-of-concept for using neuroimaging as a target for guiding neuroscience-informed intervention decisions at the level of the individual person. </p>

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Amygdala circuitry mediating reversible and bidirectional control of anxiety.

Kay M. Tye, Rohit Prakash, Sung-Yon Kim … (2011)

Anxiety--a sustained state of heightened apprehension in the absence of immediate threat--becomes severely debilitating in disease states. Anxiety disorders represent the most common of psychiatric diseases (28% lifetime prevalence) and contribute to the aetiology of major depression and substance abuse. Although it has been proposed that the amygdala, a brain region important for emotional processing, has a role in anxiety, the neural mechanisms that control anxiety remain unclear. Here we explore the neural circuits underlying anxiety-related behaviours by using optogenetics with two-photon microscopy, anxiety assays in freely moving mice, and electrophysiology. With the capability of optogenetics to control not only cell types but also specific connections between cells, we observed that temporally precise optogenetic stimulation of basolateral amygdala (BLA) terminals in the central nucleus of the amygdala (CeA)--achieved by viral transduction of the BLA with a codon-optimized channelrhodopsin followed by restricted illumination in the downstream CeA--exerted an acute, reversible anxiolytic effect. Conversely, selective optogenetic inhibition of the same projection with a third-generation halorhodopsin (eNpHR3.0) increased anxiety-related behaviours. Importantly, these effects were not observed with direct optogenetic control of BLA somata, possibly owing to recruitment of antagonistic downstream structures. Together, these results implicate specific BLA-CeA projections as critical circuit elements for acute anxiety control in the mammalian brain, and demonstrate the importance of optogenetically targeting defined projections, beyond simply targeting cell types, in the study of circuit function relevant to neuropsychiatric disease.

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Statistical improvements in functional magnetic resonance imaging analyses produced by censoring high-motion data points.

Joshua S Siegel, Jonathan D. Power, Joseph Dubis … (2014)

Subject motion degrades the quality of task functional magnetic resonance imaging (fMRI) data. Here, we test two classes of methods to counteract the effects of motion in task fMRI data: (1) a variety of motion regressions and (2) motion censoring ("motion scrubbing"). In motion regression, various regressors based on realignment estimates were included as nuisance regressors in general linear model (GLM) estimation. In motion censoring, volumes in which head motion exceeded a threshold were withheld from GLM estimation. The effects of each method were explored in several task fMRI data sets and compared using indicators of data quality and signal-to-noise ratio. Motion censoring decreased variance in parameter estimates within- and across-subjects, reduced residual error in GLM estimation, and increased the magnitude of statistical effects. Motion censoring performed better than all forms of motion regression and also performed well across a variety of parameter spaces, in GLMs with assumed or unassumed response shapes. We conclude that motion censoring improves the quality of task fMRI data and can be a valuable processing step in studies involving populations with even mild amounts of head movement. Copyright © 2013 Wiley Periodicals, Inc.

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A method for obtaining 3-dimensional facial expressions and its standardization for use in neurocognitive studies.

Ruben C. Gur, Radim Sara, Michiel Hagendoorn … (2002)

Facial expressions of emotion are increasingly being used in neuroscience as probes for functional imaging and as stimuli for studying hemispheric specialization for face and emotion processing. Available facial stimuli are 2-dimensional and therefore, their orientation is fixed and poorly suited for examining asymmetries, they are often obtained under poorly specified conditions, usually posed, lack ethnic diversity, and are of restricted age range. We describe a method for accurately acquiring and reconstructing the geometry of the human face and for display of this reconstruction in a 3-dimensional format. We applied the method in a sample of 70 actors and 69 actresses expressing happiness, sadness, anger, fear and disgust, as well as neutral expressions. Each emotion was expressed under three levels of intensity and under both posed and evoked conditions. Resulting images are of high technical quality and are accurately identified by raters. The stimuli can be downloaded in digital form as 'movies' where angle and orientation can be manipulated for inclusion in functional imaging probes or in tests that can be administered as measures of individual differences in facial emotion processing. The database of emotional expressions can also be used as a standard for comparison with clinical populations.