Elsevier

Biological Psychiatry

Volume 51, Issue 9, 1 May 2002, Pages 693-707
Biological Psychiatry

Original article
Can’t shake that feeling: event-related fMRI assessment of sustained amygdala activity in response to emotional information in depressed individuals

https://doi.org/10.1016/S0006-3223(02)01314-8Get rights and content

Abstract

Background: Previous research suggests that depressed individuals engage in prolonged elaborative processing of emotional information. A computational neural network model of emotional information processing suggests this process involves sustained amygdala activity in response to processing negative features of information. This study examined whether brain activity in response to emotional stimuli was sustained in depressed individuals, even following subsequent distracting stimuli.

Methods: Seven depressed and 10 never-depressed individuals were studied using event-related functional magnetic resonance imaging during alternating 15-sec emotional processing (valence identification) and nonemotional processing (Sternberg memory) trials. Amygdala regions were traced on high-resolution structural scans and co-registered to the functional data. The time course of activity in these areas during emotional and nonemotional processing trials was examined.

Results: During emotional processing trials, never-depressed individuals displayed amygdalar responses to all stimuli, which decayed within 10 sec. In contrast, depressed individuals displayed sustained amygdala responses to negative words that lasted throughout the following nonemotional processing trials (25 sec later). The difference in sustained amygdala activity to negative and positive words was moderately related to self-reported rumination.

Conclusions: Results suggest that depression is associated with sustained activity in brain areas responsible for coding emotional features.

Introduction

Some of the most troubling aspects of depression involve prolonged involuntary processing of emotional information, in the form of elaboration (MacLeod and Mathews 1991) or rumination (Nolen-Hoeksema 1998) on negative topics. Such sustained involuntary emotional processing has been hypothesized to result in information biases commonly observed in depression such as preferential memory for, and attention to negative information (Williams and Oaksford 1992), and has been implicated in the onset and maintenance of depression (Beck 1967, Ingram 1984, Ingram 1990, Ingram et al 1998, MacLeod and Mathews 1991; Teadsale 1988). This study examines brain mechanisms associated with sustained processing after briefly presented negative information in depressed and never-depressed individuals using Blood Oxygen Level Dependent (BOLD) contrast event-related functional magnetic resonance imaging (fMRI). The study also examined the extent to which sustained processing interfered with subsequent behavioral tasks and whether it was related to self-reported rumination.

Sustained processing and elaboration of emotional information has been inferred from a variety of indirect behavioral measures. For example, depressed individuals tend to display enhanced memory for negative information (Matt et al 1992) and to interpret events as negative (Norman et al 1988). Similarly, Wenzlaff et al (1988) have shown dysphoric individuals display intrusive negative thoughts, even during thought suppression. Elaborative processing also has been advanced as an explanation for delays by depressed individuals in naming the color in which emotional words are written (Williams and Nulty 1986), in the absence of early attentional effects (MacLeod et al 1986).

A more sparse literature has used continuous peripheral physiological signals to demonstrate sustained recruitment of cognitive resources in the seconds following the presentation of emotional information, particularly in depressed individuals Deldin et al 2001, Christenfeld et al 2000, Siegle et al 2001a, Siegle et al 2001c, Nyklicek et al 1997. For example, sustained processing of emotional information, indexed by sustained pupil dilation (a correlate of cognitive load), has been observed in depressed individuals up to 6 sec after their responses to stimuli on an emotional valence identification task (Siegle et al 2001a). Such sustained pupil dilation was not present in response to nonemotional processing tasks, for example, a cued reaction time task, suggesting that the phenomenon could reflect elaborative emotional processing. Similarly, Deldin (2001) has reported that depressed individuals display increased slow-wave activity up to 13 sec following presentation of negative material, and Larson and Davidson (2001) have suggested that relative to controls, dysphoric individuals experience increased startle blink potentiation for up to 6 seconds following the presentation of negative pictures, particularly those displaying frontal electroencephalogram (EEG) asymmetry. No previous studies have examined brain mechanisms specifically associated with sustained processing using neuroimaging, potentially due to 1) a lack of hypotheses regarding brain mechanisms underlying sustained processing and 2) the difficulty, until recently, of examining sustained processing in an event-related context using neuroimaging. The following sections describe such a theoretical framework and an fMRI design for testing it.

Various cognitive mechanisms for sustained affective processing in depression have been advanced. Ingram (1984) suggests that if cognitive activity involves the spread of activation between nodes in a cognitive network representing semantic and affective information (Bower 1981), depressed individuals suffer from strongly activated connections between negative affective nodes and multiple semantic nodes, creating feedback loops that propagate depressive affect and cognition. More biologically plausible neural models of emotional information processing are consistent with Ingram’s (1984) cognitive theory. A great deal of evidence suggests that emotional information is processed in parallel by brain systems responsible for identifying emotional aspects of information (the amygdala system) Gallagher and Chiba 1996, LeDoux 1993, LeDoux 1996 and other brain areas primarily responsible for identifying nonemotional aspects of information (the hippocampal system) (LeDoux 1996). These systems are highly connected and subject to feedback (Tucker and Derryberry 1992). Ingram’s notion of increased feedback between structures responsible for processing primarily cognitive and emotional features could thus suggest increased feedback between the amygdala system and brain structures responsible for identification of nonemotional aspects of information including the hippocampus. Amygdala hyperactivation, in particular, has been demonstrated in depressed individuals Abercrombie et al 1998, Drevets et al 1992 and has been implicated in the maintenance of depression (Dougherty and Rauch 1997). Disruptions in both volume and activity of these structures have been noted in depressed individuals Drevets et al 1992, Drevets 1999, Hornig et al 1997, Sheline et al 1999 and in animal models of depression (Zangen et al 1999).

Other research suggests depression involves disinhibition of the amygdala system. Such disinhibition of emotional-processing structures motivates interventions such as cognitive therapy, in which depressed individuals are taught to distance themselves from emotional reactivity through processes such as cognitive reappraisal of emotional situations. A potential candidate mechanism for such disinhibition involves decreased inhibition from integrative cortical brain structures such as the dorsolateral prefrontal cortex (DLPFC) (Davidson 2000). While such inhibitory pathways have not been empirically identified, inverse relationships between DLPFC and amygdala activity have been shown through functional neuroimaging (Drevets 1999). Moreover, multiple studies have demonstrated decreased DLPFC activation in depressed individuals Davidson 1994, Davidson 2000, Baxter et al 1989, Bench et al 1993. Similarly, nondepressed individuals have decreased DLPFC activation during induced sad moods Baker et al 1997, Gemar et al 1996, Liotti et al 2000a. Thus, the amygdala is suggested to be important in maintaining processing of emotional information in depressed individuals. The current research therefore focused on identifying sustained (∼30 sec after a stimulus) disruptions in amygdala activity in depressed individuals, as well as associated disruptions in areas directly connected to the amygdala such as orbitofrontal cortex, in which activity has been associated with amygdala activity in neuroimaging studies (Zald et al 1998) or areas such as DLPFC that may have inverse relationships to amygdala activity. The following sections outline methods used for assessing this sustained activity and predictions for depressed individuals.

Functional magnetic resonance imaging provides a noninvasive central measure believed to correlate with brain activity on a trial-by-trial basis and was therefore chosen as a dependent measure for the current study. Potentially, the clinical relevance of sustained processing in response to affective stimuli would be enhanced if it interfered with subsequent tasks. For example, if an individual is criticized, elaboration on the criticism rather than working could result in poor job performance. To examine such interference effects, depressed and never-depressed individuals completed tasks in which trials alternately required emotional processing and nonemotional processing. A common approach to provoking emotional processing was used in which individuals are asked to name the affective valence (positive, negative, or neutral) of presented stimuli (a “valence identification task”) (Hill and Kemp-Wheeler 1989; Mathews and Milroy 1994; Siegle et al 2001a, Siegle et al 2001b, Siegle et al 2001c). The common delayed match to sample, or “Sternberg memory” task was chosen as an appropriate nonemotional processing task. This task involves showing participants three numbers followed by a fourth number. Participants were asked whether the fourth number was in the set of the first three. The task was chosen because there is a wealth of behavioral and psychophysiological data on it, as it takes a few seconds to complete a trial in which stimuli are being continuously presented, allowing detection of residual activity from the previous trial, and is easy enough that depressed individuals would not get frustrated by the task. “Affective interference” was operationalized as the degree to which the affective content of the emotional stimulus predicted brain activity on the subsequent nonemotional processing trials.

Our basic hypothesis was that depressed individuals would show more sustained activation in brain areas responsible for recognizing emotional information during the emotion-processing trial, which would carry over into the subsequent nonemotional processing trial, leading to more affective interference for depressed than never-depressed individuals. Because the preceding theories involve complex interacting systems of disruptions (e.g., positive feedback between the hippocampal and amygdala systems, decreased inhibition of amygdala), it is difficult to predict 1) whether these systems are expected to interact nonlinearly, 2) whether sustained processing is expected to occur for all stimuli or just some as a result of relevant disruptions, and 3) what the precise time course of relevant changes in information processing are expected to be. Computational simulation allows quantitative integration of assumptions about underlying cognitive and biological systems (Siegle and Hasselmo 2001) and was therefore used to further specify hypotheses.

Predictions for changes in fMRI scanner signal in response to positive, negative, and neutral stimuli were made using a computational neural network model of emotional information processing disruptions in depression. A brief summary of the model, described more fully in other papers Siegle 1999, Siegle and Hasselmo 2001a, Siegle and Ingram 1997 follows. In neural network models, activation spreads between connected nodes that loosely represent populations of connected neurons. By systematically changing the strength of connections between these nodes, the model can be made to associate incoming activity with subsequent activity (or a response to a stimulus), and can thus be said to learn associations. Our network was constructed to identify emotional stimuli as positive, negative, or neutral, based on physiologic models (LeDoux 1996). As shown in Figure 1, stimuli (locally coded in the stimulus units) are processed in parallel by units responsible for identifying affective features (an analog of amygdala system functions) and nonaffective features (an analog of hippocampal system functions). Feedback occurs between these layers as a simplified analog of feedback between these brain systems. These layers project to units responsible for making decisions about the information. Activity in the decision units inhibits the emotional processing units, as an analog of the idea that integrative cortical activity could inhibit amygdala processing. Emotionality is encoded (trained) by strengthening connections from input and nonaffective feature units to affective feature units representing either a positive or negative valence. Personal relevance is encoded by the amount the network is exposed to stimuli. More exposure yields enhanced connections between the affective and nonaffective processing systems, using a Hebb learning rule (pathways between simultaneously active features become strengthened). Importantly, model layers are not meant to represent detailed biological features of the involved structures but only their hypothesized functional activity.

To reflect the idea that depression often follows a negative life event (Paykel 1979) that is thought about or well-learned, environmental aspects of depression are operationalized in the model as prolonged exposure to some negative information. Connections to representations of this negative information are thereby strengthened. To represent the decreased inhibition of emotional processing areas by cortex, the strength of activation of the decision units was decreased. Feedback between affective and nonaffective feature detection units was also manipulated as an analog of Ingram’s (1984) idea that depression involves diffusely increased connections to representations of sadness in a depressed person’s semantic network. Manipulation of each of these parameters has been shown to reflect cognitive factors associated with depression (Siegle and Ingram 1997).

To represent alternation between emotional and nonemotional processing (Sternberg memory) trials the model was first presented with an emotional stimulus for valence identification for 300 epochs followed by three nonemotional cues that had no relationship to word stimuli (50 epochs each) and a nonemotional target to identify (300 epochs). A match was judged if activation in response to the target was above an arbitrary threshold, which decreased rapidly over time on a negative exponential function. The decreasing threshold was used to represent the idea that participants respond to nearly every stimulus; as time passes, they apply less strict criteria to making the correct decision. While this simulation does not represent many aspects of the Sternberg task, it does accomplish its primary mission: to allow examination of residual activation from the valence identification task during a period in which nonemotional stimuli are presented. Network parameters are listed in the Appendix.

The network’s behavior was simulated in response to positive, negative, and neutral stimuli on the valence identification task, before and after manipulation of variables related to depression. To make predictions regarding the time course of amygdala activity in response to emotional stimuli, activity in the network’s valence units were summed and convolved with an expected hemodynamic response. The network along with its behavior over time on a valence identification of nonpersonally relevant negative information/Sternberg memory trial pair is depicted on the top of Figure 1. The left side of the figure displays the activity in the network’s valence identification units. In the top graphs an analog of time is on the x axis and activity is on the y axis. The original network’s representation of negative information becomes active and quickly drops off (top left Affective Feature Unit activity graph). In the network in which aspects of depression were simulated, the network’s activity in response to negative information is more sustained (top right Affective and Nonaffective Feature Unit activity graphs). To obtain a prediction for fMRI data, the sum of the network’s valence units was convolved with a gamma function representative of a hemodynamic response. As shown on the bottom graphs on the Affective Feature Unit activity panel, it is predicted that the depressed individuals will display a sustained response to negative words. The network’s valence units, convolved with a gamma function in response to each type of stimulus, is shown on the bottom. As shown in the figure, manipulating parameters analogous to aspects of depression in the network makes its responses to negative words larger and more sustained.

More generally, systematic manipulation of the three parameters relevant to simulating depression (overtraining on negative information, feedback between affective and semantic processing units, and decreased inhibition from decision units) suggested that decreasing inhibition from decision units and increasing feedback within the network made the network’s valence-unit responses to both positive and negative stimuli stronger and more sustained (bottom middle panel of Figure 1); overtraining the network on negative information made its responses to negative words particularly strong (bottom right panel of Figure 1). With strong inhibition of the valence units, overtraining the network had little effect. These observations lead to the novel prediction that disinhibition of the amygdala alone would result in diffusely sustained activity, but not particularly high activity in response to negative information; a more specific additional mechanism such as overlearning of negative associations would be needed to engender particularly sustained amygdala activity in response to negative stimuli. These parameters interacted such that increasing all three parameters resulted in nonlinearly higher responses to negative information than would be expected by any method alone.

Of note, the qualitative character of these behaviors were largely independent of other network parameters listed in the Appendix. For example, the number of nodes governed how many stimuli the network could code; decreasing this number increased the effects of overtraining, but did not change the fact that overtraining led to sustained processing.

Based on the network’s performance, the following analytic strategy was adopted: 1) behavioral data were examined to be sure that stimuli deemed negative and personally relevant were perceived that way by subjects, and that there were no gross differences in reaction times to stimuli among groups. Interference of emotional information processing with Sternberg reaction times was predicted for depressed individuals. 2) In the imaging data, primary hypotheses regarded the detection of sustained amygdala activity in depressed individuals in response to negative information. If depression involves primarily disinhibition of the amygdala system (e.g., as a consequence of deceased cortical activity or increased amygdala-hippocampal feedback) the network’s performance suggested that depressed individuals would display sustained amygdala activity to all emotional stimuli, in comparison with controls. In contrast, if depression also involves strengthening of connections or representations specifically associated with negative information, depressed individuals would display particularly high and prolonged levels of sustained amygdala activity in response to negative information, even after being asked to respond to subsequent unrelated stimuli. 3) To examine whether other brain areas (those implicated by the model and other areas) also preserved sustained activity to negative information, a whole-brain analysis was performed. It was expected that hippocampal activity would co-vary with amygdala activity, and that activity in the dorsolateral-prefrontal-cortex would be diffusely decreased in response to all emotional stimuli in depressed individuals who displayed increased amygdala activity. 4) The clinical relevance of sustained amygdalar processing can be inferred by examining the extent to which it is related to clinically documented phenomena. Since the simulated mechanisms bear resemblance to mechanisms proposed for depressive rumination Siegle and Ingram 1997, Siegle and Thayer in press, we predicted that sustained amygdala activity to negative information would be associated with self-reported rumination. Thus, self-report measures of rumination were also administered and sustained amygdala activity occurring in the seconds following emotional stimuli was examined in relation to self-reported rumination.

Section snippets

Methods and materials

IRB approval for the study and associated consent forms was granted by the University of Pittsburgh IRB and Pittsburgh VA Healthcare System IRB.

Results

Hypotheses generated using the computational model were evaluated. As hypotheses primarily regarded the valence identification task, these data are discussed below. Data from the cued reaction time task are also examined as a nonemotional-processing contrast. As expected, the depressed group scored as significantly more dysphoric on the BDI than the control group (depressed M(SD) = 21.6(9.9), control M(SD) = 2.4(1.8), t(15) = −6.0, p < .0005, Difference (D) = 19 points). The groups also did not

Discussion

The preceding data suggest that depressed individuals display sustained amygdala processing in response to negative information in comparison with controls. Specifically, when a negative word is presented briefly (150 msec), depressed individuals appear to continue to process that information for up to 30 sec, even when they are given a subsequent nonemotional distracting task, designed to provoke activation in brain areas hypothesized to be active in shutting off the amygdala. Moreover,

Acknowledgements

Supported by MH55762, MH01306-05, MH16804, and the Department of Veterans Affairs.

This material is the result of work supported with resources and the use of facilities at the VA Pittsburgh Healthcare System, Highland Drive Division.

The authors thank and acknowledge Wiveka Ramel, Stefan Ursu, Michael Lightfoot, and members of the Clinical Cognitive Neuroscience Laboratory, Biometrics Research Laboratory, and Depression Treatment and Research Program for help in the experimental design,

References (65)

  • A Zangen et al.

    Increased catecholamine levels in specific brain regions of a rat model of depressionNormalization by chronic antidepressant treatment

    Brain Res

    (1999)
  • H.C Abercrombie et al.

    Metabolic rate in the right amygdala predicts negative affect in depressed patients

    Neuroreport

    (1998)
  • S.C Baker et al.

    The interaction between mood and cognitive function studied with PET

    Psychol Med

    (1997)
  • L.R Baxter et al.

    Reduction of prefrontal glucose metabolism common to three types of depression

    Arch Gen Psychiatry

    (1989)
  • J Beatty

    Task-evoked pupillary responses, processing load, and the structure of processing resources

    Psychol Bull

    (1982)
  • A.T Beck

    DepressionClinical, Experimental, and Theoretical Aspects

    (1967)
  • C.J Bench et al.

    Regional cerebral blood flow in depression measured by positron emission tomographyThe relationship with clinical dimensions

    Psychol Med

    (1993)
  • G Bower

    Mood and memory

    Am Psychol

    (1981)
  • M.M Bradley et al.

    Affective Norms for English Words (ANEW)Technical Manual and Affective Ratings

    (1997)
  • C.S Carter et al.

    Parsing executive processesStrategic vs. evaluative functions of the anterior cingulate cortex

    Proc Nat Acad Sci USA

    (2000)
  • N Christenfeld et al.

    On the reliable assessment of cardiovascular recoveryAn application of curve-fitting techniques

    Psychophysiology

    (2000)
  • R.J Davidson

    Assymetric brain function, affective style, and psychopathologyThe role of early experience and placticity

    Dev Psychopathol

    (1994)
  • R.J Davidson

    Affective style, psychopathology, and resilienceBrain mechanisms and plasticity

    Am Psychol

    (2000)
  • P.J Deldin et al.

    A Slow Wave Investigation of Working Memory Biases in Mood Disorders

    J Abnorm Psychol

    (2001)
  • D Dougherty et al.

    Neuroimaging and neurobiological models of depression

    Harv Rev Psychiatry

    (1997)
  • W.C Drevets

    Prefrontal cortical-amygdalar metabolism in major depression

    Ann N Y Acad Sci

    (1999)
  • W.C Drevets et al.

    A functional anatomical study of unipolar depression

    J Neurosci

    (1992)
  • H.L Fritz

    Rumination and adjustment to a first coronary event

    Psychosom Med

    (1999)
  • M.C Gemar et al.

    Effects of self-generated sad mood on regional cerebral activityA PET study in normal subjects

    Depression

    (1996)
  • E Granholm et al.

    Pupillary responses index cognitive resource limitations

    Psychophysiology

    (1996)
  • N Hirono et al.

    Frontal lobe hypometabolism and depression in Alzheimer’s disease

    Neurology

    (1998)
  • S.D Hollon et al.

    Cognitive self-statements in depressionDevelopment of an automatic thoughts questionnaire

    Cognit Ther Res

    (1980)
  • Cited by (719)

    View all citing articles on Scopus
    View full text