Siegle et al, Sustained Amygdala Activity in Depression 1 Can’t Shake that Feeling: Event-related fMRI Assessment of Sustained Amygdala Activity in Response to Emotional Information in Depressed Individuals

Background. Previous research suggests depressed individuals engage in prolonged elaborative processing of emotional information. A computational neural network model of emotional information processing (Siegle 1999) suggests this process involves sustained amygdala activity in response to processing negative features 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 fMRI during alternating 15 second emotional processing (valence identification) and nonemotional processing (Sternberg memory) trials. Amygdala regions were traced on highresolution structural scans and co-registered to the functional data. The time course of activity in these areas during emotional and non-emotional processing trials was examined. Results. During emotional processing trials, never-depressed individuals displayed amygdalar responses to all stimuli, which decayed within 10 seconds. In contrast, depressed individuals displayed sustained amygdala responses to negative words that lasted throughout the following non-emotional processing trials (25 seconds 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. Siegle et al, Sustained Amygdala Activity in Depression 3 Introduction Some of the most troubling aspects of depression involve prolonged involuntary processing of emotional information, in the form of elaboration (e.g., MacLeod & Mathews 1991) or rumination (e.g., 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 (e.g., Williams & Oaksford 1992), and has been implicated in the onset and maintenance of depression (e.g., Beck 1967; Ingram 1984, 1990; Ingram, Miranda, & Segal 1998; MacLeod & Matthews 1991; Teadsale 1988). This study examines brain mechanisms associated with sustained processing after briefly presented negative information in depressed and never-depressed individuals using 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. Evidence for Sustained Processing in Depression 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 (e.g., Matt et al, 1991), and to interpret events as negative (e.g., Norman et al, 1988). Similarly, Wenzlaff et al (1988) have shown dysphoric individuals display intrusive negative thoughts, even during thought-supression. Elaborative processing has also been advanced as an explanation for delays by depressed individuals in naming the color in which emotional words are written (e.g., Williams & Nulty, 1986), in the absense of early attentional effects (e.g., MacLeod et al, 1986). Siegle et al, Sustained Amygdala Activity in Depression 4 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 (e.g., Deldin et al, 2001; Christenfeld et al 2001; Siegle et al 2001a,c; 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 seconds 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 non-emotional processing tasks, e.g., 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 seconds 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 six seconds following the presentation of negative pictures; particularly those displaying frontal EEG assymetry. 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. Mechanisms Underlying Sustained Processing 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 (e.g., Bower 1981), depressed individuals suffer from strongly activated connections between negative Siegle et al, Sustained Amygdala Activity in Depression 5 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, e.g., Gallagher & Chiba 1996; LeDoux, 1993, 1996) and other brain areas primarily responsible for identifying nonemotional aspects of information (e.g, the hippocampal system, LeDoux, 1996). These systems are highly connected, and subject to feedback (e.g., Tucker & 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 non-emotional aspects of information including the hippocampus. Amygdala hyperactivation, in particular, has been demonstrated in depressed individuals (Abercrombie et al. 1998; Drevets 1999) and has been implicated in the maintenance of depression (Dougherty & Rauch 1997). Disruptions in both volume and activity of these structures have been noted in depressed individuals (e.g., Drevets et. al. 1992; Drevets 1999; Hornig, Mozley, & Amsterdam 1997; Sheline, Sanghavi, Mintun, & Gado 1999) and in animal models of depression (e.g., Zangen, Overstreet, & Yadid 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; e.g., Davidson, Siegle et al, Sustained Amygdala Activity in Depression 6 2000). While such inhibitory pathways have not been empirically identified inverse relationships between DLPFC and amygdala activity have been shown through functional neuroimaging (e.g., Drevets 1999). Moreover, multiple studies have demonstrated decreased DLPFC activation in depressed individuals (e.g., Davidson 1994, 2000; Baxter et al 1989; Bench et al 1993). Similarly, non-depressed individuals have decreased DLPFC activation during induced sad moods (e.g., 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 seconds 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. Assessment of Sustained Affective Processing Using fMRI fMRI provides a non-invasive 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 non-emotional processing. A common approach to provoking emotional processing was used in which individuals are asked to name Siegle et al, Sustained Amygdala Activity in Depression 7 the affective valence (positive, negative, or neutral) of presented stimuli (a “valence identification task,” e.g., Hill & Kemp-Wheeler 1989; Mathews & Milroy 1994; Siegle et al 2001a,b,c). The common delayed match to sample, or “Sternberg memory” task was chosen as an appropriate non-emotional processing task. This task involves showing participants three numbers followed by a fourth number. Participants are 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, because 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 non-emotional 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 non-emotional 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 non-linearly, 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 & Hasselmo, 2001) and was therefore used to further