Salience in persistent depression

A striking finding from the Study 6 predictive processing model was the relative attenuation of target salience and amplification of cue salience among depressed participants in comparison to healthy controls, suggesting that this group may have been less able to discriminate targets or to potentiate target processing relative to the processing of irrelevant cues. This finding is of great theoretical interest, given the centrality of salience processing to information processing in general.

In order to register and adapt to shifting environmental contingencies, it is necessary for the brain, in its creation of an online inferential working model of that environment, to monitor a constant stream of incoming sensory information and to amplify those aspects of it that are relevant for model updating. Salience within predictive processing accounts has been defined as Bayesian surprise (Itti & Baldi, 2009; Parr & Friston, 2019), which in terms of Bayesian probability distributions is the extent of the change from prior to posterior belief occasioned by the observation of new data. Salient data, therefore, are data which are both precise and informative with respect to existing goals or expectancies, whether because of their motivational significance or due to their novelty and unexpectedness. Saccades, foraging, and exploration are all examples of experimental actions which have the function of eliciting salient information: at a phenomenological level, Parr and Friston (2019) equate salience with intrinsic motivation, which is associated with spontaneous exploration, interest and curiosity (Oudeyer & Kaplan, 2009). According to these definitions, a reduction or loss of specificity in the salience of sensory signals arising in the environment appears very consistent with the phenomenology of persistent depression.

A key neuromodulator underpinning salience processing in the brain is noradrenaline (NA). NA is largely synthesised in the locus coeruleus (LC) and supplied throughout the brain via widespread efferent projections (Amaral & Sinnamon, 1977). LC activity has a tonic mode, associated with arousal and wakefulness, and a phasic mode, in which discharge occurs in response to salient or novel events. High tonic activity is associated with scanning attention and behavioural flexibility, while phasic activity is observed during focused attention and is thought to potentiate the cortical response to motivationally significant sensory information (Berridge & Waterhouse, 2003). Phasic LC discharge is typically observed when tonic activity is moderate, and, like focused task performance, is suppressed when tonic firing rates are either low or high (Aston-Jones, Rajkowski, & Cohen, 1999). It has been proposed that high tonic firing occurs in response to contextual uncertainty, disengaging task-focus

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and promoting exploration in order to collect new data (Aston-Jones & Cohen, 2005), while phasic activity may operate as a network reset, dynamically reconfiguring neural networks in response to stimuli which signal shifts in environmental contingencies in order to facilitate rapid behavioural adaptation (Bouret & Sara, 2005). Yu and Dayan (Dayan & Yu, 2006; Yu & Dayan, 2005) have proposed that the function of NA release is to signal unexpected uncertainty, indicating a need to reset model expectations and to amplify relevant sensory signals to inform a new model of the current context . A related theory was recently advanced by Sales, Friston, Jones, Pickering, and Moran (2019), who have modelled both tonic and phasic LC activity as responses to prediction error which potentiate flexible belief updating.

As a key aspect of salience processing, NA plays a central role in detecting and responding to both threat and potential reward (Berridge & Waterhouse, 2003), and the noradrenergic system is therefore extremely responsive to stress (e.g., Morilak et al., 2005). During acute stress, NA is released both centrally and peripherally, and high tonic LC activity may disengage task-focused attention and promote bottom-up sensory signals in a manner consistent with hypervigilance or scanning for threat (Valentino & Van Bockstaele, 2008). Over the longer-term, both acute and chronic stress induce plasticity in the NA system with likely implications for mood and anxiety disorders (Borodovitsyna, Joshi, & Chandler, 2018), and although the precise relationships between chronic stress, changes in NA signalling and depression are not yet clear (Maletic, Eramo, Gwin, Offord, & Duffy, 2017), there is robust evidence for noradrenergic system disruption in individuals with depressive illness (e.g., Leonard, 2001; Moret & Briley, 2011).

A possible electrophysiological marker of NA function is the P3 wave of the event-related potential (ERP) in EEG studies, a late component that is typically observed in oddball tasks and in response to attended, novel or salient stimuli (Pritchard, 1981). Its amplitude is inversely related to the probability of the stimulus, and positively related to its salience (Nieuwenhuis et al., 2005), and it has been suggested that it indexes prediction error (Feldman & Friston, 2010) or context updating (Donchin & Coles, 1988). On the basis of similarities in the observed response patterns, Nieuwenhuis et al. (2005) have suggested that the P3 is an electrophysiological correlate of phasic LC activity. Of interest, a substantial literature suggests that the amplitude of the P3 wave is typically blunted in depression, (Bruder et al., 2012; Klawohn, Santopetro, Meyer, & Hajcak, 2020), consistent with the proposal that salience registration and associated context updating may be dampened in depressive illness.

In line with this proposal, in our Study 6 electrophysiological simulation, following Feldman and Friston (2010) and based on parameter estimates derived from our empirical data, we found that of all

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simulated ERP components, the one that was attenuated most drastically in the depressed group was the one considered to be analogous to the P3 in response to an unexpected target. This attenuation reflected a failure to fully update context representations and was the result of reduced target salience which contributed to a dampening of both sensory precision and its expectation in depressed participants. This simulation suggests the hypothesis that as a result of disturbed salience processing, persistent depression may be characterised by failures in the updating of online working models of the current context or environment. In line with this proposal, perseverative errors in set-shifting tasks and difficulties in inhibiting irrelevant information in working memory updating tasks have been repeatedly observed in depressed individuals (Gotlib & Joormann, 2010; Harvey et al., 2004; Le, Borghi, Kujawa, Klein, & Leung, 2017; Rock et al., 2014; Snyder, 2013) and may provide an alternative index of the same difficulties in salience attribution and subsequent context updating.