The reward processes

As mentioned above, reward processes include at least three components: “liking” or con-summatory pleasure (current experience of pleasure), “wanting” or anticipatory pleasure (an-ticipation of future pleasurable experiences) and reinforcement learning (associative learning a cue to a reward/loss) (Berridge and Kringelbach, 2015). Findings regarding reward pro-cessing in schizophrenia, population at risk for psychosis and the 22q11DS will be described in details in the followings sections.

Consummatory and anticipatory pleasure

Historically, patients with psychosis were described as having global impairments in the experience of pleasure, referred to as anhedonia (Ribot, 1896). Thus, the investigation of pleasure experience became a main focus of interest in the field of schizophrenia. Specifically, several studies demonstrated that patients with schizophrenia experience similar amounts of positive emotions compared to healthy individuals during hedonic judgments (Cohen and Minor, 2010; Kring and Moran, 2008; Llerena et al., 2012) and in daily-life (Gard et al., 2007;

Myin-Germeys et al., 2000; Oorschot et al., 2013). Progressively, a distinction between the ability to anticipate and experience pleasure has been emphasized (Berridge et al., 2009). In order to examine the consummatory and anticipatory pleasure dimensions separately, Gard et al., (2006) developed the Temporal and Experience Pleasure Scale (TEPS, (Gard et al.

2006). This scale has been repeatedly used and the majority of the studies highlighted that patients with schizophrenia reported intact consummatory but impaired anticipatory plea-sure compared to healthy individuals (Chan et al., 2010; Favrod et al., 2009; Gard et al., 2006; Lui et al., 2015; Mote et al., 2014; Wynn et al., 2010). For example, in the original study from Gard et al. (2007) conducted in 51 patients with schizophrenia and 50 healthy participants, the authors observed significant differences for the anticipatory pleasure but not for the consummatory dimension (Gard et al., 2007). The same authors confirmed these results in an experience sampling study conducted in 47 patients with schizophrenia (N=31) or schizoaffective disorders (N=16) and 41 healthy participants. In this study, patients re-ported to anticipate goal-directed activities as less enjoyable than healthy participants (Gard et al., 2014). Nevertheless, some evidence suggested impairment in both pleasure dimensions (Schlosser et al., 2014) or in the consummatory pleasure dimension only (Li et al., 2015b;

Strauss et al., 2011). In individuals with CHR or people from the general population with high negative schizotypy traits, most studies reported alterations in both anticipatory and consummatory pleasure compared to controls (Gooding and Pflum, 2012; Li et al., 2015b;

Martin et al., 2011; Schlosser et al., 2014), whereas one study observed alterations in the anticipatory pleasure component only (Shi et al., 2012). The examination of the association between the pleasure dimensions and the severity of negative symptoms revealed controver-sial results. Indeed, some studies reported associations between both pleasure dimensions and negative symptoms (Chan et al., 2010; Favrod et al., 2009; Gard et al., 2006; Li et al., 2015a; Loas et al., 2014; Lui et al., 2015), additional studies found specific association be-tween anticipatory pleasure and negative symptoms (Engel et al., 2013), and others observed associations between anticipatory pleasure and positive symptoms (Strauss et al., 2011). A few years later, the Anticipatory and Consummatory Interpersonal Pleasure Scale was cre-ated (ACIPS, (ACIPS Gooding and Pflum, 2014) in order to answer to the disadvantage of the original TEPS. Indeed, the TEPS focused on the assessment of physical pleasure whereas the ACIPS also assessed social aspects of pleasure. Surprisingly, no study to date has com-pared the ACIPS subscales between individuals with and without schizophrenia, and only the association with negative symptoms was examined (Gooding et al., 2018). Consistent with studies using the TEPS, associations between the ACIPS scores and the negative symptom severity was observed in a sample of individuals with schizophrenia. The divergent results obtained with these questionnaires might be due to the fact that consummatory assessment through a self-report does not reflect real in-the-moment pleasure and could be influenced by cognitive factors such as episodic memory or deficit in internal representation of the stimuli value (Gold et al., 2008).

At the brain level, in order to examine the two pleasure dimensions distinctly, the majority of studies used adapted version of the monetary incentive delay task. In this task,

partici-pants are asked to press a button when a target symbol appears. Cues signaling potential reward magnitude or no outcome are previously presented, which consists to the anticipation phase. Success is acknowledged by presenting the picture of the reward, which refers to the consumption phase. Studies conducted in the general population revealed that the two plea-sure dimensions are largely underpinned by distinct neural mechanisms. While anticipatory pleasure mainly relies on the ventral striatum, in particular the nucleus accumbens (NAcc), consummatory pleasure mainly involves the ventromedial frontal cortex (VMFC) as well as the ventral striatum, yet to a lesser extent than anticipatory pleasure (Knutson et al., 2001). As behavioral studies indicated that the anticipatory pleasure dimension appears mostly impaired in individuals with schizophrenia, the majority of neuroimaging research focused on reward anticipation deficit. Mainly, hypoactivation of the ventral striatum has been reported during reward anticipation in unmedicated patients with schizophrenia and those treated with typical antipsychotics compared to healthy controls (Arrondo et al., 2015;

Dowd and Barch, 2010; Ernst et al., 2004; Grimm et al., 2014; Juckel et al., 2006; Mucci et al., 2015; Nielsen et al., 2012; Richter et al., 2015; Simon et al., 2010; Subramaniam et al., 2015). Furthermore, ventral striatum hypoactivation has been found to be associated with overall negative symptoms severity (Juckel et al., 2006), the motivational domain uniquely (Arrondo et al., 2015; Mucci et al., 2015; Simon et al., 2010), depressive (Arrondo et al., 2015)and positive symptoms (Nielsen et al., 2012). In individuals at-risk for psychosis, while one study did not observe divergent activation within the ventral striatum in UHR patients during reward anticipation (Juckel et al., 2012), another study reported reduced activation within this region in individuals with high psychosis-like symptoms (Simon et al., 2010). Re-cently, one study conducted in the 22q11DS population reported reduced activity in medial frontal regions (precuneus and posterior cingulate) during reward anticipation compared to healthy controls (van Duin et al., 2016). No association with negative symptoms was found.

A few studies also examined neural correlates of reward consumption in schizophrenia (See for a review Yan et al., 2015). Recently, Yan et al. (2015) conducted a meta-analysis of func-tional imaging studies and revealed that the most robust and consistent results consist in a decrease of activation within the rostral medial frontal cortex in patients with schizophrenia compared to healthy controls during consummatory pleasure. Nevertheless, one study ob-served that patients with schizophrenia activated similar network than healthy participants during reward consumption (Subramaniam et al., 2015). In the studies described above, only monetary reward processing has been considered. Thereafter, a few studies examined neural correlates of pleasure dimensions between non-social (‘monetary’) and social reward processing. In the general population, only one study distinguished the two reward aspects (Rademacher et al., 2010). Authors demonstrated that during anticipation, both types of re-ward activated similar regions, in particular the ventral striatum, while rere-ward consumption involved different patterns of activation. Monetary reward mainly involved the thalamus and social reward mainly evoked the amygdala (Rademacher et al., 2010). To date, no study has compared the neural networks underlying anticipation and consumption for monetary and social rewards in schizophrenia or in the 22q11DS population. For this reason, one study of this project will examine neural correlates for both monetary and social reward processing

in the 22q11DS population.

In summary, in this section, we reported that pleasure dimensions deficits are observed along the continuum of psychosis. In particular, alterations of anticipatory pleasure have been observed in individuals with schizophrenia and have been associated with dysfunction within the ventral striatum. Whereas self-reports showed intact consummatory pleasure in people with schizophrenia, neuroimaging studies suggest impaired activation in the rostral medial frontal cortex during reward consumption. Thus, it seems that self-reported question-naires do not successfully reflect the consummatory dimension and additional methodologies should therefore be considered (e.g. experience sampling).

Reinforcement learning

Nowadays, reinforcement learning has received less attention than pleasure dimensions in schizophrenia. Nevertheless, the few studies that have been conducted suggest im-paired reward learning and association between reward learning and psychotic symptoms in schizophrenia. Although studies varied considerably in terms of paradigms (go-no-go, probabilistic learning tasks, Iowa Gambling Task), the majority reported deficits in reward learning (Barch et al., 2017; Dowd et al., 2016; Gold et al., 2012; Nestor et al., 2014; Schla-genhauf et al., 2014; Strauss et al., 2011), while only one observed no significant difference in terms of reward learning between individuals with schizophrenia and healthy controls (Lewandowski et al., 2016). For example, Barch and colleagues (2017) recently examined reinforcement learning across the psychosis spectrum in a sample composed of patients with schizophrenia (N=65), schizoaffective (N=53), bipolar disorders (N=50) and healthy con-trols (N=60). Authors found that patients with schizophrenia or schizoaffective disorders performed significantly worse on reinforcement learning than healthy controls. Some stud-ies also reported specific associations between reward learning deficit and avolition/apathy domain (Barch et al., 2017), negative symptoms total score (Gold et al., 2012; Nestor et al., 2014; Strauss et al., 2011) or positive symptoms (Schlagenhauf et al., 2014). In popula-tion at risk for psychosis, to our knowledge only one study has examined reinforcement learning and authors found that people at risk for psychosis have a similar percentage of correct choices compared to healthy controls, suggesting intact reinforcement learning in this population (Ermakova et al., 2018). In the 22q11DS population, one study examined reinforcement learning in 13 individuals with 22q11DS and 18 healthy controls. Authors revealed that patients with 22q11DS earned less money and had worse overall accuracy dur-ing the reinforcement-learndur-ing task, suggestdur-ing impaired reinforcement learndur-ing compared to healthy controls (van Duin et al., 2018). A few neuroimaging studies have examined the neural correlates of reward learning impairment in psychosis. Mainly, reinforcement learning deficits have been found to be associated with alterations in striatal brain regions (Koch et al., 2010; Schlagenhauf et al., 2014; van Duin et al., 2018). For example, Schlagenhauf et al. (2014) reported hypofunction in the ventral striatum during reward learning in 24 patients with schizophrenia compared to 24 healthy controls.

When I began this PhD project in 2016, there was no existing study investigating reward-related processes in the 22q11DS population. It was only in parallel of this project that two studies on this topic were published (van Duin et al., 2016, 2018). Nevertheless, given the large evidence of reward processing impairments in the field of psychosis and their link with negative symptoms, the examination of these processes in the 22q11DS appeared of crucial importance. In addition to the role of reward-related-processes, motivation components have also been described as involved in goal-directed-behavior generation Studies focusing on mo-tivation components in the field of psychosis will be described in the next sections.