these interventions showed relatively small efficiency in the treatment of negative symptoms.
Antipsychotic medications, which are commonly prescribed in the context of schizophrenia, have shown a very modest effect in the treatment of negative symptoms. Although, new generation of antipsychotics have received interest, current findings do not support a sig-nificant difference compared to atypical antipsychotics (Harvey et al., 2016; Moosavi et al., 2015; Shoja Shafti and Fallah Jahromi, 2014). Additional pharmacological treatments target-ing the glutamatergic, dopaminergic, serotonergic or noradrenergic system have been tested without showing any promising effects on negative symptoms (See for a review Veerman et al., 2017). Several psychological interventions have also been proposed in the treatment of negative symptoms. The majority of these interventions are based on a cognitive conceptu-alization of negative symptoms (Beck and Rector, 2005). Mainly, the effect of psychosocial therapies such as cognitive behavioral therapies (Grant et al., 2014; Valmaggia et al., 2005), cognitive remediation (Demily and Franck, 2008; Eack et al., 2009; Hogarty et al., 2004), or cognitive adaptation training (Velligan et al., 2008) have been tested. However, only mod-erate effects on negative symptoms treatment have been reported. Recently, Velligan et al.
(2014) developed the MOtiVation and Engagement Training (MOVE) to specifically address each negative domain (Velligan et al., 2014). A first randomized pilot study conducted in 51 patients with persistent negative symptoms was conducted. Preliminary results showed that MOVE improves overall negative symptoms assessed with the SANS and Negative As-sessment Scale after 9 months of treatment (Velligan et al., 2015). Nevertheless, moderate effect sizes were observed and testing the efficacy of MOVE in larger samples is still required.
2.4 Neuroimaging findings associated with negative symptoms
In the field of schizophrenia, although numerous brain regions have been shown as correlated to the severity of negative symptoms (See for a review Galderisi et al., 2015), very few studies have examined these brain changes in subgroups of patients characterized by predominant or persistent negative symptoms. Based on previous reviews (Galderisi et al., 2015; ˙Ince and U¸cok, 2018), we will provide a description of the structural and functional alterations that¨
have been observed in subgroups of patients marked by predominant negative symptoms (in particular patients with deficit schizophrenia) and patients with persistent negative symp-toms.
Deficits versus non-deficit schizophrenia
A few studies have examined brain correlates in patients with deficit schizophrenia (i.e.
marked by primary and persistent negative symptoms). At the structural level, controversial finding of ventricular enlargement in deficit versus non-deficit patients have been reported (Arango et al., 2008; Galderisi et al., 2008; Gur et al., 1994; Quarantelli et al., 2002; Sig-mundsson et al., 2001). While a single study observed ventricular enlargement in deficit compared to non-deficit patients (Arango et al., 2008), the rest of the studies reported op-posite results (Galderisi et al., 2008; Gur et al., 1994; Quarantelli et al., 2002; Sigmundsson et al., 2001). A few studies examined brain volume in deficit and non-deficit schizophrenia.
Mainly, increased volume in prefrontal regions including the dorsolateral prefrontal (DLPFC) cortices have been suggested in deficit vs. non-deficit patients (Buchanan et al., 1993; Quar-antelli et al., 2002; Volpe et al., 2012). Nevertheless, Fisher et al. (2012) revealed a lack of structural DLPFC anomalies in deficit patients using a segmentation analysis. Consistent with others studies, the authors observed reduced volume in superior prefrontal and tempo-ral region in deficit compared to non-deficit patients (Fisher et al., 2012). Another study, based on voxel-based morphology found reduced grey matter volume in temporal regions but also in additional brain regions including the insula, amygdala, anterior cingulate, me-dial prefrontal, putamen and precuneus (Cascella et al., 2010). This result is in accordance with Takayanagi et al. (2013) who reported anterior cingulate volume reduction in deficit patients compared to non-deficit and healthy controls (Takayanagi et al., 2013). However, one study found no evidence of divergent gray matter volume between deficit and non-deficit patients ( ¨Ozdemir et al., 2012). White matter studies provided more consistent findings, with impaired integrity of the white matter reported mostly in the superior longitudinal fas-ciculus (Rowland et al., 2009), uncinate fasfas-ciculus (Kitis et al., 2012; Voineskos et al., 2013), inferior longitudinal fasciculus, and actuate fasciculus (Voineskos et al., 2013). At the func-tional level, several positron emission tomography studies have been conducted and showed hypometabolism within the thalamus, frontal and parietal cortices in deficit compared to non-deficit patients (Gonul et al., 2003; Heckers et al., 1999; Lahti et al., 2001; Vaiva et al., 2002). Moreover, a recent fMRI study observed reduced caudate activation during reward anticipation in deficit patients compared to both non-deficit and healthy subjects (Mucci et al., 2015).
Persistent negative symptoms
Persistent negative symptoms (PNS) are a broader concept defined by the presence of negative symptoms during at least 6 months. In a recent Activation Likelihood Estimation meta-analysis examining gray matter volume in patients with persistent negative symptoms,
reduced brain volume in the bilateral medial frontal, left precentral, left middle frontal, bilat-eral parahippocampal gyri as well as in some sub-cortical regions including the left anterior cingulate, left caudate nucleus, the thalamus and the insula was observed. In a study con-ducted by Hovington and Lepage (2012), summarizing the temporal and more particularly the hippocampus alterations in patients with PNS, a reduction of the amygdala-hippocampal complex volume was mainly reported (Anderson et al., 2002; Makowski et al., 2017; Shenton et al., 2002). Moreover, the few studies examining cortical thickness revealed increased cortical thinning in patients with PNS in the right parahippocampal and right orbitofrontal gyri (Benoit et al., 2012; Bodnar et al., 2014). Additional regions including the bilateral anterior cingulate, right posterior cingulate, bilateral temporal and fusiform appear to be thinner in patients with PNS. In addition, white matter (WM) studies revealed that patients with PNS have disrupted white matter integrity in the fornix compared to healthy controls, while PNS versus non-PNS patients exhibit lower WM integrity in the left supe-rior longitudinal fasciculus (Hovington et al. 2015). To date, the functional neuroimaging correlates associated with PNS have not been examined.
22q11DS population
In the 22q11DS population, one study conducted a cluster analysis in order to identify morphological brain differences in patients marked by negative symptoms (Mihailov et al., 2017). Authors revealed that 22q11DS patients with high negative symptom severity have lower gyrification in the left medial occipito-temporal, lateral temporo-parietal cortices and right medial temporal/posterior cingulate cortex compared to patients with low negative symptoms.
In summary, in the previous sections we demonstrated the importance of negative symp-toms in the field of psychosis. Additionally, we also pointed out the core place of negative symptoms in the 22q11DS clinical picture. Nevertheless, in view of the moderate effects of treatments targeting negative symptoms, a better understanding of the mechanisms in-volved in their emergence appears of crucial importance. For these reasons, we propose in this project to investigate risk factors for negative symptoms in association with their un-derlying cerebral networks.
CHAPTER
3
CURRENT MODELS OF NEGATIVE SYMPTOMS
As illustrated in the previous section, given the persistence of negative symptoms, their poor response to treatment, and their strong association with functioning, there has been a resurgence of interest to study the mechanisms involved in the emergence and maintenance of negative symptoms. In this third chapter, we will first briefly present the different factors that have been hypothesized to be related to negative symptoms. We will then focus on the current explanatory models of negative symptoms that particularly point toward reward-related-processes and social cognition and will provide a review of the behavioral and neural underpinnings of these models.
3.1 Negative symptoms mechanisms: an overview
Over the decades, several factors have been hypothesized as involved in the expression of neg-ative symptoms in the field of psychosis. Among these factors, the role of positive symptoms, specific comorbid symptoms as well as neurocognitive deficits have been pointed out. Nev-ertheless, in view of the small effect of interventions targeting these factors in the treatment of negative symptoms, new explanatory models of negative symptoms have progressively been proposed. In this section, we will briefly describe the factors that have been previously thought to be at the origin of negative symptoms together with the reasons that led to a
shift toward new explanatory models of negative symptoms. Millan and colleagues (2014) in a recent review demonstrated that negative symptoms appear to be interrelated to other core features of schizophrenia (Figure 3.1) including positive symptoms, specific comorbid symptoms as well as neurocognitive deficits(Millan et al., 2014). First, literature in the field of schizophrenia suggested that positive symptoms might account for some negative symptoms (Messinger et al., 2011). Indeed, some positive symptoms such as suspicious-ness and paranoia can interfere with social motivation and lead to asociality and additional aspects of negative symptoms. Additionally, co-morbid symptoms such as depression and anxiety might also contribute to the expression of negative symptoms. The consummatory anhedonia of depression and anticipatory anhedonia of schizophrenia having been distin-guished (See for a review Krynicki et al., 2018); comorbid depression may thus aggravate negative symptoms by compromising hedonic states and therefore affecting processes guid-ing goal-direct-behavior accomplishment. Anxiety is also very common in schizophrenia as well as social anxiety, which could interfere with engagement in social interactions and thus specifically lead to social withdrawal (Pallanti et al., 2004; Romm et al., 2011; Voges and Addington, 2005). However, positive symptoms as well as co-morbid symptoms have been shown to be associated with a single class of negative symptoms: the secondary negative symptoms, whom emergence appears to be non-intrinsic of the disease (Carpenter et al., 1988). Thus, the management of positive or co-morbid symptoms will lead to improvement of secondary negative symptoms whereas negative symptoms intrinsic of the disorder, named as primary negative symptoms will still persist over time. Finally, neurocognitive deficits have been a focus of interest in negative symptoms due to their stronger association with negative than with positive symptoms (See for a meta-analysis Ventura et al., 2009). Al-though controversial results have been reported, associations between some cognitive deficits and negative symptoms have been observed. In particular, associations with impaired ex-ecutive functions, working memory, episodic memory and top-down cognitive control have been pointed out (See for a review Millan et al., 2014). Nevertheless, treatments focusing on neurocognition have shown little effect on negative symptoms (See section 2.5). Moreover, despite the fact that the majority of individuals with schizophrenia have some cognitive im-pairments, only half of them experience negative symptoms.
In this section, we presented the factors thought to be implicated in negative symptoms emergence in schizophrenia. Nevertheless, as the management of these factors have shown little effect in the treatment of negative symptoms, a focus towards new explanatory models have been made aiming to clearly identify the mechanisms leading to negative symptoms and developing more effective and targeted treatment. In particular, current works have shifted their interest toward reward-related and socio-cognitive processes.
Figure 3.1: Relationship between negative symptoms and additional features of schizophrenia.
From Millan et al., (2014).