The most ecological way to assess visual exploration is through the use of the eye-tracking method. The eye-tracker allows to measure the position of the eyes and their movement on the screen based on the optical tracking of corneal reflections. Infrared light source placed at the bottom of the screen is directed towards the center of the pupil, leading to visible reflection on the cornea. A camera captures an image of the eye showing these reflections. A vector formed by the distance between the cornea and the pupil is calculated. The direction of this vector is then used to calculate the gaze position on the screen (Figure 4.6). Most eye-tracking studies extract parameters on pre-defined regions of interest (Beedie et al., 2011) in order to determine where individuals are looking on specific stimuli. Moreover, static stimuli have been mostly used in the context of eye-tracking studies. Nevertheless, visual exploration of our own environment is highly dynamic and free of any constraints, thus from an ecological point of view, the use of data-driven analyses prevails.
In particular, in this project we used a novel data-driven method developed by Kojovic et al. (in prep). This method allows to define a frame by frame ‘normative’ visual exploration pattern from a chosen normative group by using the kernel density distribution estimation.
Gaze data from the group of interest is then compared to these normative maps. For each participant, the distance of his/her gaze data from the norm is calculated. This measure
Figure 4.6: Eye-tracking basic principles.
called ‘mean proximity’ had values ranging from 0 to 1 (higher values indicate that gaze allocation is closer to the one of the focus of normative group on a given frame)(Figure 4.7).
Based on this data-driven method, additional parameters such as the dispersion (‘vari-ability of gaze position between participants’) or number of foci (‘number of focus of interest attracting participant’s gaze’) can be computed to better understand which strategies are used by participants when viewing stimuli.
Figure 4.7: Example of a normative map for one frame of the social scene (each small red dot represents one control participant from the normative group; the lines represent the extent of the norm based on the kernel density algorithm. The purple circle represents the gaze fixation from a participant with 22q11DS on this specific frame. The big red circle represents the gaze fixation
from a control participant on this specific frame.
CHAPTER
5
AIMS AND HYPOTHESES
This project included patients with 22q11DS collected in the context of the “Swiss longitu-dinal cohort” which started in 2002. The Geneva cohort includes about 200 patients with 22q11DS and about 190 healthy controls (approximately 70% of them are siblings of partici-pants with 22q11DS) recruited through parent associations and word to mouth. Participartici-pants recruited in the Geneva cohort are followed longitudinally with a time interval of approx-imately three years between two visits. During each visit, clinical, cognitive, eye-tracking and MRI data are acquired. MRI data include T1-weighted imaging, resting-state fMRI, diffusion tensor imaging and additional specific fMRI paradigm imaging.
In light of the literature reported above, this project has been conducted with two major aims:
1. Investigate the implication of reward-related-processes alterations in the expression of negative symptoms
While starting this project, no study investigating reward-related processes in patients with 22q11DS had been conducted. Reward-related-processes are thought to be involved in the emergence of negative symptoms, particularly in the apathy-avolition domain. There-fore, we argue that studies of reward-related-processes would bring a better understanding of mechanisms underlying negative symptoms in the 22q11DS population. We conducted three studies aimed to examine behavioral and neural correlates of reward-related processes
in 22q11DS.
Study 1
In this study, we aimed to investigate hedonic capacity, structural connectivity of the reward system and their links with negative symptoms in 22q11DS. In line with studies conducted in at-risk population, we hypothesized impairments in both pleasure dimensions as well as a specific association between anticipatory pleasure and negative symptoms. We expected to observe alterations in structural connectivity of the reward system and an asso-ciation with hedonic capacity and negative symptoms.
Study 2
In this study, we investigated brain networks underlying social and non-social reward processing (anticipatory and consummatory) in the 22q11DS population. We expected that individuals with would exhibit different brain activation patterns during reward anticipation and consumption compared to controls. We hypothesized that alterations would be particu-larly marked for social compared to non-social reward processing. Finally, we expected that brain alterations of reward processing would be related to negative symptom severity
Study 3
This study aimed to investigate the impact of verbal and non-verbal initiation (‘goal-directed behavior’) in the expression of negative symptoms in the 22q11DS population. We expected to observe impaired verbal and non-verbal initiation in patients with 22q11DS and associations between initiations performances, social functioning and negative symptom severity.
2. Investigate the implication of social perception in the expression of negative symptoms Previous studies in schizophrenia pointed out the role of socio-cognitive impairments in the emergence of negative symptoms. In the following studies, we thus examined the be-havioral and neural substrates of a core aspect of social cognition, namely social perception, and its association with negative symptom severity in patients with 22q11DS.
Study 4
This study aimed to quantify visual processing of complex social scenes based on an eye-tracking data-driven methodology in the 22q11DS population. We explored developmental trajectory of social scenes perception (varying in terms of social complexity) in 22q11DS.
Moreover, additional parameters aimed at better characterizing visual exploration patterns in
22q11DS individuals and healthy controls were included, namely the dispersion and number of foci. These measures were compared across age groups and between groups. Association with negative symptom severity was also examined. We hypothesized that patients would show divergent visual pattern of visual exploration of social cues compared to controls, and a more atypical pattern for scenes with higher social complexity, We also expected that the atypical pattern of visual exploration would be related to socio-cognitive impairments and negative symptom severity. Finally, we aimed to identify a specific time window for the onset of deviant social perception in 22q11DS.
Study 5
This study aimed to investigate the neural substrates of socio-emotional perception in the 22q11DS population. In line with literature in schizophrenia, we expected to observe altered brain activity in the social perception network in patients with 22q11DS. Based on previous findings in 22q11DS, we expected to observe altered activation in the fusiform face area as well as in the insula and frontal regions. Finally, we hypothesized that altered ac-tivation of socio-emotional networks would be related to socio-cognitive deficits in patients with 22q11DS.
Study 6
As a follow-up of the previous study, we explored default mode network (DMN) connec-tivity, a major network of social cognition, during a social perception paradigm in patients with 22q11DS. Furthermore, we assessed whether changes in DMN connectivity could be associated with attenuated symptoms of psychosis. We predicted that individuals with 22q11DS would show divergent DMN connectivity during social perception. Additionally, we hypothesized that DMN disconnectivity would be associated with social functioning and negative symptom severity.
Part II
Results
The results reported in this thesis are based on the following research articles:
1. Lydia Dubourg, Maude Schneider, Maria Carmela Padula, L´ea Chambaz, Marie Schaer, Stephan Eliez.
Implication of reward alterations in the expression of negative symptoms in 22q11.2 deletion syndrome: a behavioural and DTI study. Psychological Medicine (2017).
2. Lydia Dubourg, Pascal Vrticka, Virginie Pouillard, Stephan Eliez, Maude Schneider.
Deficits of reward processing specific to social stimuli in the 22q11.2 deletion syndrome: an fMRI study (In prep.)
3. Lydia Dubourg, Johanna Maeder, Virginie Pouillard, Stephan Eliez, Maude Schneider.
Goal-directed-behavior in 22q11.2 deletion syndrome: role in social dysfunction and negative symptoms emergence. Frontiers Psychiatry (under review)
4.Dubourg Lydia1, Kojovic Nada , Virginie Pouillard, Marie Schaer, Stephan Eliez,Maude Schneider. Visual processing of complex social scenes in 22q11DS: relevance for social impairments? (In prep)
5. Lydia Dubourg, Maude Schneider, Pascal Vrticka, Martin Debban´e, L´ea Chambaz, Stephan Eliez, Maude Schneider. Neural correlates of socio-emotional perception in 22q11.2 deletion syndrome. Journal of Neurodevelopmental Disorders (2018).
6. Lydia Dubourg, Pascal Vrticka, Virginie Pouillard , Stephan Eliez, Maude Schneider.
Default mode network disconnectivity during social perception in the 22q11.2 deletion syndrome. Psychiatry Research: Neuroimaging (under review).
In these articles, I participated to the conception of the project. I contributed to the be-havioral and neuroimaging data collection, I processed the data and conducted the statistical analyses, I wrote the manuscripts and performed the revisions. In the following sections I will briefly summarize the methods and results of each articles. The full-length manuscripts are reported in Appendix A.
In this project, we investigated potential mechanisms and cerebral networks underlying neg-ative symptoms along two main axes reward-related-processes and social perception, a core aspect of social cognition. The first axis includes studies 1, 2 and 3 and aimed to examine the implication of reward-related processes in the expression of negative symptoms. We highlighted deficits in several reward-related components in 22q11DS. Deficits in anticipa-tory and consummaanticipa-tory pleasure (study 1), as well as in verbal and non-verbal initiation (goal-directed-behavior) (study 2) were observed in patients with 22q11DS. We supported our hypothesis of altered reward-related components in patients with 22q11DS. Moreover, we
demonstrated that some components are associated to negative symptom severity. Indeed, anticipatory pleasure and verbal initiation appear to be predictive of the negative symptoma-tology. We thus confirmed our initial hypothesis suggesting that deficits in reward-related processes would predict negative symptom severity. Study 1 revealed structural alterations of the reward system, whereas study 2 showed brain activation impairments during reward processing. Therefore, we confirmed our hypothesis of altered brain correlates of the reward system in patients with 22q11DS.
Study 4, 5 and 6 allowed us to complete our second objective, aiming to investigate the role of social perception in the expression of negative symptoms. Study 4 aimed at quan-tifying the visual exploration of social stimuli in patients with 22q11DS. We observed an atypical pattern of exploration of social information as well as an association between the di-vergent pattern of exploration and negative symptom severity in 22q11DS individuals (study 4). Thus, our initial hypothesis of altered social perception and its association with negative symptoms was confirmed. Through studies 5 and 6, we highlighted deficits of the DMN during social perception, first in terms of activation (BOLD signal) and secondly in terms of connectivity. In addition, we observed a significant association between DMN connectiv-ity (IPL-PCC/precuneus connectivconnectiv-ity) and negative symptom severconnectiv-ity in individuals with 22q11DS (study 6). Therefore, our findings confirmed our hypothesis of impaired brain cor-relates of social perception along with its association with negative symptoms severity.
2.1 Study 1: Implication of reward alterations in the expression of negative symptoms in 22q11.2
deletion syndrome: a behavioural and DTI study
2.1.1 Methods
In this study we aimed to investigate hedonic capacity and structural (DTI) connectivity of the reward system and their links with negative symptoms in patients with 22q11DS. We included 52 patients and 54 healthy individuals aged between 11 and 31 years old. The Temporal Experience of Pleasure Scale (TEPS; (Gard et al. 2006) Favrod et al. 2009) was administered in order to assess anticipatory and consummatory dimensions of pleasure.
The accumbofrontal tract was extracted using the generated mask from the Karlsgodt et al.
(2015) study (http://karlsgodtlab.org/HBM accumbofrontal/) (Figure 2.1). The bilateral accumbofrontal tracts were normalized to each subject’s diffusion space. Preprocessing of the DTI data and extraction of the diffusion measures were performed with the FSL Diffu-sion Toolbox (http : //f sl.f mrib.ox.ac.uk/f sl/f slwiki/). Univariate ANOVAs were used to examine group differences on the TEPS pleasure dimensions. To examine the impact of pleasure scores with psychotic symptoms, linear regression analyses using the positive and negative symptoms scales from the Positive and Negative Symptoms Scale (PANSS) were conducted. Mann-Whitney U test with age, gender and white matter volume as covariates were used to examine group differences in DTI measures. Spearman correlation with age and gender as covariates were used to investigate the association between structural connectivity and pleasures scores or symptoms scores.
2.1.2 Results
As illustrated in (Figure 2.2) patients with 22q11DS had lower scores on the anticipatory (F(1, 101) = 6.21, p = 0.014) and consummatory (F(1, 106) = 12.58, p = 0.001) dimensions compared to healthy controls. In patients with 22q11DS, anticipatory pleasures scores signif-icantly predict PANSS negative (t = 2.306, p =0.026) and PANSS positive scores (t =2.288, p = 0.027). No significant association with consummatory pleasure scores was observed.
Patients with 22q11DS showed impaired structural connectivity of the accumbofrontal tract (Figure 2.3). Additionally, no significant association between DTI measures and pleasures dimensions or psychotic symptoms was observed (all p>0.05).
Figure 2.1: Atlas of the accumbofrontal tract connecting the nucleus accumbens to the orbitofrontal cortex as defined in Karlsgodt et al., 2014.
Figure 2.2: Group comparison of hedonic components. **p<0.01. *p<0.02.
Figure 2.3: Mean DTI measures in the accumbofrontal tract presenting significant differences between groups. The value of mean FA ranges between 0 (isotropic diffusivity) and 1(anisotropic diffusivity). The values of RD are expressed in mm2/s. The horizontal bars indicate the means
and S.D. per group.