ABSTRACT BOOK 2018

Les Diablerets, Switzerland September 2-3, 2018

Organizing Committee:

Paola Bezzi and Jean-Pierre Hornung (UNIL-DNF), Bogdan Draganski (CHUV-DNC), Micah M. Murray (CHUV-RAD and Eye Hospital)

Coordination: Ulrike Toepel

Table of Contents

(Page number = Abstract/Poster number) - Alphabetical order within topic sections -

Behaviour, Cognition, Neuroimaging ......................................................... 1

Achargui R ...................................................................................................................... 45

Allaman L ........................................................................................................................ 24

Almeida J ........................................................................................................................ 11

Antico L ............................................................................................................................. 7

Baez S ............................................................................................................................... 3

Baumeler D ..................................................................................................................... 16

Belles L ............................................................................................................................ 10

Blake Y ............................................................................................................................ 19

Cardis R ............................................................................................................................. 4

Carlson H, ....................................................................................................................... 41

Contestabile A ................................................................................................................ 17

Debracque C ................................................................................................................... 15

Denervaud S ................................................................................................................... 37

Dirupo G ......................................................................................................................... 39

Dubourg L ......................................................................................................................... 9

Franza M ......................................................................................................................... 22

Habiby Alaoui ................................................................................................................. 32

Harada M ........................................................................................................................ 44

Huber C ........................................................................................................................... 14

Jadhav K .......................................................................................................................... 13

Jaquerod M..................................................................................................................... 20

Joessel A ......................................................................................................................... 31

Klaassen A-L .................................................................................................................... 29

Kojovic N ......................................................................................................................... 42

Legendre G ..................................................................................................................... 27

Marin Bosch B .................................................................................................................. 8

Modenato C .................................................................................................................... 26

Mutel S ........................................................................................................................... 33

Nguyen N ........................................................................................................................ 30

Nicolle J........................................................................................................................... 25

Pagnotta M ..................................................................................................................... 21

Palchaudhuri S ................................................................................................................ 28

Peek L ............................................................................................................................. 34

Perizzolo V ...................................................................................................................... 18

Philippides A ................................................................................................................... 12

Prévost-Solié C.................................................................................................................. 5

Qiao-Tasserit T ............................................................................................................... 23

Schaerlaken S ................................................................................................................. 36

Simonet M ...................................................................................................................... 38

Tautvydaitė D ................................................................................................................. 35

Triana-Del Rio R ................................................................................................................ 6

Turoman N ........................................................................................................................ 2

Xu H .................................................................................................................................. 1

Yanguez Escalera M ........................................................................................................ 40

Computational Neuroscience .................................................................. 46

Bertoni T ......................................................................................................................... 48

Colombo F ...................................................................................................................... 50

Conrad M ........................................................................................................................ 47

Falahi M .......................................................................................................................... 51

Gastaldi C ........................................................................................................................ 49

Hovsepyan S ................................................................................................................... 46

Development .......................................................................................... 52

Agirman G ....................................................................................................................... 53

Baumann N ..................................................................................................................... 52

Oberst P .......................................................................................................................... 54

Tomasello U .................................................................................................................... 55

Molecular and Cellular Neuroscience ...................................................... 56

Fodoulian L ..................................................................................................................... 57

Gastaldo G ...................................................................................................................... 68

Guiraud L ........................................................................................................................ 63

Kiss-Bodolay D ................................................................................................................ 65

Nacher Soler G ................................................................................................................ 61

Nuno-Perez A ................................................................................................................. 62

Peng Z ............................................................................................................................. 58

Piguet O .......................................................................................................................... 67

Thoeni S .......................................................................................................................... 56

Vachey G ......................................................................................................................... 64

Wellbourne-Wood J, ...................................................................................................... 66

Zehnder T ....................................................................................................................... 59

Neurological or Psychiatric Conditions ...................................................... 69

Aicua Rapun I .................................................................................................................. 70

Blochet C ........................................................................................................................ 72

Cantonas L-M ................................................................................................................. 71

Carboni M ....................................................................................................................... 69

Carrard A ........................................................................................................................ 78

Cherix A .......................................................................................................................... 77

Gyger L ............................................................................................................................ 75

Mullier E ......................................................................................................................... 81

Padmasola G ................................................................................................................... 80

Sandini C ......................................................................................................................... 79

Simmler L ........................................................................................................................ 74

Skupienski R .................................................................................................................... 73

Stephan A ....................................................................................................................... 76

Neuron-glia interactions ......................................................................... 82

Boillat Y ........................................................................................................................... 82

Sensory and Motor Systems .................................................................... 83

Barra B ............................................................................................................................ 88

Borgognon S ................................................................................................................... 84

Corbet T .......................................................................................................................... 85

Ho A ................................................................................................................................ 89

Lavalley A ........................................................................................................................ 87

Orset B ............................................................................................................................ 86

Tivadar R ......................................................................................................................... 83

Signalling and Excitability........................................................................ 90

de Castro Abrantes H ..................................................................................................... 92

Rothenfußer K ................................................................................................................ 91

Vantomme G .................................................................................................................. 90

Techniques in Neuroscience .................................................................... 93

Filippova A ...................................................................................................................... 93

Notter M ......................................................................................................................... 95

Tsartsalis S ...................................................................................................................... 94

Yuzgez O ......................................................................................................................... 97

Abstract # 1

Behaviour, Cognition, Neuroimaging Time Course of Prediction Errors in Sequential Decision Making Xu H1, Herzog M 1 EPFL1 In reinforcement learning, an agent makes sequential decisions to maximize reward. During learning, the actual and expected outcome are compared to tell whether a decision was good or bad. The difference between the actual outcome and expected outcome is the prediction error. The prediction error can be categorised into state prediction errors (SPE) and reward prediction errors (RPE) which can serve as a teaching signal in reinforcement learning. FMRI studies revealed the brain areas where the reward prediction error and the state prediction error are computed (Haruno & Kawato 2006; McClure et al. 2003; O’Doherty et al. 2003; D’Ardenne et al. 2008; Glascher et al. 2010). Here, by using 128-channel EEG, we show when the SPE and RPE are computed. In our study, participants saw an image on the computer screen and were asked to click one out of three or four buttons, which, depending on the choice, led to the presentation of a new image until a goal image was reached. After participants have learned the path to the goal, we swapped two images. The swapped images created a SPE, which was correlated with a significant change in the frontal N1 component in the Event-Related Potential. To estimate the RPE, we fit participants’ performance to a reinforcement learning algorithm SARSA-Lambda. A time window at 200-400ms in the ERP reflected well the magnitudes of the RPEs of this algorithm (r = 0.51, p = 0.02). Our results show that the frontal P3 component in ERP reflects the reward prediction process, while the state prediction process is reflected by the frontal N1 component, which is in line with the mismatch negativity studies (Campbell et al. 2007).

Abstract # 2

Taking attention back to school: Multisensory processes influence developing visual attention control Turoman N1, Tivadar R1, Murray M1, Scerif G2, Matusz P 1 CHUV1, University of Oxford2 We investigated if children’s visual attention is involuntarily sensitive to multisensory processes, and if schooling experience impacts this sensitivity. While attentional control over visual stimuli is known to impact educational outcomes, multisensory processes (typical for classrooms) alter neurocognitive functions, including attention. dEEG was recorded from Swiss 1st-grade (age: 4-5) and 3rd-grade (age: 6-7) children, and adults searching for colour-defined targets where colour and colour-sound distractors preceded the search array. Spatial-cueing effects and N2pc component (analysed canonically, and within electrical neuroimaging [EN] framework) served as behavioural and EEG markers of attention. Only older children (and adults) showed top-down control over visual stimuli and bottom-up multisensory enhancement of visual attention. Reliable adult-like N2pc (183-282ms) was not found in 3rd-graders. EN analyses revealed that 3rd-graders lacked one stable configuration of brain sources that dominated adult N2pc’s. First-graders showed no attentional effects. Our results are the first demonstration that children can have adult-like control over visual attention already after 2 years of schooling but multisensory processes influence visual attention around the same time. Our work showcases how adapting rigorous adult paradigms (and associated behavioural and EEG measures) can inform how attention develops in naturalistic, multisensory settings, enriched by robust mechanistic insights into developmental change offered by electrical neuroimaging of traditional EEG correlates.

Abstract # 3

Carry-over effects of empathy for suffering in the brain activity and connectivity of elderly people Baez S1, Vuilleumier P1, Klimecki O 1 UNIGE1 While empathy is well studied in younger adults, empathy-related brain functions in elderly are poorly understood. In order to assess 1) neural representations of empathy in elderly and 2) whether empathy-related situations produce carry-over effects on brain activity and connectivity, we acquired functional resonance imaging (fMRI) data while 122 participants over 65 years watched emotional video clips from the Socio-affective Video Task (SoVT) followed by resting periods of 90s. Participants also provided self-reports on their feelings in response to each video. While confirming previous findings from younger adults (Klimecki et al., 2013; Cerebral Cortex) on higher empathy and negative feelings, and lower positive feelings in response to others' suffering compared to everyday life situations, we additionally observe higher emotional responses in elderly compared to young participants. Furthermore, the confrontation with others' suffering induced greater brain activity in areas related to empathy and social cognition, including anterior insula, middle cingulate gyrus, and medial prefrontal cortex. Furthermore, functional connectivity analyses revealed lower activations in the default mode network following videos depicting other's suffering compared to videos depicting everyday life situations. Our results suggest that being faced with others' suffering induces emotional states that can persist over time and modulate the brain's resting state in elderly participants.

Abstract # 4

The 0.02 Hz-oscillation in sleep spindle dynamics sets the timing of spontaneous switches out of non-REM sleep Cardis R1, Lecci S2, Lüthi A 1 UNIL1, CHUV2 Objectives: Why do we sometimes arouse from sleep so easily? The mechanisms regulating the microarchitecture of non-REM sleep (NREMS), in particular fluctuations in arousability levels, are critical for sleep stability and pathological sleep fragmentation. Optogenetic manipulations of specific neuronal populations trigger shifts in arousal probability, yet correlates of arousal-prone episodes in undisturbed NREMS are unclear. We investigated spontaneous exits from NREMS with respect to the infra-slow 0.02 Hz-oscillation in sigma power (10-15 Hz), which describes the dynamics of sleep spindles and correlates with permissive windows for auditory stimulus-induced NREMS-wake transitions (Lecci et al., Science Adv., 2017). Methods: We performed 48 hours of polysomnographic recording (EEG/EMG) in freely-moving mice sleeping in undisturbed conditions. The behavioral state was scored with a 4-s resolution and the temporal dynamics of specific frequency bands were analyzed with respect to beginnings or ends of NREMS bouts. Results: Spontaneous exits from NREMS to both wake and REMS occurred during the fragility period defined by the descending phase of the 0.02 Hz-oscillation in sigma power. Moreover, the sigma power surge preceding NREM-REM transitions arose from the 0.02 Hz-oscillation. Microarousals occurred in 25% of fragility periods, after which the 0.02 Hz-oscillation continued undisturbed. Before a transition to REMS, the 0.02 Hz-oscillation seemed strengthened, whereas after prolonged wakefulness or REMS, the oscillation was weakened. Conclusions: We propose a biological correlate for the microarchitecture of sleep, the 0.02 Hz-oscillation in sigma power. Spontaneous exits from NREMS occur preferentially during permissive windows defined by the phase of the 0.02 Hz-oscillation.

Abstract # 5

Role of VTA dopamine neurons during social interactions in Shank3 ASD-related mouse model Prévost-Solié C1, Righetti B1, Bellone C 1 UNIGE1 Social interactions are highly complex behaviors that ask to adapt constantly to a stimulus. Although it is known ventral tegmental area (VTA) dopamine (DA) neurons are involved in decision-making, reward seeking and goal-directed behavior, their role in sociability traits remains unclear. Using in-vivo recording in freely moving mice, we show that VTA DA activity increases during free interaction with a conspecific, at a large timescale, while no change occurs during non-inanimate object interaction. Interestingly, global loss of the autism spectrum disorders-associated post-synaptic scaffolding protein SHANK3 alters VTA DA activity in response to a social stimulus. Moreover, while the VTA DA activity is correlated with social behavior in control mice, SHANK3 KO mice show a deficit to express proper social interactions. Altogether, these findings further link, in a direct way, social behaviors with VTA DA neurons.

Abstract # 6

Oxytocin mediates the switch from passive to active defensive reactions in the central amygdala Triana-Del Rio R1, Scheggia D1, Hegoburu C1, Ciobanu A1, Van den Burg E1, Stoop R 1 CHUV1 In rodents, different behaviors can be expressed at facing dangerous threats: from passive defensive reactions (freezing), to active actions to escape from the threat (active avoidance). In addition, translational studies have shown that the basolateral amygdala (BLA), in communication with the central amygdala (CeA), can adaptively adjust escape behavior from imminent threats. In this work, we showed that avoidance behaviors are modulated by excitatory projections from BLA to a specific population in the CeA that expresses the oxytocin receptor (OTR). By using the threat escaping test (TET), we categorized two populations of rats depending on their successful escape-responses to imminent threats: high escapers (HE) and low escapers (LE). Then, we measured plasticity in BLA-induced excitatory synaptic transmission ex vivo onto different types of CeL neurons after TET training. By whole-cell patch-clamp recordings, we measured the AMPA/NMDA ratios of pharmacologically and functionally identified OTR+ and OTR-neurons in CeA. The AMPA/NMDA ratio of OTR+ neurons in HE was higher than the one expressed by OTR+ neurons in LE or unconditioned animals. Behaviorally, acute pharmacological modulation of OTR+ neurons in CeA modulated the switch from passive (freezing) to active (avoidance) responses to imminent threat, in an acute but not long-lasting manner. At the moment, we are running further experiments to elucidate the functional mechanism of OTR in CeA during the TET training, by behavioral, biochemical and electrophysiological means. Furthermore, to assess the role of endogenous oxytocin in the different groups (HE, LE, unconditioned animals); we are measuring oxytocin by mass spectrometry in cerebrospinal fluid and blood. Current data support the necessity of the oxytocin signaling in the CeA to modulate the plasticity of a circuit that switches from passive to active defensive responses.

Abstract # 7

Does my pain affect your disgust? Cross-modal influence of first-hand aversive experiences in the appraisal of others’ facial expressions people’s facial expressions Antico L, Corradi-Dell’Acqua C

UNIGE Embodied models of social cognition argue that others’ affective states are processed by re-enacting a representation of the same state in the observer, characterized by sensory-specific information. However, neuroimaging studies suggest that a reliable part of the representation shared between self and others is supramodal in nature, and relates to dimensions such as unpleasantness or arousal, common to many qualitatively-different experiences. Here we investigated whether representations of first-hand pain and disgust influenced the subsequent evaluation of facial expressions in modality-specific fashion, or in terms of unpleasantness or arousal. 30 volunteers were subjected to thermal painful and olfactory disgusting events, and subsequently were asked to classify computer-generated faces expressing pain (characterized by high unpleasantness and arousal), disgust (high unpleasantness and low arousal), surprise (low unpleasantness and high arousal), and hybrid combination thereof. We found that the appraisal of facial expressions was biased by the prior stimulus, with more frequent pain classifications following thermal stimuli, and more frequent disgust classifications following olfactory stimuli. Critically, this modulation was cross-modal in nature, as each first-hand stimulation influenced in comparable fashion facial traits diagnostic of both pain and disgust, without instead generalizing to features of surprise. Overall, these data support the presence of shared coding between one’s aversive experiences and the appraisal of others’ facial responses, which is best describable as supramodal (but not sensory-specific) representation of the unpleasantness (but not arousal) of the experience.

Abstract # 8

Effect of acute physical exercise on motor sequence learning Marin Bosch B1, Bringard A2, Logrieco M1, Imobersteg N2, Ferretti G2, Schwartz S1, Igloi K 1 UNIGE1, UNIGE HUG2 Recent studies suggest that acute physical exercise improves memory functions by increasing plasticity in the hippocampus. In animals, a single session of physical exercise has been shown to boost BDNF (Brain Derived Neurotrophic Factor) levels, a growth factor known to enhance synaptic plasticity in the hippocampus. In this study we combined blood biomarkers, behavioral measures, NIRS and fMRI to assess the impact of moderate and high intensity acute physical exercise on motor sequence learning and underlying neurophysiological mechanisms in humans. For this, we tested fifteen healthy participants across three visits using a serial reaction time task (SRTT). The SRTT was performed in fMRI before and after a period of exercise (moderate or high intensity) or rest monitored using prefrontal NIRS. We report an overarching effect of physical exercise: increasing performance levels, enhancing BDNF levels and NIRS signaling, as well as increased activity in the right hippocampus and caudate after exercise compared to after rest. We find that vasomotion measured by NIRS during high intensity exercise correlated with both BDNF and hippocampal activity. These findings shed light on the mechanisms underlying the beneficial influence of acute physical exercise on motor sequence learning.

Abstract # 9

Default mode network disconnectivity during social perception in the 22q11.2 deletion syndrome Dubourg L, Schneider M, Eliez S

UNIGE Aim: This study examined default mode network (DMN) connectivity, a major network of social cognition, during a social perception paradigm in the 22q11DS population. Method: We used the psychophysiological method to investigate functional connectivity of the DMN during social perception in the 22q11DS population compared to healthy controls. Association between DMN connectivity and attenuated symptoms of psychosis was examined. Results: 22q11DS patients exhibited stronger connectivity between the inferior parietal lobule (IPL) and the posterior cingulate cortex (PCC)/precuneus, as well as lower connectivity between the precuneus and middle/superior frontal regions compared to controls. A significant association between IPL-PCC/precuneus connectivity and negative symptoms was found in individuals with 22q11DS. Conclusion: Our findings indicate divergent DMN connectivity during socio-cognitive tasks in patients with 22q11DS, which could partially support social functioning deficits observed in the syndrome. Moreover, the significant association between DMN connectivity and negative symptoms severity reported in patients with 22q11DS point out the importance of the DMN in the psychopathology of the 22q11DS.

Abstract # 10

Effects of early environmental variables on striatal D2/3 receptors, impulsivity, novelty-seeking and cocaine-seeking behavior in rats. Belles L1, Dimiziani A1, Tsartsalis S2, Millet P2, Herrmann F2, Ginovart N 1 UNIGE1, HUGE2 Vulnerability to addiction is considered to result from the interaction of highly entangled factors like genetics, personality and social environment. Among personality traits, high impulsivity and high novelty seeking (NS) have both been linked with an increased vulnerability to drug abuse through possibly a common underlying neurochemical substrate, a deficit in striatal D2/3R. Besides, previous studies suggested that early environmental variables might influence these factors related to predisposition to drug abuse. The current study investigated the effects of environmental enrichment (EE) and impoverishment (EI) on D2/3R availabilities in the striatum and its relationship with traits of impulsivity and NS as well as vulnerability to cocaine addiction in high impulsive Roman high avoidance (RHA) rats. Rats were raised in an enriched or impoverished condition beginning at PND 21. At three months of age, rats were tested in the NIPP and straightaway trained in the 5-CSRTT. Striatal D2/3R density was then measured using SPECT imaging and [123I]IBZM and rats were then trained to self-administer cocaine. Compared to EI rats, EE rats were significantly more impulsive and less novelty-seekers. In addition, EE rats showed significantly higher BPND than EI rats. Moreover, EE rats showed a faster rate of acquisition of cocaine self-administration compared with EI rats. This study confirms that early environmental variables have an effect on D2/3R availability in striatum and influences personality traits thought to predispose to drug abuse. It also challenges the finding that striatal D2/3R deficits are associated with higher levels of impulsivity and predispose to drug abuse.

Abstract # 11

The effect of Music on neonatal brain: Diffusion MRI ROI and tractography analysis Almeida J1, Lordier L2, Kunz N3, Bastiani M4, Lazeyras F5, Hüppi P 2 UNIGE1, HUG2, EPFL3, FMRIB, University of Oxford4, CIBM5 Prematurity is often accompanied by neurodevelopmental impairments since occurs when brain is maturing rapidly and hence vulnerable to environmental stressors. Music can trigger neural substrates later implied in cognitive-socio-emotional functions and thus modulates neural networks affected by prematurity. Using diffusion tensor imaging (DTI) we aimed to assess the impact of prematurity and a music intervention on newborn brain development. MRI with DTI sequence was performed at term-equivalent age in 30 preterm infants: 15 exposed to music (PTM) during neonatal-intensive-care-unit (NICU) stay and 15 without music exposition (PTNM); and 15 full-term newborns. Region of interest (ROI) and tractography seed-based approaches were used to derive white matter (WM) DTI measures. Considering an average of 20 ROI, mean fractional anisotropy (FA) was significantly higher in full-term newborns vs PTNM, but not significantly different between full-term vs PTM, while mean diffusivity (MD) was significantly lower in term vs PTNM, but not significantly different between term vs PTM. Tractography analysis of acoustic radiations evidenced higher FA values in preterm vs full-term infants, with a significantly higher FA in PTM vs full-term. In uncinate fasciculus, PTM evidenced significantly higher FA and significantly lower MD than PTNM. Overall, microstructural maturity was decreased in preterm at term vs full-term infants, except in acoustic radiations. When at term, preterms exposed to music intervention evidenced overall FA and MD values similar to full-term newborns with uncinate fasciculus evidencing higher maturation in PTM vs PTNM, supporting a beneficial effect of music as a non-invasive early postnatal neuroenhancement intervention during NICU stay.

Abstract # 12

Structural correlates of neuroprosthetic learning Philippides A1, Galinanes G1, Prsa M1, Huber D 1 UNIGE1 Brain-Machine-Interfaces (BMI) can potentially provide powerful means to replace impaired motor functions. To improve the current devices it is important to gain a better understanding of the neuronal mechanisms underlying neuroprosthetic control. We have recently demonstrated that learning related changes in neuronal firing can be highly specific to the conditioned neuron. These changes are most likely the result of neuronal plasticity such as long term potentiation or more synchronous input to the conditioned neuron. Since changes in size of the dendritic spines can be good indicators of the synaptic plasticity, we expect to observe a more extensive reorganization along the dendrite of the conditioned, as compare to the neighboring, non-conditioned neurons. To track structural changes related to neuroprosthetic learning we designed a novel multiple focus two-photon microscope able to simultaneously track structural and functional changes across several layers. We will present our first results combining structural, functional and behavioral data during neuroprosthetic learning.

Abstract # 13

Adolescent stress and hypofrontality: Towards a rodent model of ADHD Jadhav K1, Ciobanu A2, Stoop R2, Boutrel B 3 CNP-CHUV, UNIL1, CNP-CHUV2, CNP-CHUV, UNIL, Division of Child and Adolescent Psychiatry3 Aim: Attention-deficit/hyperactivity disorder (ADHD) is a neurological disorder affecting the adolescents, characterized by hyperactivity, impulsivity and inattention. A dysregulated prefrontal cortex (PFC) is considered critical in the emergence of ADHD. Considering the dearth in studies evaluating the deleterious impact of stress during adolescence, and the vulnerability of PFC to stress, we endeavor to develop a model of ADHD by subjecting adolescent rats to chronic mild stress. Methods: Adolescent male rats were subjected to chronic unpredictable mild stress for 3 consecutive weeks starting from the post-weaning phase. The rats were then exposed to a series of behavioral tests. A set of rats was sacrificed immediately after the stress procedure and the prelimbic pyramidal neurons were tested electrophysiologically. Results: The stress rats exhibited an attenuated corticosterone response to acute stress and a disinhibited behavior on the elevated plus maze and the open filed test. These rats exhibited signs of impulsivity and inattention on the 5-Choice Serial Reaction Time Task and the Delay Discounting Task. Further they also displayed a higher vulnerability for developing a compulsive phenotype for saccharine, cocaine and alcohol use. Finally, the prelimbic cortex pyramidal neurons of the stress rats showed an attenuated ex vivo intrinsic excitability as evidenced by lower input resistance translated into a lower excitability at similar levels of current injections. Conclusion: This model exhibits the phenotypic hallmarks of ADHD, namely, disinhibition, hyperactivity, impulsivity and inattention that correlates with decreased excitability of pyramidal neurons of the prelimbic cortex.

Abstract # 14

Microendoscopic imaging of functional responses of claustrum projection neurons during behavior Huber C, Carleton A

UNIGE The claustrum (CLA) is a thin sheet of gray matter that is highly interconnected with the neocortex. Presently, though the CLA has been hypothesized to be involved in conscious perception of sensory stimuli, little is known about its actual function. Here we use a transgenic mouse in which a cre recombinase is expressed in glutamatergic neurons of the claustrum. Using cre-dependent adeno-associated virus, we forced the expression of the genetically encoded calcium indicator GCaMP6f. Using a microendoscope implanted above infected CLA neurons, we imaged calcium responses in freely moving mice during various behavioral conditions. We report that various ensembles of neurons are recruited during different behavior such as open field locomotion and attentional set-shifting tasks. Interestingly, we observed remapping of task representation in couple of trials associated to new rule learning. In conclusion, we report for the first time functional responses of CLA neurons during various behavioral context and our data suggest that multiple specific cell assemblies are recruited during complex behavioral tasks.

Abstract # 15

Evolutionary approach to emotion using affective prosody: an fMRI study Debracque C1, Ceravolo L1, Slocombe K2, Clay Z3, Gruber T1, Grandjean D 1 UNIGE1, University of York2, University of Durham3 In recent years, the emergence of affective sciences led to a better understanding of emotion decoding by the human brain. Several studies investigated the ability to decode a speaker’s emotional state through functional neuroimaging, using affective prosody, i.e., the variations of voice acoustical properties, as a clue. Beyond the involvement of voice sensitive temporal areas in both right and left hemispheres such as the middle superior temporal gyrus (STG), these studies suggested a crucial role of the inferior frontal gyrus (IFG) in attentive decoding and cognitive evaluation of emotional cues in human vocalizations. Humans are primates, belonging to the hominid family together with other great apes (chimpanzees, bonobos, orangutans, gorillas). Because of this close genetic proximity, it is likely that humans would be able to recognize emotions expressed in other apes’ vocalizations, possibly displaying a gradient of activation in bilateral STG and IFG according to the phylogenetic tree. In this study, our goal was to investigate via functional Magnetic Resonance Imaging (fMRI) how humans categorize emotions of primate vocalizations. All participants were exposed to human voiced affective bursts (extracted from the Montreal Affective Voices) and calls produced by chimpanzees, bonobos and macaques. Human stimuli were expressed with angry, fearful or happy intonations. Equivalent calls for primate vocalizations expressed: aggressor screams (anger); victim screams (fear) and positive food grunts (happiness). Preliminary results of this fMRI experiment will be discussed in the light of a comparative and evolutionary approach.

Abstract # 16

Detecting covert shifts of attention in the Attentional Repulsion Effect Baumeler D, Born S, Kerzel D

UNIGE The Attentional Repulsion Effect (ARE) is supposed to be a bias attributed to a covert shift of attention towards a briefly flashed peripheral cue, which in turn repulses the perceived position of a target stimulus presented outside the focus of attention (Suzuki & Cavanagh, 1997). Previously, microsaccades, a type of fixational eye movement, have been used to measure covert shifts of visual attention. These microsaccades reveal a specific rate and directional signature: after cue presentation, microsaccade rates are inhibited followed by an enhancement. During the inhibition phase, microsaccades tend to be in direction of the cued location whereas this is reversed during the enhancement phase (Laubrock, Engbert & Kliegl, 2005). To reveal a potential underlying covert shift of attention, the aim of the current study was to examine rates and directional signatures of microsaccades during an ARE task. Microsaccadic responses to cue onset displayed typical rate dynamics with an inhibition followed by a rebound interval. During inhibition, microsaccades were directed towards the cued location, however, the expected shift into the reversed direction after the inhibition phase was only seen for trials on which subjects showed a repulsion bias in behavior. These findings support the idea that a covert attentional shift might lead to a change in the spatial reference point around fixation. Although target positions are assessed in relation to this biased spatial reference point, subsequent responses are thought to be given in comparison to the initial point of fixation which then induces a repulsed spatial representation of the target.

Abstract # 17

SHANK3 downregulation in the VTA accelerates the extinction of contextual associations induced by non-familiar conspecific interaction Contestabile A1, Bariselli S1, Tzanoulinou S1, Bellone C 1 UNIGE1 Conditioned place preference (CPP) paradigms, traditionally adopted to study the reinforcing properties of drugs of abuse, have been developed to investigate the neurobiological mechanisms underlying the reinforcing properties of social stimuli. These protocols are largely based on single-housing before and/or during social stimulus-contextual cues acquisition phase. Here, based on previously established social interaction-induced CPP paradigms, we characterize a new place preference task relying on the reinforcing properties of free interaction with a non-familiar (novel) conspecific. In this new CPP paradigm, the formation of contextual associations induced by interaction with a non-familiar social stimulus does not require single-housing, and undergoes extinction. Generally, this CPP paradigm necessitates dopamine (DA) receptor 2/3 (D2/3R) but not D1R activation to allow social induced-contextual associations. Interestingly, general knockout of the autism spectrum disorder-related protein SHANK3 significantly impairs formation of social induced-contextual associations. On the other hand, specific downregulation of SHANK3 in the ventral tegmental area (VTA) does not affect contextual associations, but accelerates extinction of CPP responses. Thus, inspired by the literature on drug of abuse-induced contextual learning, we propose that acquisition and extinction of CPP might be used as behavioral assays to assess social-induced contextual association and social-seeking dysfunctions in animal models of psychiatric disorders.

Abstract # 18

EEG recording during an emotional face-matching task in children of mothers with interpersonal violence-related posttraumatic stress disorder Perizzolo V1, Berchio C1, Moser D2, Puro Gomez C3, Vital M3, Arnautovic E3, Torrisi R3, Rusconi Serpa S3, Michel C1, Schechter D 4 UNIGE1, Mount Sinai Hospitals2, HUG3, UNIGE/NYU4 The aim of this study was to examine the effects of maternal interpersonal violence-related posttraumatic disorder (IPV-PTSD) on child appraisal of emotion, as measured by high-density electroencephalography (HD-EEG) during an Emotional Face-matching Task (EFMT). We recorded HD-EEG in 47 children of mothers with and without IPV-PTSD during an Emotional Face-matching Task (EFMT). Mothers and children each performed the EFMT. Behavioral results demonstrated that both mothers who were directly exposed to violent events, and their children, presented attentional bias in emotion-processing toward negative emotions. EEG findings confirmed differences in emotion appraisal between children of IPV-PTSD mothers and non-PTSD controls at scalp-level and in source localization investigation where children of IPV-PTSD mothers demonstrated decreased activation in the right dorsolateral prefrontal cortex (dlPFC) in response to angry and fearful faces compared to non-PTSD children during the N170 component. This research is to our knowledge the first study to show that maternal IPV-PTSD significantly affects a mother’s own neural activity, as well as her child’s neural activity in response to expressions of negative emotion. These findings are important in the development and study of effective interventions to interrupt intergenerational cycles of violence and trauma.

Abstract # 19

Anxiety and Neurodegenerative Loss of Amygdala Inhibition in patients with Mild Cognitive Impairment Blake Y1, Terburg D2, Walsh E3, Donati A3, Von Gunten A3, van Honk J4, Stoop R 1 UNIL/CHUV1, University of Utrecht2, CHUV3, University of Cape Town4 My work examines anxiety symptoms in patients with Mild Cognitive Impairment (MCI), a frequent precursor of Alzheimer’s disease (AD). Emotional symptoms, including anxiety, are frequently observed in MCI and AD patients and can be highly distressing for patients and caregivers (e.g. Nowrangi et al., 2015; Ismail et al. 2017). I consider the role of the basolateral and central amygdala (BLA and CeA) in these symptoms. The amygdala is critically involved in anxiety, and atrophy of the BLA is common early in MCI and AD (e.g. Miller et al., 2013; Younes et al., 2014), while recent evidence suggests that the CeA remains relatively intact (Miller et al., 2012; Miller et al., 2015). The CeA is important for the unconditioned, instinctive fear response, whereas the BLA can exert modulatory control over CeA activity. Patients with bilateral, circumscribed BLA lesions show hyper-anxiety, likely arising from a loss of inhibitory control of the BLA over the CeA (Terburg et al., 2012; Terburg, Scheggia et al., in press). Anxiety symptoms in MCI patients may similarly be related to a loss of CeA inhibition. I run a number of tasks to test participants’ sensitivity to anxiety-related stimuli, their ability to inhibit this anxiety and the interplay between emotion and episodic memory. Results reveal differences between MCI patients and controls, but also implicate the importance of other factors in determining anxiety symptoms. Work is currently ongoing to examine whether these behavioural differences are related to differences in deterioration of amygdala sub-regions.

Abstract # 20

Early attentional modulation in young adult ADHD patients during a risky decision-making task Jaquerod M1, Mesrobian S1, Bader M2, Villa A1, Lintas A 1 UNIL1, CHUV, SUPEA2 Impaired decision making and Working Memory (WM) are among the characteristic symptoms of patients affected by Attention Deficit/Hyperactivity Disorder (ADHD). The inattention inherent to the disorder is likely to be the reason behind the poor decisional process. The difficulty for patients to focus on one task is related to impaired sensory gating mechanisms, the ability of the central nervous system to inhibit irrelevant sensory input. In this study, we recorded event-related potentials (ERP) with the aim at comparing the processing of a risky decision before and after 20 days of WM training in young adults ADHD participants and matched controls. Although no significant change in risky behavior, our study demonstrates that WM training affects in a different way the neural systems involved in a high-order cognitive task of control and ADHD participants. ERP analyses in ADHD participants reveal a significant effect of the training with Dual N-Back on early sensory processes in frontal sites, which might signal a better processing of sensory input in patients whose sensory-gating mechanism is likely to be impaired. In control participants, late ERP components associated with cognitive and more conscious processes are affected by the training with only the baseline variant of the game. This is the first study, to our knowledge, to find an objective neural marker of the benefits of WM training on early attentional components of a decisional process in adults suffering of pathological attention deficits.

Abstract # 21

Functional mechanisms of feature-based attentional control as revealed by fMRI and EEG Pagnotta M1, Pascucci D1, Plomp G 1 University of Fribourg1 To compensate for the limited capacity of our visual system, mechanisms of selective attention allow prioritizing the processing of behaviorally relevant locations and features. We here investigate the brain mechanisms underlying feature-based attention at central location, when relevant and irrelevant visual features either coexist independently or are fused. We recorded fMRI and EEG in separate sessions, while twenty human participants performed either an orientation discrimination task or a motion discrimination task on stimuli with overlaid or merged features. Overlaid stimuli consisted of random dot kinematograms (RDK) and sinusoidal gratings (Gabor patches), such that RDK’s coherent motion direction and Gabor orientation were independent features. For merged stimuli, by contrast, the features were not independent: orientation information emerged from sinusoidal contrast patterns in the RDK, and motion information was present in the shape of the oriented grating. fMRI results showed task differences and stimulus-task interaction effects in areas that are typically associated with attentional mechanisms, motion processing and orientation discrimination; while stronger responses were observed for overlaid stimuli compared to merged stimuli in regions of the cingulate and middle/orbitofrontal cortex, which are commonly associated with cognitive control. These findings allowed identifying regions of interest (ROIs) that have been used to estimate location-specific cortical activations, by employing source-reconstruction techniques on EEG data. Future directions of this study include time-varying connectivity analysis on this network of ROIs to investigate the dynamic pattern of directed influences between cortical areas that gives rise to feature-based selective attention.

Abstract # 22

The contribution of conscious perception in the rubber hand illusion: a transcranial magnetic stimulation and virtual reality study Franza M1, Sorrentino G1, Faivre N1, Bassolino M1, Blanke O 1 EPFL1 Bodily self-consciousness (BSC) is defined as the implicit and pre-reflexive experience of being the subject of a given experience. One well-known approach to manipulate BSC is the Rubber Hand illusion (RHI) in which the simultaneous application of multisensory stimuli on a participant’s hand and on a rubber hand leads to the illusory feeling of owning (ownership) and controlling (agency) the rubber hand. As of today, most paradigms have relied on supra-threshold stimuli to induce the RHI. Here, we assessed whether conscious access to peripheral stimuli is necessary to induce changes in ownership and agency. For that, we elicited peripheral stimuli consisting in muscular contractions triggered by transcranial magnetic stimulation (TMS) applied over the motor cortex (motor evoked potentials, MEP), while participants observed a virtual hand performing realistic TMS-induced movements. Crucially, we employed peri-threshold TMS pulses to induce MEPs and subjective percepts of hand somatosensory/kinaesthetic sensations in half of the trials. After each TMS pulse, participants were instructed to rate the illusory feeling of ownership and agency toward the virtual hand and to report TMS-evoked hand perception. Results showed that higher illusory feelings of ownership and agency were elicited when subjects reported TMS-evoked hand perception regardless of the presence of MEPs. These results indicate a critical role of conscious bodily perception in triggering the illusion, even in absence of any peripheral stimuli. Altogether, this suggests an important contribution of top-down cognitive processes in the generation of a unitary sense of owning and controlling a body.

Abstract # 23

Influence of emotions on theory of mind

Qiao-Tasserit T, Corrado Corradi-Dell’Acqua, Patrik Vuilleumier.

University of Geneva.

How do our own emotions influence the way we think about others’ emotions? The embodiement theory predicts that we use our own body to infer others’ feelings. Thus, when we are positive or negative, it should be easier to infer others’ positive or negative emotions respectively, out of others’ emotional cues. On the other hand, the Broaden-and-build theory states that we are more open towards other people when we are positive and self-centered when we are negative. Thus, compared to negative, when we are positive, it should be easier to infer others’ emotions, positive and negative, regardless of the emotional cues modality. Here, we induced emotions in participants in an fMRI machine, using positive, neutral and negative movie clips. We then asked participants to read theory of mind scenarios. After each scenario, they answered a question about the characters’ feelings and beliefs. At the end, participants also listened and watched positive, neutral and negative voices and faces. We used multi pattern voxel analyses to reveal supramodal representations of others’ emotions that are common when processing others’ emotions out of a story, a voice or a face. Preliminary results speak for the Broaden-and Build theory. Supramodal representations were detected after positive movies not only of others’ joy but also of others’ fear in Superior Temporal Gyrus and after neutral movies in medial Prefrontal cortex. Interestingly, no supramodal representations were detected after negative movie clips in those regions, suggesting that negativity prevent from representing others’ emotions at a supramodal level.

Abstract # 24

Influence of resting-state functional connectivity on peri-threshold processing and visual perception Allaman L1, Mottaz A1, Guggisberg A 1 UNIGE - HUG1 The posterior alpha rhythm has for long been viewed as reflecting processes of attentional disengagement and being intrinsically inhibitory. Nonetheless, recent research shows that resting-state functional connectivity in the alpha band correlates with performance in various tasks, in healthy subjects and neurological patients. Parieto-occipital alpha oscillations play a role in visual perception and visuo-spatial attention. Pre-stimulus alpha power influences stimulus perception, speed of detection as well as discrimination and post-stimulus alpha power changes are related to visual consciousness. The present study explores the link between resting-state FC, neural processing of visual target and visual perception. 18 healthy subjects performed a visual detection task while 128-channel EEG was recorded. Peripheral targets were presented at perithreshold contrast either on the left, on the right or bilaterally. The paradigm was built in blocks starting with a resting period (15-20 s) followed by seven trials of the target detection task. A 10 minutes eyes-closed resting-state recording was also collected beforehand. We compute maps of FC between brain areas as well as in-task power changes and correlate the results with measures of visual performance, across and within subjects. Our preliminary results show a relation between resting-state FC in the alpha band in primary visual areas and visual detection performance (here defined as the threshold contrast level for each subject and condition). We also show a decrease in alpha power over the same regions following stimulus presentation. This decrease is greater in trials in which subjects consciously detected the target.

Abstract # 25

Altering the phonemic rhythm with 30 Hz tACS in dyslexics Nicolle J1, Marchesotti S 1 UNIGE1 Developmental dyslexia is a failure to acquire reading and writing abilities. According to the phonological theory deficit, the core underlying cause of dyslexia involves abnormal representations of speech units (Ramus, 2001).which is now associated with atypical neural oscillations in the auditory cortex as compared to controls. However, specific involvement of atypical neural oscillations in the phonological deficit is still debated. In this study, we propose that the phonological deficit in dyslexia could result from a deficit in temporal processing in the left auditory cortex involving low gamma oscillations (25-35 Hz), which would manifest as a decreased response to amplitude modulation to auditory stimuli (Lehongre, Ramus, Villiermet, Schwartz, & Giraud, 2011). The goal of the present study is to boost neural responses at this specific location and frequency with transcranial alternating current stimulation (tACS) in dyslexics. We thus hypothesize that unusual phonemic representation format could be normalized by applying tACS at the optimal frequency for phonemic processing (i.e. 30 Hz). We expect to improve the phonological processing of language in dyslexics and to demonstrate a causal role of cortical gamma oscillations in phonemic encoding. Results show that tACS induced an improvement in phonemic representation and phonological retrieval as well as a power increase response to amplitude modulation to auditory stimuli at 30Hz which corroborates the role of low gamma oscillations in the phonemic processing efficiency and the involvement of this frequency range as potential cause of the phonological disorder in dyslexia.

Abstract # 26

The impact of recurrent copy number variants on brain anatomy Modenato C, Draganski B

CHUV Recurrent Copy Number Variants (CNVs) in the human genome have incomplete penetrance with phenotypic effects that range from normal functioning to developmental disorders and increased risk for psychiatric disorders. In this study, we focus on deletions and duplications carriers of CNVs at three genomic loci: 22q11.2, 16p11.2 and 1q21.1. These CNVs are risk factors for autism, schizophrenia and although they share a very similar clinical phenotype, little is known about the related neuroanatomical alterations. Our aim is to investigate the gene dosage effect on brain alterations, by comparing deletions and duplications carriers of each CNV, and to investigate whether these alterations present some overlaps between them that might explain the common genetic risk for psychiatric disorders. Our data sample includes structural T1 weighted MRI images coming from Europe and United States on 40 1q21.1 carriers, 150 16p11.2 carriers, 90 22q11.2 carriers and 280 controls. Preliminary results show a significant overlap regarding gene dosage effect of 16p11.2 carriers and 22q11.2 carriers on the bilateral insula. These results are consistent with the general pattern of grey matter impairment identified in psychiatric disorders and with brain abnormalities reported in studies investigating individually both CNVs. Further analysis will investigate the shared pattern of brain alteration between deletions or duplications of each CNV aside from the gene dosage effect. Moreover, in order to increase our understanding of the impact of genetic risk factors on brain structure, the next step of this work will focus on relating brain structural changes to the clinical phenotype.

Abstract # 27

Reinstatement of emotional associations during human sleep: an intracranial EEG study. Legendre G1, Seeck M2, Spinelli L2, Schwartz S1, Sterpenich V 1 UNIGE1, HUG2 Memory replay occurs spontaneously during sleep and promotes consolidation. Such replay can be experimentally triggered by presenting sensory cues that had been paired with encoded information. Whether this same procedure may allow the reactivation and consolidation of associated emotional states is still unknown. Here we recorded intracranial EEG signal in 7 epileptic patients (undergoing presurgical investigation; N=7). Six patient had an electrode implanted in the amygdala (N=6), six in the hippocampus (N=6) and five in the orbitofrontal cortex (N=5). They heard two different sounds presented together with either funny or neutral pictures. After this conditioning phase, both sounds were played while patients had a nap, and after the nap. We analyzed the evoked response to both sounds of the amygdala, hippocampus and orbitofrontal cortex. During sleep, we found that the emotionally conditioned sound increased oscillations implicated in memory (theta and beta frequencies) in the two regions. Together with this effect, a stronger connectivity between the orbitofrontal cortex and the hippocampus was observed. To summarize, we showed that, during sleep, the emotional components of memories are replayed in limbic circuits when cued. Moreover, we showed that this process implicates an increase in oscillations and connectivity typically involved in memory encoding and retrieval. The predominance of these oscillations in contrast with more classical sleep oscillations (like sleep spindles or slow-oscillations) suggests a complex interplay across frequencies and regions. We hope these clues will provide new insights into the involvement of the different frequency bands in shaping memories during sleep.

Abstract # 28

Insular cortex provides powerful glutamatergic drive to the lateral amygdala relevant for threat learning Palchaudhuri S1, Kintscher M1, Berret E1, Schneggenburger R 1 EPFL1 Threat learning is a robust behavioural protocol to study neural circuits related to memory formation. During cued threat learning, an emotionally neutral stimulus such as a tone (conditioned stimulus, CS), acquires a negative valence when paired repeatedly with an aversive footshock (unconditioned stimulus, US). The association between the CS and US relevant for threat learning is thought to occur in the lateral amygdala (LA). However, the origin of the US afferents to the LA remains unclear. Early anatomical studies described a pathway from the insular cortex (InsCx) to the LA, but its role in threat learning is unknown. We injected AAV:FLEX:Chrimson-tdTomato in the pInsCx of Fos-Cre-ERT2 mice that were later fear-conditioned, for activity-dependent labelling of aversive neurons. We observed cFos+ (Chrimson-tdTomato+) neurons in the InsCx which sent axons to the LA. To functionally characterize this connection, we used ex-vivo optogenetic mapping, with Cre-dependent expression of channelrhodopsin in the pInsCx of CamKII-Cre mice, followed by slice recordings of neurons in the LA. We observed robust optically-evoked glutamatergic EPSCs in LA pyramidal neurons composed of AMPA-R and NMDA-R mediated EPSCs. Evoked EPSCs increased gradually in amplitude with increasing light intensity, suggestive of multiple independent inputs from various axons arising from the InsCx. With high frequency train stimulations, EPSCs exhibited short-term depression. Evoked EPSCs were phasic for the first few pulses, but release appeared more de-synchronized during later stimuli. Thus, we functionally identified an InsCx to LA synapse, a connection that is potentially involved in aversive signalling during threat learning.

Abstract # 29

The role of the basal forebrain in processing of complex sounds in rat auditory thalamus and cortex Klaassen A-L, 1, Lozano L1, Harvey M1, Rainer G 1 UNIFR1 The basal forebrain (BF) projections play an important role in modulating sensory processing, for example by enhancing visual and auditory responsivity. The BF projections regulate sensory function by providing the major source of cholinergic as well as GABA- and glutamatergic input to the thalamus and primary sensory regions of the neocortex. Here, we aim to investigate the neuromodulatory influence of the BF on auditory processing by combining optogenetic stimulation in the BF with electrophysiology in the auditory thalamus (MGN) and the primary auditory cortex (A1) in rats. To study the functional contribution of the BF projection system on sensory processing and behavior, we developed an auditory discrimination paradigm. Rats learned to discriminate segments of different Fourier-amplitude-matched classical music pieces using an operant conditioning paradigm. We employed classical music as it is a spectrally rich and dynamic stimulus that may more closely approximate ecologically important sounds than pure tones. Preliminary analyses suggest that rats (n=4) learn this task in about 21 days and achieve a ceiling performance of about 75% correct. In addition, rats are able to generalize to other segments of the learned classical music pieces. We have obtained recordings suggesting that our stimuli robustly activate both MGN and A1 in a stimulus specific manner. By optic BF stimulation experiments (n=3), we observed impaired discrimination performance with more false and less correct responses. Electrophysiological measurements revealed a generation of oscillatory activation in PFC, A1 and MGN during stimulation suggestive of a functional impact of BF on cortical and sensory networks.

Abstract # 30

Sex differences in mental transformation of visuospatial information: study on event-related potentials and source localization in two different processes Nguyen N, Brandner C

UNIL Although the advantage of men’s performance over women’s in mental rotation tasks appears to be robust, the neural correlates underlying this difference are still unclear. Moreover, mental rotation is not the only strategy allowing object to be represented from different views, since imagining the object from an alternative standpoint could be equally effective. The objective of this study twofold: (a) to investigate these alternative strategies and (b) to expand knowledge of brain mechanism underlying sex differences in these two types of mental transformations. Fifty-five participants (21 females and 29 males) performed classical 3D mental rotation (MR) and perspective taking (PT) tasks while event-related potentials (ERPs) were recorded. Behavioral results revealed that in both tasks men made less errors than women, despite similar reaction times. ERP analyses revealed gender differences during the time window corresponding to rotational process (459-596 ms), but only in MR with women who exhibited higher mean amplitude potentials than men. They also revealed a Task X Gender interaction on P1, N1 and P3a components, which may be linked to visual attention. Further analyses showed gender differences in P1 during the PT task, and in N1 and P3a during the MR task. Again for women exhibiting higher mean amplitudes. These results highlight possible differences in processing across gender for both types of transformation. This effect might rely on higher requirements for cognitive resources in women in early stages of visual processing, as well as during later mental manipulations.

Abstract # 31

Investigating the neural predictors of flow using fMRI Joessel A1, Magontier M1, Rosenberg M2, Pichon S1, Chun M3, Bavelier D 1 UNIGE1, Yale 2, Yale3 Flow, popularly referred as being in the zone, can be described as a state of optimal performance. The subjective experience corresponding to this state has been well characterized using 9 psychological constructs, such as concentration, transformation of time or sense of control, as measured through a self-report questionnaire called the Flow State Scale (Jackson & Marsh, 1996). However, little is known of the neural correlates of flow. Only a handful of brain imaging studies have investigated the neural correlates of flow and all have done so by contrasting two different task conditions, making it unclear whether the observed differences in activity are truly flow-related rather than task-related. To remedy this, we take here a different approach based on the method presented in Rosenberg et al. (2016), where sustained attention-related networks were defined using resting state connectivity and performance on a sustained attention task administered at a different time. Similarly, we identify flow-related neural markers using resting state connectivity and a measure of flow collected at a different time. Importantly, this approach avoids any possible confounds from task-related differences since the behavioural and connectivity data are not acquired simultaneously. We have already validated our ability to measure the propensity to enter flow by contrasting flow questionnaire responses after playing a video game at an optimal level of challenge versus at an over-challenging level. As in Rosenberg et al. (2016), we ask whether individual flow states can be predicted from patterns of resting state connectivity. We predict these patterns will reveal a rather unique network highlighting the combined contribution of attention-related, emotion-related and reward-related networks to the experience of Flow.

Abstract # 32

Processing of negative prediction errors in a deterministic and a probabilistic learning task: a human evoked-potential study Habiby Alaoui S, Adam-Darqué A, Schnider A HUG Human learning is driven by the difference between expectation and experience. The non-occurrence of anticipated outcomes (negative prediction errors) may induce a learning process called extinction, defined as the ability to learn when a previously valid anticipation is not valid any more. We have previously found that the inability to adapt behavior after extinction trials in a deterministic learning task, when the outcome has a 100% association with the predictive stimulus, predicts an inability to adapt behavior to current reality in everyday life. This state is clinically manifest in disorientation and confabulations. In healthy subjects, such extinction trials activate the orbitofrontal cortex at 200-300ms after outcome presentation. Different results were obtained in animal experiments conducted in a probabilistic environment, where outcomes have a probability <100% of following the predictive stimulus. In this situation, the absence of the expected outcomes did not activate the OFC. In contrast, there was activation of the anterior cingulate in trials followed by a behavioral switch. Thus, the brain appears to process the non-occurrence of anticipated outcomes differently according to the probability of the outcome and its behavioral significance. Sixteen healthy subjects performed two versions (deterministic and probabilistic) of a reversal learning paradigm. During the tasks, each participant underwent a high-density EEG recording. We hypothesize that absence of the anticipated stimulus induces early orbitofrontal activity (200-300 ms) in the deterministic task, but not in the probabilistic task. At this stage, behavioral results show rapid comprehension of both tasks and an adaptive choice strategy over time in the probabilistic task.

Abstract # 33

Claustrum to medial prefrontal cortex glutamatergic projections control attentional shifts Mutel S1,2, O. Gschwend1,3, R. Salazar1, C. Huber1,2, R. Leone1,2, J.-R. Renfer1,2, L. Fodoulian1,2, I. Rodriguez2, A. Carleton1; 1Dept. of Basic Neurosciences, 2Dept. of Genet. and Evolution, Univ. of Geneva, Geneve, Switzerland; 3Cold Spring Harbor Lab., Cold Spring Harbor, NY The claustrum, a subcortical structure located between the putamen and the insular cortex, forms extensive reciprocal connections with most cortical areas. Such a widespread pattern of connectivity drove several hypotheses about its function, which encompass saliency detection and attention. However, due to the difficulty to specifically alter CLA activity without affecting surrounding brain areas, we are currently lacking causal evidence to its role. We used a transgenic mouse line expressing a Cre recombinase in glutamatergic CLA neurons to specifically study CLA connectivity and to modulate its activity. Viral tracing showed that while CLA neurons project to the entire neocortex, they preferentially innervate associative areas, such as the medial prefrontal cortex (mPFC). Calcium imaging of the CLA during the attentional set-shifting test (ASST), a task that evaluates cognitive flexibility, revealed the recruitment of specific ensembles of CLA neurons. To confirm the critical involvement of CLA neurons in this task, we either chemogenetically inhibited or optogenetically stimulated these neurons. All of these manipulations specifically impaired extra-dimensional shifts. Given the established role of the mPFC to cognitive flexibility, we further characterized the role of CLA projections into the mPFC. First, we optogenetically stimulated CLA terminals in the mPFC, a modulation which disrupted ASST extra-dimensional shifts performance. Second, we demonstrated a monosynaptic excitatory drive on mPFC pyramidal neurons using channelrhodopsin-assisted circuit mapping. In conclusion, the activity of glutamatergic CLA projections to the mPFC is crucial to the ability to perform extra-dimension attentional shifts.

Abstract # 34

Learning to regulate subliminal perception in the healthy human brain Peek L and Vuilleumier P Dept. of Neurosciences, University Medical School of Geneva, Switzerland Research in healthy people indicate that briefly presented face stimuli in masking paradigms can evoke subliminal activation in specific visual areas, while they are not consciously perceived by the subject (Brooks et al., 2012). In the current project, real-time fMRI neurofeedback was used to train 20 healthy volunteers to enhance such subliminal activation in the fusiform face area (FFA). While being presented with masked subliminal fearful faces, fourteen participants succeeded to increase their evoked responses over sessions (learners) while six subjects failed to do so (non-learners). In line with our expectations the learned ability to increase subliminal brain responses reduced the threshold for conscious perception of subliminally presented faces as measured with a behavioral task. However, this effect was nonspecific to emotion; a similar decrease was observed for subliminally presented happy faces. Preliminary, subject specific region-of-interest (FFA) analyses show that the observed increase in real-time was also significantly greater offline for the learners, and that this difference increased over sessions. Furthermore and conform our predictions, initial analyses of pre- and post-training resting-state data show that successful NFB training is related to enhanced functional connectivity between extra-striate visual areas (FFA) and fronto-parietal attention networks (IPS, dlPFC).

Abstract # 35

EEG evidence for early medial temporal lobe encoding process

Tautvydaitė D1, Alexandra Adam-Darque1, Aurélie L. Manuel1 and Armin Schnider 1, 2 1 Laboratory of Cognitive Neurorehabilitation, Department of Clinical Neurosciences, University Hospital of Geneva and University of Geneva, Switzerland 2 Division of Neurorehabilitation, Department of Clinical Neurosciences, University Hospital of Geneva and University of Geneva, Switzerland The medial-temporal lobe (MTL) plays an important role in episodic memory, but there is growing evidence for its implication in short-term memory. Recent electroencephalographic (EEG) studies demonstrated that stimuli repeated immediately within a continuous recognition task (CRT), as opposed to delayed repetitions and new presentations, evoke a frontal potential between 250 and 350 ms, emanating from the MTL and thought to reflect encoding. In the present study, we composed a new CRT to evaluate encoding in a more direct and intuitive way. We recorded brain activity with high density EEG in 21 healthy subjects. The task presented new stimuli which were then repeated up to 4 times, allowing for comparison of the processing between unequivocally novel, and thus encoding-inducing stimuli with overly familiar stimuli. Our hypothesis is that new stimuli presented in this context will induce MTL activation, presumably at 200-300 ms. To test for possible correlations between encoding and recognition of the stimuli, subjects performed a recognition task 30 min later. If the hypothesis is confirmed, this study would be the first to demonstrate in an unequivocal way the early, transient MTL activity reflecting encoding. Data analysis is in progress.

Abstract # 36

Towards the neural circuitry of perceived expressive intents in musical performance Schaerlaken S, Grandjean D University of Geneva How can we appreciate the expressive intent of a musical piece? The tiny variations in timing, pitch, timber, and movements carrying the expressive content of a piece are an important part of music experience. Up and foremost, they are linked to a more pleasurable experience of music for both the audience and the musicians. In this study, we aimed to investigate the neural correlates responsible for differentiating between expressive and non-expressive excerpts while taking into account the effects of both musical expertise and audio and visual modalities. In order to do so, we asked 12 musicians and 11 non-musicians to judge small clip of musical pieces presented using three different modalities: audio, sound, and audio & sound. Behavioral results brought to light that musicians and non-musicians rated differently how expressive the stimuli were. When showing non-expressive audio excerpts, controls tended to rate it as more expressive than musicians. In the case of one modality being presented, the fMRI results showed that controls recruited brain regions associated with the non-presented modality possibly to make better predictions; for example, visual regions are strongly activated in controls compared to musicians when presented with only audio stimuli. The musicians used on the contrary the corresponding dedicated areas trained during practice. When audiovisual stimuli were presented, musicians recruited regions associated with motor planning (supplementary motor area) and emotional content (insula). The difference in perception of expressive intents in musical experience appears therefore greatly impacted by the expertise of the audience and modality presented.

Abstract # 37

School Setting Impacts Post-Error Monitoring and Exploratory Behavior Denervaud S 1,2, Jean-François Knebel3,4, Eleonora Fornari4, Micah M. Murray3,4, David Sander1,2, Patric Hagmann4, Edouard Gentaz1,2 1 The Center for Affective Sciences (CISA), Campus Biotech, University of Geneva, 1202 Geneva, Switzerland 2 Faculty of Psychology and Educational Sciences (FAPSE), University of Geneva, 1204 Geneva, Switzerland 3 The Laboratory for Investigative Neurophysiology (The LINE), Department of Radiology and Department of Clinical Neurosciences, Vaudois University Hospital Center and University of Lausanne, 1011 Lausanne, Switzerland 4 Department of Radiology, Vaudois University Hospital, 1011 Lausanne, Switzerland Early life experiences of tackling adversities, in particular during schooling, may shape how adults cope with failures. Using both behavioral and neuroimaging measures, we specifically addressed the role of traditional vs. Montessori school environments on post-error monitoring in childhood. Traditional schooling typically involves, as from 8y.o., frontal teaching, tests and grades in a single-level age group. These characteristics were reported to often induce cheating behaviors, and anxiety, while lessen creativity. The Montessori system instead consists of multi-age classes. Individual learning is achieved with self-corrective sensorial materials, so that children seek solutions by themselves without external feedback such as grades or evaluations. Our results show that Montessori schoolchildren have an invariant post-error slowing (PES) across age, whereas the traditional pupils have a higher PES as from 8 y.o. We found that small PES was related to higher creativity and self-correction rate. In a reward task, error-rate was found higher in Montessori schoolchildren, without impacting their efficiency score, which was interpreted as a more explorative behavior. Multi-sensory (MS) development was studied as a potential explanation of these differences. The extent to which a child exhibited multisensory benefits in their reaction times on a simple detection task not only predicted benefits on a continuous recognition task typically used in laboratory settings, but also predicted working memory scores measured using standardized test batteries. Interestingly, children in Montessori settings showed a 1.3-fold higher propensity for exhibiting multisensory benefits on simple reaction times. These results shed light on the impact of school settings in this development.

Abstract # 38

The neural correlates underlying the use of contextual and kinematic information during anticipation

Simonet M 1, 2, Boumediene H. Meziane2, Oliver R. Runswick3, Jamie S. North1, A. Mark

Williams1, 4, Jérôme Barral2, André Roca1 1Expert Performance and Skill Acquisition Research Group, School of Sport, Health and Applied Science, St Mary’s University, Twickenham, London, UK 2 Brain electrophysiology attention movement laboratory, University of Lausanne 3 Department of Sport and Exercise Sciences, University of Chichester, UK 4 Department of Health, Kinesiology and Recreation, College of Health, University of Utah, Salt Lake City, Utah, USA Anticipation is the ability to accurately predict the outcome of an opponent’s actions ahead of the act itself. This ability relies on at least two broad sources of information, namely low-level kinematic information from the postural orientation of opponents and high-level contextual information related to the event. Using electroencephalogram, we assessed neural activity in 8 expert and 15 novice cricket batters when anticipating deliveries from bowlers in a video-based simulation task where the type of information presented to participants was manipulated. Trials were occluded immediately after the ball release and anticipation measured by marking predicted ball location on scaled diagrams. Altogether, 120 videos clips were displayed across the three conditions, including 24 clips where participants were only exposed to contextual information, 24 clips where only kinematic information was provided and 72 clips with both information sources provided. The electro-cortical changes were evaluated using time frequency analyses. Preliminary results demonstrated that expert batters showed better anticipation accuracy across the three conditions. The EEG data showed a pre-stimulus alpha event-related synchronisation in the three conditions for the skilled group. This result would reflect a shift from cerebral inactivity before stimulus onset to excitatory processes after the stimulus. We also computed the θ(Fz)/α(Pz) ratio which has been used to assess cognitive load. In the three conditions, the skilled group presented a higher θ(Fz)/α(Pz) ratio, which was driven by a higher frontal θ power. Our results present evidence of a cognitive engagement during the anticipation process (from the contextual to the kinematic information sources).

Abstract # 39

Social Cues influence the evaluation of pain in others, an fMRI study on medical practitioners and controls Dirupo G, Corradi del`Aqua University of Geneva Medical Practitioners often underestimate patients’ pain, sometimes even when aware of their self-reports. We tested whether this phenomenon could be explained through the neural mechanisms underlying feedback-based learning, according to which Anterior Cingulate Cortex (ACC) and Insular Cortex (I) codes error signals and promotes behavioral adjustments, whereas the ventral striatum processes a “reward-like” response triggered by feedbacks of good proficiency. We engaged medical students and controls in an experiment where they rated the unpleasantness of painful facial expressions videos. After each evaluation, they were exposed to two independent feedbacks: the self-report of the protagonist of the video and the average rating of 20 physicians who examined the same expressions in a previous session. In both populations, ACC and I displayed an activity that parametrically increased with the distance between the participants’ initial evaluation and that of the feedbacks of both protagonist and physicians’. Interestingly, Insula and Dorsolateral Prefrontal Cortex responded differently to the two cues depending from the group, indeed ACC and I were more sensitive to the deviation from the protagonist in controls and from the physicians in medical students. In both populations the ventral striatum was more sensitive to the compliance to the protagonist cue rather than to the physicians’ one, no group interaction was found. In conclusion, contrary to lay controls, error detecting brain system in medical students is more active in presence of a deviation from physicians’ opinion. This effect can contribute in explaining patients’ pain underestimation in medical settings.

Abstract # 40

Physical Activity, Fitness level and EF in children: exploring the moderating effects of gender, age and motivation for exercise Yanguez Escalera M & Julien Chanal University of Geneva Research in children indicates that physical activity (PA) and enhanced cardiorespiratory fitness (CRF) may have a positive impact in an ensemble of cognitive processes known as executive functions (EF). Nevertheless, the effects of PA and CRF on the three core EF (inhibition, working memory and cognitive flexibility) have not been replicated consistently. The vast majority of the studies on this topic have only used one task to measure each EF construct, and that is one of the main criticism evoked by experts on cognition to explain the inconsistent results observed in the literature. This work proposes to use several tasks to measure each of the three core EF and advanced statistical methods to enable a more comprehensive evaluation of EF in children. During the school year 2017-18, 69 children aged 8 to 12 years old have been recruited in schools from Geneva. To evaluate EF, we used 9 classical EF tasks (e.g. Flanker, Trail Making Test, Digit Span Task, etc.). To evaluate CRF, children completed the Leger test. This test requires continuous running between two lines 20 meters apart, speed increases every minute (+0.5 km/h, starting at 8 km/h). Two sessions were necessary to complete the 9 EF tasks; in the third session children performed the fitness test. This work shows preliminary data from a large study, in which we examine whether factors such as age, gender or motivation for exercise moderate the relationship between PA, CRF and EF.

Abstract # 41

The Effect of Valenced Smells on Resting State Connectivity Carlson H, Patrik Vuilleumier, & David Sander University of Geneva When people are instructed to lie quietly in an fMRI and rest, distinct brain areas spontaneously become more active, forming what has been called the "default mode network". The amount of activation in the default mode network can depend on the nature of the preceding cognitive task. Even particular states of mood can have an impact on resting state activity, where emotions induced through watching joyful, fearful, or neutral movies had a lasting impact on resting state brain activity. Resting state can thus be an extremely useful measure of quick, transient emotions which occur after valenced stimuli, and can potentially affect thoughts and behaviours. This study examines the impact of valenced smells on subsequent resting state connectivity. Smells are thought to have extremely powerful effects on memory retrieval and emotions, due to the physiology of olfactory processing. As such, being able to measure how smells alter network connectivity during rest can give us an indication as to how they begin to affect our emotional experiences and moods. We created a paradigm where participants were exposed to smells in an MRI for a long period of time, with the purpose of creating transient emotional responses. Following the smell, they underwent a 90 second resting state. The subsequent connectivity showed drastic differences brought about by the valence of the smells, as well as the anxiety state trait of the participant.

Abstract # 42

Patterns of visual exploration of complex social scenes are increasingly deviant over time in preschoolers with ASD: a cross-longitudinal study Kojovic N 1, Martina Franchini2, Daniela Zöller, Tonia A. Rihs3, Reem K. Jan1,3, Holger F. Sperdin1 & Marie Schaer1

Developmental Imaging and Psychopathology (DIP) Lab, Office Médico-Pédagogique, Department of Psychiatry, University of Geneva School of Medicine, Geneva, Switzerland; 2. Dalhousie University / IWK Health Centre, Halifax, NS, Canada; 3. Functional Brain Mapping Laboratory, Dept. of Fundamental Neuroscience, University Medical School, Geneva, Switzerland Background: Numerous studies using eye tracking have highlighted atypical visual exploration patterns in individuals with ASD, e.g. less focus on eyes and faces compared to typically developing (TD) individuals. Little is known about the emergence of these atypical patterns and their change with age. Objectives: This study aimed developing a method that defines age-appropriate dynamic “norms” of visual exploration of dynamic social scenes. Besides definition of characteristic gaze behavior for a given group, it allows quantification of its change with age (i.e. change in group focus precision), thus discriminating normal and atypical developmental processes. Methods: A 3-minute cartoon was displayed on a Tobii eye-tracker device for 59 males with ASD (aged 3.7±1.4) and 35 males with TD (aged 3.8±1.3). For 16 males with ASD (aged 3.5±0.3) and 17 TD males (aged 3.3±0.3) longitudinal data were also acquired (a year later). By employing kernel density distribution estimation on the raw gaze data of TD individuals the “normative” gaze pattern distribution was created for each frame. For each patient the “distance” of his/hers gaze coordinates form this “norm” was obtained in a frame-by-frame manner. The Proximity index-PI represented the average of these values for the duration of the video. Its higher values indicate the visual exploration being more similar to the one of TD subjects. The PI was further correlated with clinical behavioral data and a measure of social complexity (number of interacting characters). A measure of dispersion of gaze data was calculated for each frame of the video, in both groups. Results: We found positive correlation between proximity from the “norm” and general adaptive (r = 0.41; p =. 001) and communication skills (r = 0.42; p =. 001) in our ASD group (cross-sectional design). While TD gaze behavior showed increasing focus with age (less dispersion, p < 0.0000 r = 0.25), preschoolers with ASD showed a more dispersed gaze pattern a year later (p < 0.0001, r = 0.05). In a group of males with ASD, higher PI characterized scene sequences with less social content (one character alone), while in sequences with two or three characters this index was lower (p = 0.004). Conclusion: Our results show that this data-driven method can be used to characterize change in visual exploration in typical and atypical development. In one year TD preschoolers showed increased attunement in visual exploration of complex social scenes while the opposite was observed in our group of males with ASD. This finding highlights the importance of early intervention to help preventing the derailment from the typical development at these young stages of development. Increasing social complexity correlated with the smaller PI thus corroborating previous findings of increased social attention impairment in scenes including more than one person in ASD (see meta-analysis of Chita-Tegmark, 2016).

Abstract # 43

Abstract # 44

Neural basis of addiction vulnerability Harada M, Lüscher C

CMU Geneva Drug seeking even when facing negative consequences is a defining symptom of addiction. This compulsive behavior is also observed in a subset of mice trained for optogenetic dopamine neuron self-stimulation (oDASS). However, the neuronal adaptations underling compulsive behavior is not fully understood. Here, we used a mouse model of compulsive oDASS seeking where only a fraction of mice persevere to lever press when they have to endure a punishment (electrical foot shock). Compulsivity has been proposed to involved dorsal striatum. We therefore now search for neural correlates of this behavior by recording ex vivo cortico-striatal synapses. Preliminary results are showing that synapses of striatal neurons receiving input from the orbitofrontal cortex (OFC) are potentiated only in persevering mice while synapses receiving input from the medial prefrontal cortex (mPFC) are potentiated in both persevering and renouncing mice.

Abstract # 45

Risk factors of Addiction

Achargui R, Lüscher C

CMU Geneva

Natural stimulation of the mesolimbic dopamine system reinforces goal-directed behavior. Besides, repetitive activation by chronic drug use or optogenetic dopamine neuron self-stimulation (ODASS) can transform the natural reinforcement into a compulsive reinforcement. When confronted to the possibility of such stimulation, only part of the mice called “resistant” persevere if they have to endure an electric shock while “sensitive” mice give up the stimulation. This compulsive reinforcement, one of the characterizing symptoms of addiction, is in part related to an alteration of the transmission of the Orbitofrontal cortex. However little is known about the genetic risk factors that could predispose a given mouse to become sensitive or resistant to major negative consequences in order to maintain its compulsive reinforcement. Here we propose a strategy to identify such risk factors

Abstract # 46

Computational Neuroscience

A predictive coding model of speech perception with (and without) neural oscillations Hovsepyan S1, Olasagasti I1, Giraud A-L 1 UNIGE1 Theoretical and empirical work suggests that neural oscillations play a role in several aspects of speech processing. In particular, coupled theta and gamma oscillations could help to segment continuous speech into syllable-like units and organize gamma activity into decipherable spike-trains. On the other hand, speech comprehension is heavily dependent on predictions. Although both neural oscillations and neural predictions seem to play a role during speech perception, it is unclear how the two notions can co-exist and interact with each other. In this study, we built a generative model that recognizes syllables in continuous speech, to explore how theta-gamma coupling affects top-down and bottom-up information flows in the brain during speech perception. In the model, theta oscillations extract syllable onset information from the envelope, which, then, is used to align the model's gamma activity with the onsets of syllables. Such alignment is crucial to line up predictions with the incoming input. Although internal expectations about syllable duration could provide an alternative way to predict syllable boundaries, the simulations demonstrate that the model performs best when it combines top-down temporal expectations about syllable duration, with bottom-up information about syllable onsets. These results suggest that the interaction of theta oscillations, with top-down and bottom-up information flows, is an important factor for continuous speech perception. More generally, this work shows the superiority of models that combine the notion of predictive coding with that of neural oscillations.

Abstract # 47

Mutual information vs. transfer entropy for experimental spike train analysis Conrad M1, Jolivet R 1 UNIGE1 Although the brain represents only about 2% of the body mass in humans, it is responsible for about 20% of the body’s resting energy metabolism. The highest energy use is at synapses, which represent approximately 60% of the brain’s energy consumption through the generation of postsynaptic potentials. Thus, energy constraints might limit and shape information processing in the brain and it has been shown previously that synapses maximize energy efficiency of information transfer rather than information transfer itself. To address these questions and investigate computation by neural systems, measuring the amount of information transferred between stimuli and neural responses is essential. Information theory offers a range of tools to calculate information flow in neural networks. Choosing the appropriate method is particularly important in experimental contexts where technical limitations can restrict the amount of data that can realistically be collected. We will discuss the comparative advantages of two different metrics: mutual information and transfer entropy. We will compare their performance on biologically plausible spike trains, and discuss their accuracy depending on various parameters and on the amount of available data, a critical limiting factor in all practical applications of information theory to experimental electrophysiological data. We will first demonstrate these metrics’ performance using synthetic random spike trains before moving on to more realistic spike-generating models. We will conclude by discussing how these metrics can be used to study brain function and performance.

Abstract # 48

Learning a representation of the peripersonal space in a neural network model Bertoni T, Serino A

CHUV The Peripersonal Space (PPS) is the region of space immediately surrounding the body. Studies on primates described a network of multisensory neurons, dedicated to PPS representation. Such neurons have visual or auditory receptive fields spatially anchored to specific body parts, and tactile receptive fields covering the same body parts. Magosso and Serino developed a neural network model using two unisensory layers (auditory/visual, tactile) connected with a multisensory layer to build a PPS representation for the hand. The model reproduces behavioral data, but it directly encodes the visual/auditory input in a hand-centered reference frame, without modeling the computation needed to generate these body-part centered coordinates. To overcome this limitation, we add a proprioceptive layer to the model, so that it can account for the above mentioned reference frame transformation. Moreover, we implement an Hebbian learning rule to model the spontaneous development of the connectivity scheme. The network is initialized with random connectivity, and trained by presenting stimulation patterns that reproduce the natural associations between tactile, proprioceptive, and visual inputs. The network learns to integrate the information from the proprioceptive and visual populations in order to coherently predict tactile input in the presence of a visual stimulus close to the hand. This requires the network to implicitly encode the hand-centered coordinates of the visual stimulus, integrating sensory information consistently with an emergent body model. We confirmed the plausibility of the proposed architecture by running a behavioral experiment, showing that proprioceptive and visual information are integrated to affect tactile processing on the hand.

Abstract # 49

Optimal stimulation protocol in a bistable synaptic consolidation model Gastaldi C EPFL Consolidation of synaptic changes in response to neural activity is thought to be fundamental for memory maintenance over a timescale of hours. In experiments, synaptic consolidation can be induced by repeatedly stimulating presynaptic neurons. However, the effectiveness of such protocols depends crucially on the repetition frequency of the stimulations and the mechanisms that cause this complex dependence are unknown. Here we propose a simple mathematical model that allows us to systematically study the interaction between the stimulation protocol and synaptic consolidation. We show the existence of optimal stimulation protocols for our model and, similarly to LTP experiments, the repetition frequency of the stimulation plays a crucial role in achieving consolidation. Our results show that the complex dependence of LTP on the stimulation frequency emerges naturally from a model which satisfies only minimal bistability requirements.

Abstract # 50

Learning to Generate Music with BachProp Colombo F, Brea J, Gerstner W LCN, BMI and IC, EPFL As deep learning advances, algorithms of music composition increase in performance. However, most of the successful models are designed for specific musical structures. Here, we present BachProp, an algorithmic composer that can generate music scores in many styles given sufficient training data. To adapt BachProp to a broad range of musical styles, we propose a novel representation of music and train a deep network to predict the note transition probabilities of a given music corpus. New music scores generated by BachProp are compared with the original corpora as well as with different network architectures and other related models. We show that BachProp captures important features of the original datasets better than other models and invite the reader to a qualitative comparison on a large collection of generated songs.

Abstract # 51

The Cost of Changing Mind: Coase theorem and Endowment Effect Falahi M & Preuschoff K Geneva Finance Research Institute & Swiss Center for Affective Sciences Endowment effect, as a cognitive bias in decision making processes, refers to the fact that the owners of a good evaluate their good more than the people who may want to buy that good. This phenomenon in decision making has been considered as a contradiction to Coase theorem. Coase theorem proposes if the transaction costs are zero or near zero, transaction would happen to produce an efficient allocation of the resources (without any effect caused by the initial resource allocation). However, in real world, transactions are usually carried out with a cost. This cost can be a monetary cost, opportunity cost, social cost, or any other cost which the parties should cover for a transaction to happen. Additionally, it has been shown that the initial resource allocation itself influences the transaction and can potentially prevent it. We are proposing another transaction cost as decision cost. This cost refers merely to the biological limits on processing which is done by nerves system. Decision cost has not been explored enough and consequently is not considered as a transaction cost for explaining endowment effect. To show the importance of considering decision cost as a factor contributing to the transaction cost, a hypothetical experiment has been designed. The result of this experiment cannot be explained by rational theories of choice. Additionally, a simple mathematical model has been proposed to explain the mechanism by which decision cost contributes in transaction costs.

Abstract # 52

Development

When were you born where? A dynamic brain-wide atlas of VZ-born neurons Baumann N1, Wagener J1, Abe P1, Serralva Lopez A 2 UNIGE1, UNIL2 During development of the mammalian central nervous system, neurons are born from two distinct types of germinal zones: (1) ventricular zones (VZ), which line the walls of the ventricular system, or (2) sub-ventricular zones (SVZ), located away from the ventricular cavities. Understanding the dynamic relationships between VZ and SVZ-born neurons across brain regions during development may be important to understand brain structure and circuit function, yet classical methods of neuronal birthdating using thymidine analogues to label DNA does not distinguish between VZ- and SVZ-born neurons. Here, we use the FlashTag birthdating approach developed in our laboratory (Telley, Govindan et al., Science 2016) to label VZ-born neurons as they undergo their final division in contact with the ventricular wall. By combining FlashTag labeling with chronic BrdU administration, we are generating a dynamic spatio-temporal map of VZ-born neurons between embryonic days (E)10.5 and E17.5 in the mouse brain. The results are combined in an online atlas to systematically investigate the relationship between neuronal localisation and date of birth. This could help in understanding the principles underlying brain architecture and wiring patterns across the central nervous system.

Abstract # 53

Large-scale parallel tracing of cell-type specific transcriptional trajectories in the developing mouse neocortex Agirman G1, Telley L2, Prados J1, Oberst P1, Nguyen L3, Dayer A1, Jabaudon D 1 UNIGE1, UNIL2, ULiège3 The cerebral cortex is a cellularly heterogeneous structure, whose circuits underlie our high-order cognitive and sensorimotor abilities. During development, distinct subtypes of glutamatergic neurons are sequentially born and differentiate from dynamic populations of progenitors located below the cortex, in the ventricular zone. The aggregate competence state of these progenitors progresses as corticogenesis proceeds; likewise, newborn neurons transit through sequential transcriptional states as they differentiate. Little is known on the orthogonal molecular mechanisms driving on the one hand the developmental progression of progenitors through competence states, and on the other hand the differentiation of newborn neurons through cell-type specific differentiation states. To address these questions, we used FlashTag (Telley et al., Science 2016) to trace the developmental trajectories of successive waves of isochronic neurons and progenitors throughout corticogenesis and performed a large-scale, parallel single cell transcriptional profiling of these time-locked populations. Our results identify chronotopic transcriptional maps defining the type-specific organization of transitions through cellular states, and unravel the principles allowing emergence and consolidation of type-specific neuronal identities in the developing cerebral cortex.

Abstract # 54

Plasticity in neurogenic competence of cortical progenitors in the developing mouse neocortex

Oberst P1, Cristina Concetti1, Denis Jabaudon1, 2 1 Department of Basic Neurosciences, University of Geneva, 1 Rue Michel Servet, 1211 Geneva, Switzerland 2 Department of Neurology Geneva University Hospital, 4 Rue Gabrielle-Perret-Gentil, 1205 Geneva, Switzerland During neocortical development, progenitors located in the ventricular zone sequentially give rise to distinct subtypes of excitatory neurons which assemble to form the circuits for high-order sensory-motor and cognitive functions. Deep layer neurons are born first, in the early stages of corticogenesis, while superficial layer neurons are born later on, toward the end of corticogenesis. The successive production of deep and superficial layer neurons results from an aggregate progression in the neurogenic competence of progenitor cells, but little is known on the mechanisms driving competence progression as well as on the contribution of intrinsic and environmental factors to this process. To address these questions, we used FlashTag (Telley et al., Science 2016) to isolate isochronic cohorts of progenitor cells and investigate their neurogenic commitment using heterochronic transplantation. Our results provide a cell-type specific account of the plasticity of neocortical progenitors at sequential stages of neurogenesis.

Abstract # 55

Role of the schizophrenia-risk gene miR-137 in corticogenesis layer assembly Tomasello U, Dayer A Department of Basic Neurosciences, University of Geneva, 1 Rue Michel Servet, 1211 Geneva, Switzerland A variety of microRNAs are expressed during cortical development and are thought to regulate early steps of cortical circuit assembly. Interestingly, and in an evolutionary perspective, miR-137 may be linked with cortex folding of gyrencephalic mammal species. A microarray performed on the postnatal cortex of the ferret at postnatal day 2 revealed increased expression of miR-137 in the prospective splenial gyrus as compared to the prospective lateral sulcus in three germinal layers of the visual cortex. In addition, in humans, miR-137 may act as a schizophrenia (SZ) risk gene. Here we aim to investigate the role of miR-137 in the development of upper-layer projection neurons (PNs) using a gain-of-function approach. Using in utero electroporation targeting the dorsal pallium at E14.5, miR-137 was overexpressed in progenitors of PNs and its impact on cell cycle dynamics and migration was analyzed at several subsequent embryonic time points. Our results indicate that cell cycle length is increased by miR137 overexpression and that PNs reach the cortical plate prematurely. Analysis at post-natal stages revealed that miR-137 overexpression inhibits layer 4 identity marker RorB, thus promoting a shift in the production of layer 2-3 PNs. Current studies are designed to determine the molecular mechanisms through which miR-137 controls early steps of progenitor dynamics. Overall, this study indicates that the SZ-risk gene miR-137 has a major regulatory role on cortical progenitor cell dynamics and specification.

Abstract # 56

Molecular and Cellular Neuroscience Resolving plasticity at accumbal to lateral hypothalamus synapse and its implication in feeding behaviour

Thoeni S1, O'Connor E 2 UNIGE1, Roche2 Our previous work has shown that nucleus accumbens (NAc) medium spiny neurons (MSNs) projecting to the lateral hypothalamus (LH) express mainly the dopamine D1 receptor (D1-MSNs). Activation of this projection inhibits LH GABA neurons and leads to cessation of feeding. Here we describe the plasticity of this synapse in naïve conditions and in response to altered food intake. As opposed to NAc-pallidum and -midbrain projections, high frequency stimulation or pharmacological PKA activation did not potentiate the NAc-LH synapse in naïve mice. This was true for the two identified postsynaptic target LH GABA and glutamate neurons. Moreover, depression of the NAc-LH synapse was observed following activation of GABA-B or CB1-receptors, but not with a low frequency stimulation protocol shown to be efficient at the NAc-pallidum synapse. Consistent with these observations, tracing experiments revealed that NAc-D1-MSNs projecting to LH are distinct from those that project to the midbrain and the pallidum. We then subjected mice to a regime combining food restriction and exercise for three days resulting in rapid weight loss. When resuming normal diet, we observed a period of hyperphagia and weight gain. Interestingly, PKA activation at this time point led to potentiation of the NAc-to-LH synapse, most likely reflecting a decrease in release probability at these terminals during hyperphagia. Taken together, our findings point to a model in which experience-dependent plasticity at the NAc-LH synapse may drive excessive food intake in periods following weight loss. This model may reflect elements of weight gain associated with human yoyo dieting.

Abstract # 57

Profiling claustral and layer 6 neocortical neurons using single-cell transcriptomics Fodoulian L1, Carleton A1, Rodriguez I 1 UNIGE1 The claustrum (CLA) is a thin sheet of subcortical grey matter located between the insular cortex and the putamen. It has dense reciprocal connections with a large number of neocortical regions, which suggests a role in attention, consciousness and saliency detection. However, its function and the underlying neuronal mechanisms remain elusive. This lack of evidence results from the scarcity of tools to specifically modulate CLA activity. In particular, gene-targeted mouse lines are lacking, due to the poorly defined genetic characteristics of CLA neurons. Here, we aimed at identifying the transcriptional identity of mouse CLA projection neurons. To ensure an unbiased sampling of CLA neurons, we injected a fluorophore-encoding transsynaptic adeno-associated virus in the primary motor cortex of the mouse. Anatomical validation of this tracing showed the transsynaptic labelling of CLA neurons. Subsequent to CLA dissection and cell dissociation, GFP+ cells were FACS sorted and captured on a C1TM high-throughput (HT) integrated fluidic circuit (IFC) (Fluidigm). Following single-cell RNA-sequencing, an unsupervised graph-based clustering of 579 cells identified 4 main cellular populations. Differential gene expression analysis revealed that one of these clusters corresponds to CLA projection neurons, while the three remaining were formed of cortical layer 6 (L6) pyramidal neurons, oligodendrocytes and striatal medium spiny neurons. CLA neurons were differentiated from L6 pyramidal neurons by a wide range of specific markers. Consistent with previous reports, typical CLA markers were also identified by our analysis. However, some of those genes, considered as canonical markers of the CLA, such as Nr4a2 and Gnb4, also appeared to be expressed by a substantial proportion of L6 neurons. In conclusion, we identified a series of genes discriminating claustral from cortical neurons, which represents a first step in the molecular dissection of the claustral circuitry.

Abstract # 58

Acid-sensing ion channels expressed in the hypothalamus are regulated by hydrogen sulfide Peng Z, Kellenberger S

UNIL Hydrogen sulphide (H2S), known as ‘gas of rotten eggs’, is a toxic and colorless gas. In mammals, the expression of the enzymes of H2S biosynthesis is predominantly found in the brain. Recently, H2S emerged as the third gasotransmitter, and was shown to exert sensory and metabolic control by interacting with ion channels. The aim of this study was to investigate whether acid-sensing ion channels (ASICs) are regulated by H2S. In CHO cells transfected with ASICs, we found that H2S time- and concentration-dependently increased the acid-induced ASIC1a peak currents. The enhancing effect of H2S on ASIC1a peak currents was detectable at a concentration of 100 µM, exposed during 40 seconds. Similar to ASIC1a, H2S also time-dependently increased the peak and sustained acid-induced currents in ASIC3-expressing cells. On other ASIC isoforms, we found that H2S time-dependently increased the acid-induced ASIC1b and ASIC2a peak currents. Notably, the enhancing effect of H2S on the peak ASIC1a currents was not pH dependent, since H2S exposure did not change the acid sensitivity of ASIC1a. In cultured hypothalamus neurons, H2S enhanced the acid-induced endogenous ASIC peak currents in a time- and concentration-dependent manner. We observed also that the acid-induced ASIC current density in the hypothalamus neurons changed depending on the time of the day, thus ASICs may be expressed according to a circadian rhythm in the cultured hypothalamus neurons. Our findings indicate that H2S regulates time- and concentration-dependently recombinantly expressed ASICs as well as the endogenous ASICs of the hypothalamus.

Abstract # 59

Astrocytic mitochondrial impairments in an animal model of schizophrenia Zehnder T1, Petrelli F1, Gogos J2, Bezzi P 1 UNIL - DNF1, Columbia University2 One of the main candidate risk gene for behavioral phenotype of 22q11 deletions syndrome (22q11DS) is the gene encoding for proline dehydrogenase (PRODH), a mitochondrial enzyme involved in the metabolism of L-proline. The expression of PRODH is typically ascribed to proliferating tissues (Polyak et al., Nature, 1997) where it regulates cell proliferation (Donald et al., Cancer Res, 2001) and metabolism (Liu et al., PNAS, 2012). The functional role of PRODH in the brain is not completely understood. We and others have found that PRODH expression in the brain is particularly high during postnatal development, the temporal period commonly associated to gliogenesis (Bandeira et al., PNAS, 2008). Interestingly, we also found that PRODH expression in astrocytes seems to be enriched into the prefrontal cortex (PFC), one of the brain main area associated to cognitive processes. We also found that these astrocytes, similar to the proliferating cells, undergo a progressive activation of oxidative phosphorylation (OxPho) during postnatal maturation, a situation that could render developing astrocytes more susceptible to mitochondrial perturbations (Fulda et al., Nature Rev Drug Disc, 2010). In astrocytes of PRODH deficient mice (Paterlini et al., Nature Neurosci., 2005), the activation of OxPho is perturbed and both the respiratory capacity and the ATP levels were significantly impaired. We concluded that PRODH expression during postnatal development is necessary to maintain a proper mitochondrial function. During the last year we investigated the effect of PRODH and OxPho impairments on the postnatal maturation of astrocytes in terms of gene expression, cellular proliferation and integration into the network. Support contributed: NCCR Synapsy to P.Bezzi

Abstract # 60

Corticostriatal dysfunction and Motor skill learning deficit in early symptomatic stage in a mouse model of Huntington’s disease Espinosa P, Bellone C

UNIGE Huntington’s disease (HD) is an inherited, progressive neurodegenerative disorder characterized by motor, cognitive and psychiatric dysfunctions. The disease is caused by a mutation of the huntingtin (Htt) gene. Many symptoms of HD are associated with neuronal death of striatal neurons. However, this degeneration is preceded by synaptic dysfunctions, imbalance between glutamatergic and dopaminergic transmission onto striatal neurons. Here using the yeast artificial chromosome expressing the mutant HTT mouse model (YAC128) and cutting-edge techniques on electrophysiology associated with behavioral approaches, we characterize synaptic properties of glutamatergic transmission in an input specific manner onto medium spiny neurons (MSNs) of the dorsolateral striatum. Additionally, we investigate whether corticostriatal synapse strength and motor skill learning performance could be linked. First, we found a decrease in AMPA/NMDA ratio at corticostriatal synapses associated with a change in NMDAR subunit composition and transmission. Along with these synaptic alterations, we observed strong motor learning deficits in single pellet reaching task and in rotarod test. Strikingly, motor training induced corticostriatal plasticity is occluded in early symptomatic stage inYAC128 mice. Identifying the mechanisms that regulate synaptic dysfunctions in a HD mouse model will help to highlight new potential target for further alternative therapeutic treatments.

Abstract # 61

Novel 3R mouse model to study cisplatin ototoxicity without systemic effects Nacher Soler G1, Rousset F1, Coelho M1, Krause K1, Senn P 1 UNIGE1 Current pre-clinical models to study ototoxic side effects of cisplatin relies on strong doses of cisplatin via intraperitoneal (IP). As result, mice suffer from high systemic toxicity, showing clearly pain and stress signs. In view of the above, usually these animals are sacrificed before obtaining a robust hearing loss model to test. Seeking to apply the 3R principle and to obtain a robust model, we developed an alternative pre-clinical local model of cisplatin. The delivery was made through the bulla section close to the end of the ear canal and next to the vestibule, what brings us just in front of the oval window and close to the round window. Only one ear was operated in each animal, allowing us to have a contralateral control (non-operated) for comparison. Hearing function was assessed the day before the surgery (D0) and 7 days after the surgery (D7), to evaluate acute effects of cisplatin on hearing. Furthermore, the integrity of the sensory epithelium and the ribbon synapses was checked by D7 histological analysis. On the one hand, this new model did not show ABR threshold increase after Saline delivery, proving to be a non-aggressive method; on the other hand, robust and reproducible hearing loss was observed in mice injected with cisplatin (15 to 25Db SPL all along the tonotopic axis). The effect of local cisplatin delivery was even stronger on the synapsis density (around 60% ctbp2 decrease in the basal turn) and hair cell death (around 30% missing hair cells in the basal turn). Finally, animals did not express visible stress or pain symptoms, showing near complete weight recovery after D3.

Abstract # 62

Aversion-triggered downscaling of AMPAR-mediated neurotransmission in the lateral habenula Nuno-Perez A1, Mameli M 1 UNIL1 The lateral habenula (LHb) is an epithalamic structure contributing to the encoding of aversive external stimuli. Glutamate release onto LHb neurons from structures including the entopeduncular nucleus (EPN) of the basal ganglia, or the lateral hypothalamus (LHy), drives aversive responses in vivo by activating AMPA and NMDA receptors. This supports the behavioural relevance of habenular glutamatergic neurotransmission. However, how aversive experience alters the input-specific AMPAR/NMDAR components within the LHb remains elusive. To tackle this question, we employed an optogenetic-based strategy by neuronal targeting of the light-activatable excitatory opsin CoChR. We virally expressed CoChR in different brain structures projecting glutamatergic terminals onto the LHb: the EPN, the LHy and the bed nucleus of the stria terminalis (BNST). Three weeks after stereotaxic injections, we subjected the mice to a single session of inescapable footshock exposure (FsE, 19 footshocks during a 20-min period). Twenty-four hours later, we performed whole-cell patch-clamp recordings from LHb neurons in acute slices. Compared to the control group, FsE mice displayed reduced AMPA/NMDA ratios synaptically-evoked by extracellular stimulation and by blue-light activation of EPN-/LHy-/BNST-to-LHb synapses. Single-photon glutamate uncaging revealed a similar reduction in the AMPA/NMDA ratio. Lastly, to understand the expression mechanisms of this plasticity, we recorded AMPAR-mediated miniature excitatory postsynaptic currents that presented reduced amplitude and frequency in FsE mice compared to their control counterparts. Altogether, such global reduction in the habenular AMPAR-mediated signalling may underlie aspects of negative motivational states emerging after aversive experience.

Abstract # 63

Role of the CREB coactivator CRTC1 in mood disorders and antidepressant response Guiraud L1, Cardinaux J-R 1 Center for Psychiatric Neuroscience and Service of Child and Adolescent Psychiatry, Department of Psychiatry, CHUV1 Approximately 60% of people committing suicide worldwide suffer from a mood disorder -depressive or bipolar disorders. Major depressive disorder (MDD) is both a genetic and environmental disease, and the alteration of several susceptibility genes can promote this disease.

Neuroplasticity and cognitive functions are both altered in MDD. Chronic stress can lead to altered neuroplasticity partly resulting from decreased cAMP response element-binding protein (CREB) function. It has notably been shown that the interaction of CREB-regulated transcription coactivator 1 (CRTC1) and CREB is critical in some neuroplasticity processes, like brain-derived neurotrophic factor (BDNF) expression or maintenance of LTP in the hippocampus. To further study CRTC1’s role, our lab generated a Crtc1 knockout mouse line, which was found to exhibit behavioral and molecular features mirroring MDD.

This project aims to identify the mechanisms by which CRTC1 deficiency can lead to these features. To this end, we injected a CRTC1-expressing virus in the medial prefrontal cortex and ventral hippocampus of these knockout mice to rescue the depressive-like phenotype. We will also be working on identifying differences in the brain activity maps of these mice following a behavioral despair paradigm. Moreover, in stressed wild-type mice, we will explore the expression and regulation of different proteins of the CREB-CRTC1 pathway to identify the ones affected by chronic stress, and to define more clearly the cellular mechanisms leading to altered BDNF expression and altered neuroplasticity. In the future, we will also be conducting investigations in human brain tissue to link our studies with the etiopathophysiology of MDD.

Abstract # 64

NON-ALLELE AND ALLELE-SPECIFIC GENE EDITING FOR HUNTINGTON’S DISEASE Vachey G1, Merienne N1, Buron J1, Donat T1, Ouared A1, Stibolt C1, Kocher J1, Ferreira A1, Pellerin L2, Perrier A3, du Pasquier R1, Déglon N 1 CHUV1, UNIL2, INSERM3 Neurodegenerative disorders are a major public health problem because of the high frequency of these devastating diseases in the population. Genome editing with the CRISPR/Cas9 system is making it possible, for the first time, to modify the sequence of genes linked to these diseases in the adult brain. Here, a self-inactivating CRISPR/Cas9 system, kamiCas9, was designed for transient expression of the Cas9 protein and high editing efficiency. In the first application of this technology to neurodegenerative disorders, the gene responsible for Huntington’s disease (HD) was targeted in adult mouse neuronal and glial cells. Mutant huntingtin (HTT) was efficiently inactivated in mouse models of HD, leading to an improvement in key markers of the disease. Sequencing of potential off-targets with the constitutive Cas9 system in differentiated human iPS cells, revealed a very low incidence with only one site above background level. Importantly, the off-target frequency was drastically reduced with the kamiCas9 system.However, a selective editing of mutant HTT represents the safest approach preserving WT HTT expression and functions and allele-specific silencing of mutant HTT is potentially the optimal solution for blocking polyQ pathogenesis. We thus developed more complex strategies to discriminate mutant and wild-type HTT genes by using single-guide RNA targeting sequences containing Single Nucleotide Polymorphism (SNP) in the HTT gene. These strategies have then been validated in human embryonic kidney 293T (HEK- 293T) cells and are currently tested in HD mouse models.These results demonstrate the potential of the self-inactivating CRISPR/Cas9 editing for applications in the context of neurodegenerative diseases and a proof of principle of allelespecific disruption of the human HTT gene.

Abstract # 65

Imaging of plasticity in the mouse medial prefrontal cortex in a fear conditioning paradigm Kiss-Bodolay D 1,2, Giuliana Fossati1, Alexandre Dayer1, Anthony Holtmaat1 1Department of Basic Neurosciences, Faculty of Medicine, University of Geneva Anxiety disorders affect a relatively large part of the population and impose an enormous burden on society, but the mechanisms underlying them are poorly understood. Early-life and prolonged stress may cause anxiety states in adults that are maintained as a result of failed fear extinction. This might be the result of maladaptive and persistent plasticity in brain circuits that modulate fear responses such as the medial prefrontal cortex (mPFC). Interestingly, this part of the cortex is highly innervated by the serotonergic system that is widely targeted for pharmacological treatment of these disorders. In the current project we aim at identifying structural and functional changes in mouse mPFC circuits in response to fear learning, fear extinction, and maladaptive fear responses. Ultimately, we will investigate the role of serotonergic mPFC afferents in these processes. Using 2-photon laser scanning microscopy, we image neuronal activity and synaptic structures in the mPFC of mice that undergo a fear-conditioning paradigm, spanning the phases of fear learning, expression and extinction. Large parts of the mPFC in mice are located deep into the medial bank of the cortex, at locations that cannot be imaged through conventional cranial windows. We have adopted a method based on the surgical implantation of microprisms to obtain access to the deeper regions of the mPFC, such as the anterior cingulate and prelimbic areas. Microprisms have an oblique reflective surface that allows us to image the vertical ‘wall’ of the cortex using an upright microscope in awake head-fixed mice. We have developed a preparation that can be utilized for long-term imaging of synaptic structures and activity over days to weeks. We are currently tracking dendritic spine dynamics in GFP-expressing L5 and L2/3 pyramidal neurons, and Ca2+ responses in GCAMP6-labeled L2/3 pyramidal cells. In the future, we aim at investigating the effects of chemogenetic and optogenetic modulation of serotonergic projections on fear learning and extinction as well as neuronal plasticity in the mPFC.

Abstract # 66

Assessing the Spatiotemporal Potassium Buffering Dynamics of the Astroglial Syncytium Wellbourne-Wood J, Guillaume Azarias, Bruno Weber, Jean-Yves Chatton DNF UNIL K+ released in the extracellular space during neuronal activity is rapidly taken by astrocytes and redistributed in the astroglial syncytium. In order to assess the interplay between extracellular K+ ([K+]o), glial behavior, and neuronal activity, measuring [K+]o is of fundamental importance. Using a newly developed K+ sensitive fluorescent nanosensor based on dendrimer nanotechnology and designed for the extracellular space, we aim instead to generate a spatiotemporal map of K+ related events. After characterizing and validating the K+ nanosensor, we then demonstrate underlying spatial and temporal aspects of [K+]o flux in acute slices using two-photo microscopy. In particular, we investigate the astroglial syncytium in its role as a K+ buffering system, demonstrating that the kinetics of potassium buffering in the CNS are sensitive to pre-incubation with a higher [K+]o concentration. This suggests that the astroglial syncytium is a plastic and dynamic system that likely adapts to local [K+]o clearance demands.

Abstract # 67

Hippocampal lesion-induced plasticity in the monkey entorhinal and perirhinal cortices Piguet O 1, Loïc J. Chareyron2, Pamela Banta Lavenex1, David G. Amaral3, Pierre Lavenex1,2 1. Laboratory of Brain and Cognitive Development, Institute of Psychology, University of Lausanne, Switzerland. 2. Department of Medicine, Center for Cognition, University of Fribourg, Switzerland. 3. Department of Psychiatry and Behavioral Sciences, Center for Neuroscience, California National Primate Research Center, M.I.N.D. Institute, UC Davis, Davis, California, USA. Cell proliferation in the subventricular zone and the dentate gyrus, and the presence of immature neurons in various brain areas have been observed in the adult mammalian brain. Although it has been shown that brain injuries can increase cell proliferation and neurogenesis in neurogenic zones, little is known about the effects of focal injury on the integration of immature neurons in other brain regions. Here, we investigated the effects of selective hippocampal lesions on the number of cells expressing the protein bcl2, a marker of immature neurons, in the monkey entorhinal and perirhinal cortices. We compared three experimental groups: unoperated control (n=7), neonatal-lesioned (n=8) and adult-lesioned (n=6) monkeys. Consistent with our previous results in the amygdala, selective hippocampal lesions were associated with changes in immature neuron numbers in the entorhinal and perirhinal cortices. In the entorhinal cortex, the number of bcl2-positive cells was 40% lower in adult-lesioned monkeys as compared to controls, whereas it did not differ between neonatal-lesioned and control monkeys. In the perirhinal cortex, the number of bcl2-positive cells was 77% higher in neonatal-lesioned monkeys as compared to controls, whereas it did not differ between adult-lesioned and control monkeys. These changes in the number of bcl2-positive cells in the entorhinal and perirhinal cortices of hippocampal-lesioned monkeys might reflect the maturation of immature neurons already present in these cortices, as well as the modulation of cell proliferation and neuroblast migration from the subventricular zone. Such lesion-induced plasticity suggests potential mechanisms that may facilitate functional recovery following focal brain injury.

Abstract # 68

Altered cortico-striatal glutamatergic synapses in a mouse model for Fragile X Syndrome Gastaldo G 1, Esperanza Fernandez2, Valentina Mercaldo1, Kris Gavaert2, Seth Grant3, Tilmann Achsel1 and Claudia Bagni1,4 1University of Lausanne, Department of Fundamental Neuroscience, Lausanne, Switzerland; 2 VIB-UGent Center for Medical Biotechnology, Gent, Belgium, 3University of Edinburgh, Centre for Neuroregeneration and Centre for Clinical Brain Sciences, Edinburgh, UK;.4University of Rome “Tor Vergata”, Department of Biomedicine and Prevention, Rome, Italy; Fragile X Syndrome (FXS), the most commonly form of inherited intellectual disability, exhibits high incidence of autism spectrum disorder (ASD) and it is caused by the lack of the fragile X mental retardation protein (FMRP). Individuals diagnosed with FXS present, among other symptoms, repetitive and perseverative behaviors that have been linked to imbalance of cortico-striatal connectivity. In this study we are testing the hypothesis that aberrant behaviors are caused by affected cortico-striatal synapses. To verify our hypothesis, we took advantage of a transgenic mouse model that allowed us to stringently purify post-synaptic complexes from glutamatergic cortico-striatal synapses and characterize them by mass spectrometry from different brain regions of juvenile and mature mice. Alterations of PSD-associated proteins particularly in the striatum of FXS mice was detected and it is currently under further validation. Our findings highlight, at the molecular level, the striatum as a hotspot for altered synaptic function/s that may account for the motor, behavioral and cognitive abnormalities described in FXS.

Abstract # 69

Neurological or Psychiatric Conditions

Increased network segregation as biomarker in focal epilepsy Carboni M1, Rubega M2, Toscano G3, Tourbier S4, van Mierlo P5, Pittau F1, Hagmann P4, Seeck M1, Michel C2, Vulliemoz S 1 University Hospital Geneva1, University of Geneva2, Instituto Neurologico Mondino3, University Hospital Lausanne4, University Ghent5 Background: High-density EEG (hd-EEG) plays a central role in the multi-axial diagnosis of patients with seizure disorders. Effective connectivity analysis, which describes directionality of information transfer between one brain region to another, and graph analysis are promising tools to reveal the network patterns involved in epileptic activity and predict post-operative seizure control using hd-EEG. Purpose: We are interested in identifying differences in the network characteristics associated with post-surgical outcomes, by quantifying the altered functional dynamics in epilepsy. Methods: We analyzed the hd-EEG data of 20 patients with focal epilepsy who subsequently underwent surgery. We applied source-based directed connectivity analysis and graph analysis on the interictal spikes to estimate the directed transitivity, i.e., the segregation of the network, and its global efficiency, i.e., the combination of specialized information from distributed brain regions. Results: In patients with post-surgical seizure-freedom, we found an increased network segregation (lower directed transitivity) and lower integration (lower global efficiency) before the spike peak in good outcomes (N=13), compared to poor outcomes (N=7). (p<0.05) Conclusion: This phenomenon may represent an important biomarker for predicting the surgery outcome. It may also help us understand network adaptation, which results in “isolation” of epileptic activity and reduction of the epileptic network in patients that will recover after surgery.

Abstract # 70

Therapeutic Drug Monitoring Of New Generation Antiepileptic Drugs In Patients With Epilepsy Aicua Rapun I1, Andre P1, Rossetti A1, Decosterd L1, Buclin T1, Novy J 1 CHUV1 The aim of the project is to evaluate the tangible benefit of Therapeutic Drug Monitoring (TDM) of new generation antiepileptic drugs (AEDs) and to determine whether and how it might improve the care of people with epilepsy. The study is a randomised clinical trial, we will explore whether the systematic monitoring of new generation AEDs plasma levels provide a clinical benefit in people with epilepsy. The inclusion criteria is adult patients with an epilepsy treated with a new generation AED, which needs to be modified or is started. The patients are randomised in two groups. In both, the blood tests are done at every appointment but only in one group the AED blood levels are transmitted to the clinician. The follow up of patients is one year. The outcome is efficacy in the control of seizures and the tolerance of AEDs, measured by the retention without endpoints. We have included 151 patients from June 2016 to December 2017 seen in the outpatient clinic of epilepsy. 18 patients have finalised the one-year of follow up without getting the endpoints. In December 2017, the proportion of retention was 40% of patients. We did not find a benefit in retention in the study in patients randomised in systematic TDM versus currently used (rescued).

Abstract # 71

Impaired auditory deviance detection in adolescents with 22q11.2 Deletion Syndrome Cantonas L-M, 1, Rihs T1, Michel C 1 UNIGE1 The 22q11.2 deletion syndrome (22q11.2 DS) is one of the highest genetic risk factors for the development of schizophrenia spectrum disorders. Here, we examined the maturation of the mismatch negativity response in children and adolescents with 22q11.2 DS with high density EEG. Using a cross-sectional approach, auditory evoked potentials were measured in 20 children (mean age : 10.8) and 20 adolescents (mean age:16.5) with 22q11.2 DS, and 40, age and gender matched controls. In addition, we present data from a longitudinal follow-up for 16 participants with 22q11.2 DS and 14 controls at two time points (T1, mean age: 11; T2:15 years). We used an oddball paradigm with pure tone stimuli, 1000Hz - as standards and 1200Hz -as deviants, presented binaurally with an 8:2 ratio. We found significant decreases in amplitude during the mismatch response on fronto-central channels, in adolescents with 22q11.2 DS compared to children with 22q11.2 DS and to healthy adolescents. In addition, adolescents with 22q11.2 DS displayed a significant increase in amplitude over central electrodes during the auditory N1 component. In the longitudinal design, we observe both a decreased MMN response and increased auditory N1 component at T2 (during adolescence) for the participants with 22q11.2 DS, whereas no such differences were seen in the healthy group. These findings suggest that the auditory N1 and mismatch response follow a different developmental trajectory during adolescence in 22q11.2 DS. These maturational changes in auditory oddball detection during a critical period might co-occur with increased risk for schizophrenia spectrum disorders.

Abstract # 72

Caveolin-1 involvement in early tissue remodeling after stroke: effects on angiogenesis and astrogliosis Blochet C1, Buscemi L1, Clément T2, Badaut J3, Hirt L 1 CHUV1, Univerity of Bordeaux2, University of Bordeaux and Loma Linda University3 Complex cellular and molecular events occur in the neurovascular unit (NVU) after stroke, such as blood-brain barrier dysfunction and inflammation that contribute to neuronal death, neurological deterioration and mortality. Caveolin-1 (Cav-1) is present in brain endothelial cells and has been reported in astrocytes in culture. Cav-1 has distinct physiological roles such as caveolae formation associated with endocytosis and transcytosis. It can also modulate signaling pathways. Therefore, Cav-1 is likely to be an important player in the context of NVU dysfunction. However, its role after stroke is still controversial and poorly understood. The goal of the study was to investigate the role of Cav-1 during the first week after stroke. We compared wild type (WT) and genetically modified Cav-1 knock-out (KO) mice in a transient Middle Cerebral Artery Occlusion (tMCAO) model. Outcome measures including lesion volume, behavioral tests, and immunofluorescence staining were collected at various time-points and up to 7 days after injury. After tMCAO, Cav-1 expression was increased in new blood vessels within the lesion and we showed for the first time its presence in reactive astrocytes in the peri-lesion. Cav-1 KO mice exhibited more severe post-stroke outcomes with larger lesions and worse behavioural scores than WT mice in all the tests. Cav-1 KO mice exhibited reduced angiogenesis and modified astrogliosis compared to WT mice 3 days post injury associated with the aggravated functional deficits. Altogether, these results point towards a potential protective role of endogenous Cav-1 in the first days after ischemia by promoting both angiogenesis and astrogliosis.

Abstract # 73

In vivo MRS profiling of redox dysregulation and GSH impairment in animal models of schizophrenia: Translational tool to study interaction between oxidative stress and NMDAR hypofunction. Skupienski R1, Xin L2, Do K 3 CHUV, EPFL1, EPFL2, CHUV3 Schizophrenia (SZ), a major psychiatric disease, is a developmental syndrome involving decreased connectivity deriving from both genetic and environmental factors. The reciprocal interaction of oxidative stress and NMDAR hypofunction leading to impairment of inhibitory interneurons and neural synchronization may represent one core pathophysiology. With the aim to identify biomarkers for early detection of SZ patients, we investigate in vivo the redox and glutamate (Glu) systems during neurodevelopment in two models: 1) glutathione (GSH) deficient gclm-KO mice, 2) PCP induced NMDAR hypofunction. The NAD+/NADH (RX) and the neurochemical profile were determined using 31P- and 1H-MRS respectively. In wild type (WT) mice, increased RX was observed from P20 to P90, due to [NAD+] increases and [NADH] decreases in the frontal pole. At P20, gclm-KO show reduced [NADH] with no change in [NAD+], leading to higher RX as compared to WT. However, no RX difference was observed at P40 and P90 between WT and KO mice. Interestingly, Glutamine/Glu ratio is also increased at P20 with no change at P90 in gclm-KO. The study of PCP models is underway. Increased redox-ratio from P20 to P90 in WT mice suggests a development to higher brain oxidative state from childhood to adulthood. Results from gclm-KO mice suggest that GSH deficiency leads to high brain oxidative status in parallel to Glu dysregulation in childhood, which may be compensated at later stages. Our study paves the way to develop biomarkers profile for early detection and intervention in psychosis.

Abstract # 74

Altered synaptic transmission Sapap3-/- mice driving behavioral hallmarks of Obsessive-compulsive disorder Simmler L1, Hadjas L1, Schartner M1, Creed M1, Pascoli V1, Luscher C 2 UNIGE1, UNIGE & HUG2 Synapse-associated protein 90/post synaptic density protein 95-associated protein 3 (Sapap3) is a post-synaptic scaffolding protein involved in obsessive-compulsive disorder (OCD) pathogenesis. Knock-out (KO) mice for Sapap3 (Sapap3-/-) exhibit OCD-like behavior (e.g., overgrooming). SAPAP3 is an isoform highly expressed in the striatum and seems important for the integrity of excitatory corticostriatal synapses. However, how aberrant cortical top-down control may be responsible for overgrooming in Sapap3-/- remains poorly understood. Here we show with motion sequencing (MoSeq) method that the Sapap3-/- mice exhibit overgrooming behavior. Also, we show that Sapap3-/- mice are more susceptible to develop habits compared to wild-type mice. Finally, whole-cell patch clamp recording showed a significant decrease of AMPA/NMDA ratio in the D1- and D2-medium-sized spiny neurons (MSNs). The AMPA/NMDA change was recorded at the synapse between the primary/secondary motor cortex (M1/M2) neurons and the MSN in the dorsolateral striatum (DLS). This result adds input-specificity to the previously reported decreased synaptic strength2. Our findings suggest a neuronal substrate (M1/M2-to-DLS) that might be involved in overgrooming in Sapap3-/- mice. We are currently developing reversal strategies, such as long-term potentiation (LTP) at the terminals of the M1 projection. We aim to normalize the AMPA/NMDA in order to establish causality between the synaptic pathology and the OCD-like behavior phenotype. These findings may provide a basis for future therapeutic interventions for OCD.

Abstract # 75

Electroconvulsive therapy induced anatomy changes restricted to the anterior “limbic” hippocampus Gyger L1, Ramponi C1, Draganski B 1 CHUV1 Although electro-convulsive therapy (ECT) is established in alleviating symptoms in drug resistant depression, its routine application is frequently disputed. One of the reasons for this controversy is the lack of knowledge about the precise mechanisms underlying the therapeutic effects. One of the candidate principles of ECT action is seizure induced neurogenesis in the hippocampus. Given the complexity of hippocampus architecture and function along its longitudinal axis we sought to answer the question about differential effects of ECT along the longitudinal axis of hippocampus. We acquired magnetic resonance imaging (MRI) data in ten patients undergoing right unilateral ECT, twenty-four patients receiving pharmacological treatments and thirty healthy controls at three time points three months apart. Using dedicated mathematical algorithms for longitudinal MRI data we obtained metrics for rate of volume change in the anterior, mid and posterior parts of hippocampus and amygdala. We found a stronger increase in the rate of volume change over time in hippocampus and amygdala bilaterally in ECT treated patients compared to antidepressants receiving patients and healthy controls. When testing for differential effects between hemispheres and along the hippocampus longitudinal axis we observed higher rate of change in the anterior hippocampus and the amygdala on the right where ECT was applied. We interpret our findings in the context of ECT induced neurogenesis with particular emphasis on the “limbic” portion of hippocampus. The differential impact of ECT along the hippocampus longitudinal axis along with its side-locked effects confirm the topologically specific mode of action of ECT to explain its depression alleviating mechanism.

Abstract # 76

Can cerebellar dysfunction help differentiate idiopathic from functional cervical dystonia? Stephan A1, Da Silva Duarte M2, Benninger D 3 UNIL1, UNIL-CHUV2, CHUV3 Background Recent evidence from animal models, neurophysiology and functional and structural imaging point to a cerebellar contribution in the pathophysiology of cervical dystonia (CD). The interest of clinicians lies in differentiating patients with idiopathic CD from patients with functional CD whose treatment remains poorly efficacious. The eye-blink classical conditioning (EBCC), a well-documented form of cerebellar dependent learning paradigm, can be used for a non-invasive investigation of cerebellar function. Objective As EBCC was demonstrated to be impaired in patients with CD, we hypothesized that cerebellar functional integrity would be preserved in patients with functional CD and such a measure could be used to help differential diagnosis. Methods Cerebellar function is probed with a classical conditioning protocol in which repetitive pairing of an auditory stimulus (conditioning stimulus) with an electrically-elicited (unconditional stimulus) blink reflex which becomes conditioned to the auditory stimulus. This conditioned response of blinking the eye with this auditory stimulus is mediated by the cerebellum. We investigated EBCC in patients with CD and presumed functional CD, which were all assessed by four movement disorders neurologists. Results Preliminary results point at a preserved conditioning in functional dystonia suggesting intact cerebellar integrity in contrast to primary idiopathic CD. If the segregation of responses in both population is strict enough, EBCC could become part of the clinical investigation to differentiate idiopathic CD from functional CD.

Abstract # 77

Deletion of Crtc1 is associated with strong neuroenergetic dysfunctions in a mouse model of mood disorders. Cherix A1, Donati G1, Poitry-Yamate C2, Cardinaux J-R, 3, Gruetter R 4 Laboratory for Functional and Metabolic Imaging (LIFMET), Ecole Polytechnique Fédérale de Lausanne.1, Animal Imaging and Technology Core (AIT), Center for Biomedical Imaging (CIBM), Ecole Polytechnique Fédérale de Lausanne.2, Center for Psychiatric Neuroscience (CNP), Centre Hospitalier Universitaire Vaudois (CHUV)3, Laboratory for Functional and Metabolic Imaging (LIFMET), Ecole Polytechnique Fédérale de Lausanne.4 CRTC1 (CREB-regulated transcription coactivator 1) is a coactivator of the transcription factor CREB, and is predominantly expressed in the brain. CRTC1 plays an important role in brain plasticity, and its dysfunction has been implicated in many neurological disorders, such as neurodegenerative and mood disorders. Mice lacking the Crtc1 gene, show a depressive-like phenotype and have been proposed as a model for preclinical mood disorder studies. Using in vivo metabolic imaging tools (1H-MRS, 13C-MRS and PET), we have shown that these animals have a strong neuroenergetic alteration of the dorsal hippocampus. Crtc1 KO animals show a reduced glucose entry in the brain as well as lower cerebral metabolic rate of glucose (CMRglc9. The resulting drop in pyruvate production is compensated by a higher brain lactate entry allowing a normal mitochondrial energy production. Mitochondrial gene expression profile and 13C-MRS-measured TCA cycle were comparable in both groups as well. 1H and 31P-NMR analysis of dorsal hippocampus metabolic extracts revealed no change in ATP or NADH/NAD+ suggesting normal energy homeostasis. A significant drop of phosphocreatine observed in vivo and in vitro together with higher creatine kinase expression (mtCK and CKB) suggest however that the reduced glycolytic ATP puts the mitochondria under allostatic load. The altered metabolic profile linked to this mechanism (reduced hippocampal lactate and phosphocreatine) correlated with the depressive-like behavior and followed the behavior change upon social isolation of mice. Together these results suggest that the depressive-like behavior of Crtc1 KO mice is related to an altered neuroenergetic production efficiency putting the hippocampus under allostatic load. This work was supported by the CIBM of the UNIL, UNIGE, HUG; CHUV, EPFL and Leenaards and Louis-Jeantet Foundations.

Abstract # 78

Insights into the mechanisms underlying the antidepressant action of Lactate Carrard A1, Boury Jamot B1, Petit J-M, 1, Fiumelli H2, Michael M2, Magistretti P2, Martin J-L 1 CHUV1, KAUST2 In addition to its role as metabolic substrate that can sustain neuronal function and viability, emerging evidence supports a role for L-lactate as an intercellular signaling molecule involved in synaptic plasticity. Clinical and basic research studies have shown that major depression and chronic stress are associated with alterations in structural and functional plasticity. These findings led us to investigate the role of L-lactate as a potential novel antidepressant. We found that peripheral administration of L-lactate produced antidepressant-like effects in the forced swim test. The antidepressant response induced by acute L-lactate administration was accompanied by increases in hippocampal lactate concentration and by changes in GSK3?/? and CREB phosphorylation levels and by alterations of Arc, COX-2 and NOS1 mRNA expression. Further investigation revealed that chronic administration of L-lactate induced antidepressant-like effects in two animal models of depression, the open-space forced swim test and the corticosterone model of depression. In particular, we found that chronic administration of L-lactate partially restored mobility in the open-space forced swim test and completely reversed the corticosterone-induced anhedonia-like behavior. The antidepressant-like effects induced by chronic L-lactate administration were accompanied by changes in the expression of target genes implicated in serotonin receptor trafficking , astrocyte functions, neurogenesis, nitric oxide synthesis and cAMP signaling. Collectively, these studies identify a previously unrecognized action of L-lactate by which acute and chronic peripheral administration of L-lactate produces antidepressant-like behavioral responses. Further elucidation of the mechanisms underlying the antidepressant effects of L-lactate may help to identify novel therapeutic targets for the treatment of depression.

Abstract # 79

Exploring the role of stress, coping strategies and HPA axis development in contributing to psychopathology in 22q11.2 Deletion Syndrome. Sandini C UNIGE Introduction: Converging evidence suggests that psychopathology emerges from the complex interaction of genetic and environmental factors, with stressful life events (SLE) playing a prominent role, in combination with coping strategies and with a dysfunctional hypothalamus-pituitary-adrenal (HPA) axis. 22q11.2 Deletion Syndrome (22q11DS) is associated with increased risk for the development of psychopathology and could help probe mechanisms of gene-environment interaction. Methods: Here we firstly explored the correlation between SLE, emotional coping strategies and psychopathology in 22q11DS, performing mediation analyses to disentangle the relationship between variables of interest. Subsequently we explored developmental trajectories of PV in longitudinal sample of individuals with 22q11DS and HCs in relation to the development of overall psychopathology, cortical morphology and hippocampal volume. Results: We found that SLE and negative coping were correlated with higher psychopathology. Moreover, dysfunctional coping mediated the effect of SLE on psychopathology. Longitudinal findings demonstrated reductions of PV emerging from adolescence in 22q11D, selectively affecting patients with higher psychopathology. Altered developmental trajectories of PV were related to aberrant developmental trajectories of hippocampal volume and cortical thickness. Finally the association of PV and cortical morphology was correlated with the expression of NR3C1 quantified in the Allen Brain Atlas. Conclusions: Our findings confirm the central role of stress and coping in the pathogenesis of psychosis and psychopathology in general. Moreover they suggest that HPA dysregulation might contribute to higher overall psychopathology in 22q11DS. Correlations between PV and hippocampal volume are in line with human and translational evidence of hippocampal and cortical vulnerability to HPA dysregulation.

Abstract # 80

Development of a large scale epileptic network outside the focus in the kainate mouse model of temporal lobe epilepsy

Padmasola G, Sheybani L, Michel CM and Quairiaux C

UNIGE

Focal epilepsies are defined by the repetition of seizures and interictal epileptic discharges (IEDs) from a particular brain region called the epileptic focus (EF). However, it is known that IEDs can recruit areas remote from the EF as part of a large-scale epileptic network (EN) and that this EN contributes to cognitive brain functions. Reciprocally, the EN might modulate the activity of the focus and presumably its propensity to generate epileptic activities. In a recent study we demonstrated that a large-scale epileptic network, in which generalized interictal epileptic discharges propagate, develop in the mouse model of temporal lobe epilepsy (TLE). This large-scale EN extend broadly in the brain, invading the contralateral hippocampus and in the frontal cortex of both hemisphere. These interictal activities were dependent on the focus in the early phase of the disease but silencing the focus failed to control them in the chronic phase. In the present study we first plan to evaluate the strength of the EN in the chronic stage using computational model of ictogenesis to predict which nodes in the EN are driving epileptiform activity. These prediction will be evaluated by silencing the different nodes of the EN and studying how interictal and ictal activities are modulated using high-density surface EEG. In addition, we plan to study the influence of the EF and of the EN for the development of the disease during the latent stage based on targeted inhibitory DREADD.

Abstract # 81

N-Acetyl-Cysteine supplementation improves functional connectivity of the cingulate cortex in early psychosis

Mullier E1, Timo Roine2, Alessandra Griffa1,3, Philipp S. Baumann4, Philippe Conus4, Kim Q. Do4, and Patric Hagmann1

1Department of Radiology, Lausanne University Hospital, Lausanne, Switzerland

2Turku Brain and Mind Center, University of Turku, Finland

3Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center (UMC) Utrecht, Utrecht, Netherlands

4Department of psychiatry, Lausanne University Hospital, Lausanne, Switzerland

N-Acetyl-Cysteine (NAC) supplementation is a potential new treatment in schizophrenia. This precursor of glutathione (GSH) helps to restore the redox balance, dysregulated for schizophrenic patients due to genetic predispositions and environmental factors. MRS studies support this hypothesis by showing a decrease in GSH levels in the frontal cortex for chronic and early psychosis patients (EPPs). Widespread structural and functional brain connectivity disruptions, particularly in the cingulate cortex, are also observed in these patients. Correlations have been found, on one hand, between the clinical symptoms and the connectivity alterations, and on the other hand, between the symptoms and the GSH levels. Although studies showed that an add-on of NAC improved the symptoms and reduced the side effects of antipsychotics in patients, the effect of NAC on brain connectivity remains unexplored. Here, we investigate the effect of NAC on the functional connectivity (FC) of the cingulate cortex in EPPs. We used resting-state functional MRI to compare FC between EPPs under NAC supplementation, EPPs with a placebo treatment and healthy control subjects. We show an increase of FC between the caudal anterior cingulate cortex and the isthmus of cingulate cortex in EPPs under NAC supplementation, which can be partially explained by an increase of centrality of this connection in the functional brain network. The increase of GSH levels induced by NAC supplementation could favorably influence the functional brain connectivity and help in its rehabilitation.

Abstract # 82

Neuron-glia interactions

Decrease of metabolic costs associated with the negative BOLD response: an fMRS study Boillat Y1, Xin L1, van der Zwaag W2, Gruetter R 1 EPFL1, Spinoza Center2 An increased of the positive BOLD signal has been linked to increases of glutamate and lactate concentration associated with higher metabolic costs. However, a negative BOLD response has also been observed in different circumstances and, although it was mostly linked to neuronal deactivation, its metabolic correlates are not known. Here, our aim was to investigate both positive and negative BOLD responses by looking at the metabolic changes using functional magnetic resonance spectroscopy at 7T (fMRS). Two groups were scanned at 7T: one for the positive BOLD (20 participants) and one for the negative BOLD (21 participants). An fMRI acquisition was acquired followed by an fMRS sequence. A visual stimulation was performed with a full screen radial checkerboard (positive BOLD; STIM) or a small checkerboard ring (negative BOLD; STIM) and a gray screen (REST) for both fMRI (10s STIM–20s REST x 12) and fMRS (2min REST followed by 5min STIM and REST x 2). During a stimulation triggering a positive BOLD response, glutamate and lactate significantly increased, suggesting higher oxidative and glycolytic activities. In contrast, during the negative BOLD response, significant decreases of glutamate, lactate and GABA were observed, which may be related to a reduction of glycolytic and oxidative metabolic demand below the baseline. Additionally, the respective changes of the BOLD signal, glutamate and lactate concentrations of both groups suggest that a local increase of inhibitory activity might occur during the negative BOLD response.

Abstract # 83

Sensory and Motor Systems

Mental Rotation of Simulated Haptic Objects

Tivadar R1, Rouillard T2, Chappaz C2, Knebel J-F, 1, Turoman N1, Anaflous F3, Roche J3, Murray M 1 CHUV1, Hap2u2, FAA3 It is unknown whether individuals can create and manipulate spatial representations based on simulated haptic sensation. In partnership with Hap2u, we studied a new technology that renders haptic feedback by modulating the friction of a flat screen through ultrasonic vibration of varying amplitude. We reasoned that participants should be able to create mental representations of letters presented in normal and mirror-reversed haptic form, and manipulate them in a mental rotation task. Normally sighted, blindfolded participants felt letters at different rotations on a tablet, and indicated their perception of the presented form. Preliminary analyses revealed mental rotation effects on accuracy and reaction times for both normal and mirror-reversed letters. Our findings significantly extend research in sensory substitution by indicating that simulation of active haptic sensations can support spatial functions and may thus be a valuable tool in the mitigation of visual impairments.

Abstract # 84

Personalized brain-spine interfaces in freely-behaving non-human primates Borgognon S *1,2, Ismael Seáñez*1, Alexandra Hickey1, Christopher M. Hitz1, Shiqi Sun1, Matthew G. Perich3, Florian Fallegger1, Giuseppe Schiavone1, Xiaoyang Kang1, Flavio Raschellá1, Jonas B. Zimmermann4, Quentin Barraud1, Silvestro Micera1, Erwan Bezard5, Tomislav Milekovic3, Marco Capogrosso2, Stéphanie P. Lacour1, Jocelyne Bloch6, Eric M. Rouiller2, Grégoire Courtine1 1Center for Neuroprosthetics and Brain Mind Institute, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland; 2Dept. of Neuroscience and Movement Science, University of Fribourg, Fribourg, Switzerland; 3Dept. of Fundamental Neuroscience, University of Geneva, Geneva, Switzerland; 4Wyss Center for Bio and Neuroengineering, Geneva, Switzerland; 5Inst. of Neurodegenerative Disorder, University of Bordeaux, France; 6Dept. of Neurosurgery, Lausanne University Hospital (CHUV), Lausanne, Switzerland; *equally contributed Brain-controlled electrical spinal cord stimulation alleviates gait deficits in animal models of spinal cord injury. Currently, spinal implants are designed with a standard size and predefined electrode placements. However, anatomical differences between and within species may have important implications on the optimal positioning of the electrodes over the spinal cord. To overcome this limitation, we developed a framework that enables personalizing the position of the electrodes to the anatomical features. Using combinations of MRI and CT imaging with 3D modeling and printing technologies, we personalized the surgical protocols and electrodes placement in order to target the individual dorsal roots of the lumbosacral spinal cord. We used similar methods to personalize the shape and positioning of a titanium mesh screwed onto the skull. The mesh is covered with hydroxylapatite, which favors its osteo-integration and thus increases its resistance profile. The incorporation of multiple pedestals onto the mesh allowed the long-lasting implantation of multiple iridium oxide probes into motor areas in conjunction with pairs of electrodes inserted into muscles to record EMG activity. Wireless transmitters are screwed onto the pedestals to record broadband signals from the intracortical probes and muscles without the need for tethered connections. We developed two-tier mixture of models to decode kinematic events and the magnitude of muscle activity from neural recordings in real-time. We then linked the decoded commands to stimulation protocols reinforcing these features during different locomotor tasks. Personalized neuroprosthetics optimizing stimulation efficacy may provide a practical path to establish a similar framework for clinical applications in humans.

Abstract # 85

Sensory threshold electrical stimulation feedback leads to corticospinal tract plasticity after motor imagery training Corbet T1, Iturrate I1, Millán J 1 EPFL1 Despite an increasing interest about brain-machine interface (BMI) systems for motor rehabilitation, only few studies showed that BMI has the potential to induce brain plasticity and motor recovery. Previously, we have demonstrated that sensory threshold electrical stimulation (St-NMES) enhanced motor imagery (MI) neural correlates. Here, we tested in a cross-over design experiment, St-NMES as an online feedback for BMI system, in order to probe the influence of BMI training on corticospinal tract (CST) excitability. We recruited 10 right-handed subjects that used BMI associated to visual or St-NMES feedback. Each BMI block training was composed of three consecutive days: a calibration and two online trainings. With St-NMES feedback, subjects received sensory threshold stimulation in association with their MI performance. With visual feedback a bar on the screen moved up or down. Before and after the online sessions, we recorded 24 motor evoked potentials (MEP) of wrist extensor muscle with transcranial magnetic stimulation (TMS). The intensity of TMS and the position of the coil were similar across sessions. Results are showing a significant interaction between feedback modality and the pre-post training comparison. Only with St-NMES feedback, subjects were able to significantly increase cortico-spinal tract excitability after BMI training. Importantly, St-NMES alone did not induced changes in MEP amplitude. Our study showcases that a closed BMI based on congruent rich afferent feedback can effectively enhance CST excitability. Our new feedback modality has the potential to enlarge the impact of BMI system for motor rehabilitation by facilitating plasticity in the central nervous system.

Abstract # 86

Decoding of motor termination in imagined movement Orset B1, Millán J 1 EPFL1 Using brain signals recorded non-invasively through electroencephalogram (EEG), we investigate the feasibility to decode the termination of an imagined movement. In particular, we explore the use of neural correlates of movement termination that can be observed during imagined movement (motor imagery, MI). To do this, we designed a task where a clock was shown to a participant (N = 9 subjects). When the clock hand was initiated, the participant was asked to perform kinesthetic repetitive MI of both hands. Then, the participant was asked to stop his action while this clock hand was reaching a target. Using EEG signals, we were able to create a decoder to predict when a participant wanted to stop. Later, the subject was performing the same task in a closed-loop protocol where a feedback was shown to him. Using this feedback, the subject needed to adapt himself to his decoder in order to anticipate and stop the clock hand precisely on a specific target. The results shows that we are able to decode motor termination with a large accuracy (AUC = 0.79 +/- 0.12). Moreover, the online protocol has shown that participants were also able to anticipate and stop accurately close to the target implying a great robustness of the decoder and a small jittering.

Abstract # 87

Single-cell corticospinal tract connectivity and molecular identity Lavalley A, Jabaudon D

UNIGE The functions of the nervous system rely on the precise connectivity of neurons across brain regions, yet how single neurons connect with one another remains poorly understood. In addition, how distinct wiring motifs are determined by specific molecular programs is largely unknown. In this project, I combine a novel technology using RNA barcoding for the large- scale multiplex assessment of connectivity across multiple brain sites together with single-cell transcriptomics to identify the single-cell connectivity of the corticospinal tract and its corresponding transcriptional determinants. The corticospinal tract is the main tract underlying skilled motor control in rodents and primates. Despite the importance of this pathway, the single cell diversity underlying the connectivity to specific subcortical targets remains unaddressed. Understanding the fine-grained cellular and molecular anatomy of this pathway is crucial, however, given the functional relevance of these connections within cortico-subcortical motor networks. The experiments proposed here are targeted at providing a single-cell resolution map of this pathway, to identify canonical motor circuit motifs and their corresponding transcriptional signatures, and with the long-term aim of recruiting specific molecular programs to direct rewiring following brain and spinal cord injury.

Abstract # 88

Spinal Reflexes Elicited By Continuous Epidural Electrical Stimulation Of The Intact Cervical Spinal Cord During Reaching And Grasping In Awake Non-Human Primates Barra B 1, Sara Conti1, Matthew G. Perich3, Melanie Kaeser1, Nathan Greiner1,2, Giuseppe Schiavone4, Tomislav Milekovic3, Jocelyne Bloch5, Stephanie P. Lacour4, Gregoire Courtine2,5, Eric M. Rouiller1, Marco Capogrosso1

1 Department of Neurosciences and Movement Sciences, Section of Medicine, University of Fribourg, Platform of Translational Neuroscience, Fribourg, Switzerland 2 Center for Neuroprosthetics and Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Federale de Lausanne (EPFL), Lausanne, Switzerland 3 Department of Fundamental Neuroscience, Faculty of Medicine, University of Geneva, Geneva, Switzerland 4 Center for Neuroprosthetics, School of Engineering, Institutes of Microengineering and Bioengineering, Ecole Polytechnique Federale de Lausanne (EPFL), Lausanne, Switzerland 5 Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland Recovery of reaching and grasping is a priority for people suffering from cervical spinal cord injury (SCI). Following up on the encouraging results obtained with Epidural Electrical Stimulation (EES) in improving motor control of lower limbs, several groups are exploring the applicability of EES to the recovery of arm and hand function after cervical SCI. However, the neural control of arm and hand is markedly different from the patterned and reflex-based control of locomotion. Indeed, EES enhances locomotion by recruiting large primary afferent fibers thus increasing the excitability of the reflex circuits that are prominently active during locomotion. The efficacy of cervical EES may be limited by the reduced importance of spinal reflexes in the planning and execution of voluntary three-dimensional reaching movements. To address this question, here we studied the muscle responses elicited by continuous EES of the cervical spinal cord in intact, awake, and behaving non-human primates. We implanted a macaque monkey with a tailored soft spinal implant with eight stimulation contacts targeting C6 to T1 dorsal roots and n=8 bipolar EMG electrodes in the left arm and hand muscles. The animal was trained to perform a three-dimensional reaching and grasping task with a robotic interface while we recorded arm joint kinematics and EMG signals, along with the interaction forces of the robot. We delivered continuous supra-threshold EES at different rostro-caudal locations and stimulation frequencies. We found that each stimulation pulse elicited muscle responses locked to the stimulation frequency. As for lumbar EES, the amplitude of the evoked responses was strongly modulated during behavior, suggesting a pre-synaptic recruitment of arm motoneurons. Stimulation delivered at distinct rostro-caudal locations recruited muscles innervated by the corresponding dorsal roots mostly during their naturally active phases. For instance, stimulation of the C7 root, strongly potentiated the EMG of Triceps muscles but only during the elbow extension phase. However, the activity of non-targeted muscles was affected as well, showing both potentiation and inhibition phase-dependent effects, contingent to the stimulation parameters. These non-functional muscle activations induced by continuous EES, impaired the normal execution of the subsequent grasping and pulling phases. Consequently, time-varying stimulation profiles at different spatial locations will be required to selectively potentiate functional muscle activity for three-dimensional reaching and grasping after severe SCI.

Abstract # 89

Functional organization of the primary visual cortex of the mouse lemur Ho A, Huber D CMU Geneva The mouse lemur (Microcebus murinus) is one of the World’s smallest primates (~60gr). This nocturnal prosimian forages for fruits and hunts for insects in the Madagascan forests. To navigate with high speed through the dense branches in complete darkness, the mouse lemur must have a highly developed visual system. However, little is known about how visual information is processed at the cortical level. We have therefore recently started exploring the functional organization of the mouse lemur visual cortex by adapting a series of optical imaging, molecular and behavioral tools which were initially developed for rodents. Our first results show that these cutting edge tools can rapidly be transferred to this small primate. We have successfully performed chronic intrinsic optical signal imaging through cranial windows and revealed clear orientation selective maps in the primary visual cortex. Such maps are a classical hallmark of the primate cortex and seem absent in rodents. We will also present the first high-throughput behavioral paradigms for mouse lemurs with which we probe the psychophysical limits of their visual system. Taken together, our studies suggest that the mouse lemur has great potential to become a valuable alternative primate model in systems neuroscience and will thus complement current trends of large scale, mouse-centric efforts to understand brain circuits.

Abstract # 90

Signalling and Excitability

A novel function of the thalamic reticular nucleus in spatial navigation and memory?

Vantomme G1, Rovó Z1, Katsioudi G1, Béard E1, Fernandez L1, Lüthi A 1 UNIL1 Cortex and thalamus are abundantly connected to each other, forming parallel loops that regulate major brain functions. A crucial component of these thalamo-cortical loops is the thalamic reticular nucleus (TRN). Strongly influenced by cortical inputs, the TRN has a robust inhibitory control over the thalamus. Although the TRN was extensively studied in sensory gating and sleep, the connectivity of its non-sensory sector is not well established. We identified the subicular complex and the anterior thalamic nuclei (ATN) as part of a thalamo-cortical loop involving the non-sensory TRN. In vitro patch-clamp recordings of TRN and ATN neurons showed reliable excitatory activations upon stimulations of the subicular afferents. Both synaptic pathways showed little depression when activated repeatedly, enabling persistent membrane depolarization and repeated firing of their postsynaptic targets. Furthermore, subicular responses in ATN obligatorily recruited feedforward inhibition from the TRN. These data suggest that the TRN plays an important role in the navigation system, spatial learning and memory. To test this hypothesis we (1) recorded anterodorsal thalamic neurons from freely behaving mice and (2) combined a watermaze task with specific chemogenetic silencing of the non-sensory TRN. Preliminary results showed that (1) head-direction tuned neurons from the thalamus displayed feedforward inhibitory responses upon light activation of the subicular neurons. (2) Silencing of non-sensory TRN did not impair learning in watermaze task. However, there was a trend for a delayed reversal learning compared to controls. Together these data suggest a novel role of the TRN in head-direction signaling and spatial memory plasticity.

Abstract # 91

Astrocyte cell volume and ionic homeostasis are challenged by neural activation: a multimodal approach

Rothenfußer K, Jourdain P, Marquet, P.

UMI DP-CHUV

K+ clearance and glutamate uptake from the extracellular space (ECS) during neuronal activation are two of the many active roles played by astrocytes. The mechanisms underlying these specific functions are accompanied by transmembrane water movements, which challenge the astrocyte volume constancy. Therefore, it is likely that cell volume regulatory mechanisms are also involved in the processes of ion clearance and neurotransmitter uptake. To asses these mechanisms, we have developed a multimodal approach, combining quantitative phase digital holographic microscopy (QP-DHM), epifluorescence imaging and mathematical modeling. This approach provides the ability to quantitatively monitor both cell volume and transmembrane water movements as well as the intracellular concentrations of the specific ionic species including [Na+]i and [K+]i at the same time. Mathematical modeling helps us to identify the relevant mechanisms underlying astrocyte cell volume homeostasis and ionic movements. Preliminary results obtained from such multimodal measurements performed on primary cultures of mouse astrocytes have confirmed that: 1) Increased extracellular K+ levels causes astrocyte swelling through mechanisms involving the activation of sodium-potassium-chloride cotransporter NKCC1. Other mechanisms involving bicarbonate transport might provide an additional mechanism. 2) Glutamate applications induce astrocyte swelling through the activation of GLAST glutamate transporters. Furthermore, these multimodal measurements have permitted to establish a volume dynamics distinct from the GLAST-mediated [Na+]i rise, suggesting that the glutamate mediated net water influx must depend upon another mechanism that still remains to be clarified.

Abstract # 92

Mechanism of hydroxycarboxylic acid receptor 1 (HCA1R) activation in neurons and its interaction with other signaling pathways for the modulation of neuronal activity de Castro Abrantes H, Marc Briquet, Stefan Offermanns, Jean-Yves Chatton DNF-UNIL Hydroxycarboxylic acid receptor 1 is a pertussis toxin sensitive Gi protein coupled receptor (GPCR) with lactate as its endogenous ligand. The recent discovery of its expression in neurons of the central nervous system has pointed to additional non-metabolic effects of lactate on neuronal network activity. We found that, at the functional level, L-lactate and two non-metabolized agonists of HCA1R (3,5-DHBA and 3-Cl-HBA), reversibly decreased spontaneous spiking activity of primary cortical neurons of wild-type mice, but not of neurons prepared from HCA1R knock-out animals. We show that the downstream pathway induced by the activation of HCA1R in neurons involves the decrease of cAMP levels, the inhibition of adenylyl cyclase, and of PKA activity. A characteristic feature of GPCRs is their ability to cross-talk with other GPCRs. We found that HCAR1 cooperates with A1R, GABABR and α2AR for the modulation of neuronal network activity. The mechanism involves the Gβɣ subunit of HCAR, which leads to the activation of phospholipase C. Our results demonstrate the consequence of HCA1R activation as a non-metabolic action of lactate on neuronal activity, and decipher the downstream pathway mobilized by HCA1R activation in neurons.

Abstract # 93

Techniques in Neuroscience

Cryogel system development for study and potential treatment cell therapy of Parkinson’s disease

Filippova A1, Efremova L1, Locatelli M1, Tieng V1, Krause K-H, 1, Braschler T 1 UNIGE1 There is a vast potential in using porous cryogel scaffolds for the study and treatment of neural diseases, such as Parkinson’s disease or stroke. Cryogels are a novel form of cell culture system. In vitro, they provide the 3D structure of classical hydrogels - allowing improved natural cell interaction than a 2D culture plate. For neural cell transplantation, they also provide porosity, which is essential for i) oxygen and nutrient diffusion ii) structural support of the fragile mature neurons during brain transplantation and their interaction with the surrounding tissue. Additionally, cryogels can be designed into a variety of shapes. This feature allows to control the volume of the culture and makes it possible to create a transplantable scaffold able to support, for example, a neural tract. The first aim of our study was to develop a carboxymethyl cellulose (CMC) -based 3D cryogel culturing system. We have adjusted cryogel coating conditions, enabling optimal neuronal adhesion. We also showed the possibility of differentiation of immortalized neural precursor cells and human embryonic stem cells into mature dopaminergic neurons using our system and compared it to the standard differentiation methods. In the next step of our study, we will evaluate the biocompatibility of the CMC scaffolds in the brain and use a smaller transplantable dopaminergic scaffold to study the effect of the cryogel support on the survival and integration of mature dopaminergic neurons in vivo. Altogether, we expect to demonstrate the feasibility of using our cryogels for cell replacement therapy in Parkinson’s disease.

Abstract # 94

In vivo absolute quantification of striatal and extrastriatal D2/3 receptors with [123I]epidepride SPECT Tsartsalis S1, Tournier B1, Millet P 2 HUG1, HUG, UNIGE2 Molecular imaging of the dopaminergic system with Positron Emission Tomography (PET) and Single Photon Emission Tomography (SPECT) is a powerful tool for the non-invasive study of the living brain in clinical and translational settings. [123I]epidepride is a high-affinity radiotracer that allows imaging of striatal and extrastriatal D2/3 sites. Nevertheless, its high-affinity renders their kinetics in the striatum seriously impedes quantification in this region. Here, we describe a partial saturation approach to separately estimate Bavail and appKd in striatal and extrastriatal regions. 6 male rats underwent a 180-min SPECT scan in which [123I]epidepride was co-injected with a dose of unlabeled epidepride at a concentration occupying 50-70% of the D2/3 receptors. This protocol permits a Scatchard plot to be delineated and Bavail and appKd to be estimated. These results were compared to results of a multi-injection SPECT study (of a total duration of 6.5 hours) performed on a group of three rats by means of linear regression analysis. A 120-min SPECT scan is sufficient to estimate Bavail and appKd values of [123I]epidepride with the partial saturation method. These values are comparable and highly correlated to the corresponding values from the multi-injection experiments, as the linear regression analysis demonstrates (r=0.99, p<0.01 for Bavail and r=0.83, p<0.05 for appKd). Using the partial saturation protocol, in vivo imaging of striatal and extra-striatal D2/3 receptors is feasible. Given its high-affinity, [123I]epidepride SPECT will allow the separate estimation of Bavail and appKd and may provide information on the receptor concentration and potentially, the presence of endogenous dopamine.

Abstract # 95

fmriflows - a consortium of fully autonomous univariate and multivariate fMRI processing pipelines Notter M1, Herholz P2, Murray M 1 CHUV1, International Laboratory for Brain, Music and Sound Research (BRAMS), Philipps-University Marburg, Marburg, Hesse, Germany2 The way fMRI data are analyzed varies greatly between researchers, and processing pipelines are often rewritten for each new dataset. This, the missing code transparency and the negligence of quality control is at the core of the current reproducibility crisis in neuroimaging. Here, we introduce fmriflows, a consortium of univariate and multivariate processing pipelines for task-based fMRI data. In addition to standard pre-processing steps, fmriflows also performs non-steady-state detection, intensity non-uniformity correction, allows for flexible temporal and spatial filtering, and computes many useful nuisance factors. Each pipeline creates an informative visual report, serving as a quality control for individual processing steps and ensuring desired processing outcomes. fmriflows can be run fully autonomously on any system via version-controlled Docker containers or in a more flexible and interactive mode via Jupyter Notebooks. Similar projects, such as FMRIPrep, have documented the need and interest for such automated analysis software pipelines. However and while FMRIPrep focuses only on preprocessing for univariate analysis, fmriflows also includes multivariate analysis as well as both 1st and 2nd-level statistical analyses. The validation of fmriflows will be done in two phases. Phase I looks for faults in the software by analyzing challenging low-quality datasets, previously identified by FMRIPRep. Once those faults are fixed, Phase II will compare fmriflows performance to a standard FMRIPrep, FSL and SPM approach. Establishing fully autonomous, community developed and open-source state-of-the-art analysis pipelines with quality control reports will make the analysis of fMRI data more objective, easier to share and therefore more reproducible.

Abstract # 96

Framing side effects positively, a way to enhance analgesia? Aurore Fernandez1,2, Irving Kirsch4, Louis Noël1, Isabelle Décosterd1,2, Pierre-Yves Rodondi3, Ted Kaptchuk, 4 Marc R. Suter1,2, , Chantal Berna1,2,4

1 University of Lausanne, Switzerland, 2 Pain Center, Department of anesthesiology, Lausanne University Hospital (CHUV), 1011, Lausanne, Switzerland 3 IUMSP, UNIL, Lausanne, Switzerland, 4 Program in Placebo Studies, HMS, Boston, USA Summary: This study aimed at framing side effects as a signal of assimilation of the medication in order to enhance NSAID analgesia. This experimental model of the clinical introduction of an analgesic compound in healthy volunteers allowed to demonstrate the feasibility and the validity of such a modulation and hence served as proof of concept for a clinical study. Aim of Investigation: Commonly used treatments in pain management have frequent side effects, sometimes preceding analgesia and potentially limiting drug tolerability. Thanks to placebo research, it is known that analgesia can be modulated by several factors including information, prior treatment experience, or awareness that an active therapy is being given. In this context, we aimed to test whether patients could be brought to interpret side effects (i.e. noticeable bodily sensations associated to the drug intake) as a third-party signal, reminding them that the medication is active in the body, and conveying a message that “help is on the way”. Methods: Sixty-six healthy males (aged 18-38 years, mean: 24.3) were recruited to participate in a study to validate pupillometry as an objective measure of analgesia. This was a cover story, as they were actually randomized double-blind to a positive information (“you might take side-effects as a reminder that the analgesic medication is active in your body”) vs. control information (“do not hesitate to inform our onsite staff, we will do our best to ensure your comfort”) embedded in a longer video about medication benefits and risks. Participants rated moderately painful heat stimuli applied to the forearm on a VAS scale and pupillary response was measured. The same stimuli were repeated 1h after intake of diclofenac and atropine (deceptively presented as a co-analgesic, but used as a side effect inducer) in order to evaluate analgesia. Adverse events (AE) were reported using a standardized questionnaire just before the second heat stimuli session. Participants were finally debriefed regarding the full purpose of the study. Results: Positive information about side effects induced an increased attribution of AE to the treatment compared to the control information (t(64)=-2.703 p=.009). The combination of medication led to significant analgesia (F(1,32)=48.762, p<0.001), without a between-group difference (F(1,32)=0.335, p=0.567). However, the number of AE was correlated with analgesia (r=-.038, p=0.002); i.e., a high number of AE correlated with stronger analgesia. Differences in correlations were significant (interaction term p=.028): the correlation between AE and analgesia was significant in the positive group (symptoms: r=-.598 p<.001) but not in the control one (symptoms: r=-.228, p =.202). After watching consecutively the two different video segments about side effects, 65% of the participants said they would prefer to receive the positive message in a clinical context. Conclusions: We determined that a positive framing of side effects was credible, even preferred by the majority of participants, and efficient in tying together AE and analgesia, provided there were enough perceived AE. These results suggest feasibility and validity to investigate such a framing of side effects in a clinical context, for example in patients with chronic pain.

Abstract # 97

Pupil Size Coupling to Cortical States Protects the Stability of Deep Sleep Yuzgez O1, Prsa M, Zimmermann R, Huber D CMU Geneva1 In wakefulness, pupil diameter reflects changes in attention, vigilance, and cortical states. How pupil correlates with cortical activity during sleep, however, remains unknown. Pupil tracking during sleep is challenging since the eyelids usually occlude the pupils. Here, we present a new head-fixed sleep paradigm in combination with infrared back-illumination pupillometry (iBip) allowing continuous tracking of pupil size sleeping mice. We found that pupil size can be used as a reliable indicator of sleep states and that cortical activity is tightly correlated to pupil size fluctuations during non-rapid eye movement (NREM) sleep. Pharmacological blocking experiments suggest that the pupil size changes during sleep are predominantly modulated by the parasympathetic system. Moreover, we found that constrictions of the pupil during NREM episodes might play a protective role for sleep stability. These findings reveal a fundamental relationship between cortical activity and pupil size, which has so far been hidden behind closed eyelids.

NOTES