Academic literature on the topic 'M-PSI/02'

BackgroundAn unmet need exists for novel therapies that produce deep and durable responses in more patients with metastatic melanoma (metMEL). Encouraging clinical activity was observed with the CD122-preferential IL-2 pathway agonist bempegaldesleukin(BEMPEG) plus nivolumab(NIVO) in first-line metMEL in the phase 1/2 PIVOT-02 trial (NCT02983045),1 leading to FDA Breakthrough Therapy Designation. We present updated clinical results from PIVOT-02 in first-line metMEL, and biomarkers of response.Methods41 patients with previously untreated stage IV melanoma (known PD-L1 status by immunohistochemistry; 28–8 PharmDx) received ≥1 dose of BEMPEG(0.006 mg/kg) plus NIVO(360 mg) q3wks; 38 patients were efficacy-evaluable (≥1 post-baseline tumor scan). Primary endpoints were safety and objective response rate (ORR; RECIST v1.1; BICR); other endpoints included PFS, OS and biomarkers. Polyfunctional strength index (PSI) of circulating lymphocytes (determined using single-cell cytokine analysis [Isoplexis]) and eosinophil count (determined from hematology analysis) at baseline and Cycle1-Day8 were analyzed using the median cut-off for correlations with ORR and PFS. Biomarkers, including CD8+tumor infiltrating lymphocytes (TIL) and interferon-gamma (IFNg) gene expression profile (GEP), were measured in baseline tumor biopsies and analyzed for correlation with ORR and PFS.ResultsAt median follow-up of 25.7 months (15May2020), ORR by BICR was 53% (20/38 patients). Complete response occurred in 13/38 patients (34%): 23% PD-L1-negative (<1% tumor cell expression); 41% PD-L1-positive (≥1% tumor cell expression). Further deepening of response was observed, with 17/38 patients (45%) achieving 100% reduction in target lesions and a 79% median reduction from baseline in tumor size (previously 62%).1 Median time to response and time to complete response was 2.0 and 7.9 months, respectively. Median PFS and OS were not reached. 2-year OS rate was 77% (95% CI: 60–87; ITT). Safety was consistent with previous reports.1 IFNg GEP and CD8+ TIL in baseline tumor biopsies were significantly associated with ORR and PFS. Analysis of Cycle1-Day8 blood samples demonstrated significant increases in CD4+PSI, CD8+PSI, and eosinophils from baseline. Increased CD8+PSI was significantly associated with higher ORR and PFS; increased eosinophils were significantly associated with higher ORR.ConclusionsBEMPEG plus NIVO was well tolerated in first-line metMEL, with durable and further deepening of responses, regardless of baseline PD-L1 status. At 25.7 months‘ follow-up, mPFS and mOS were not reached. Early on-treatment (Day8) increases in CD8+PSI and eosinophils in blood were identified as non-invasive biomarkers of response that are detectable well before clinical measures of response. A phase 3 trial evaluating BEMPEG plus NIVO in first-line metMEL is enrolling(NCT03635983).Trial RegistrationNCT02983045Ethics ApprovalThe study was approved by the institutional review board of each participating site.ReferenceDiab A, Puzanov I, Maio M, et al. Clinical activity of BEMPEG plus NIVO in previously untreated patients with metastatic melanoma: updated results from the phase 1/2 PIVOT-02 study. Oral presentation at SITC; November 6–10, 2019; National Harbor, MD, USA. Abstract #O35.

OBJECTIVES/GOALS: Parent stress and coping impacts reward and motivation circuits during child development which influence self-regulation. One well known maladaptive coping response is alcohol or drinking-to-cope (DTC). This study assessed differences in stress and child behaviors among DTC parents as compared to non-DTC parents. METHODS/STUDY POPULATION: Baseline data was used from parents of a 2-5-year-old who were screened for a larger study assessing a mindfulness-based parent stress reduction intervention to improve healthy choices for themselves and their families. The sample included 172 parent-child dyads, mean parent age was 34.4 (6.1) years old, 56.3% white, mean child age was 3.6 (1.2) years old, 52.3% male. Subjective stress was assessed using the Perceived Stress Scale (PSS), parent-specific stress was assessing using the Parenting Stress Index (PSI), DTC was assessed using the COPE inventory, and child behaviors were assessed using the Devereux Early Childhood Assessment. To investigate the differences in stress and child behaviors between DTC parents and non-DTC parents independent samples t-tests were conducted. RESULTS/ANTICIPATED RESULTS: DTC was significantly correlated with PSS (r= 0.23, p<.01), PSI (r= 0.26, p<.01), child self-control (r= -0.16, p= .03), child attention problems (r= 0.22, p<.01), and total behavioral concerns (r= 0.16, p=.04). After excluding those who do not drink alcohol at all, we found significantly higher perceived stress among DTC parents (M= 27.83, SD= 9.79) compared to non-DTC parents (M= 23.79, SD= 8.40), t(80)= 2.02, p= .02. For children, we found significantly higher aggression scores for children of DTC parents (M= 47.16, SD= 31.69) compared to children of non-DTC parents (M=35.83, SD=25.72), t(84)= 1.83, p= .04. And greater attention problems among children of DTC parents (M= 73.97, SD= 26.77) compared to children of non-DTC parents (M= 56.71, SD= 34.09), t(84)=2.63, p=.01. DISCUSSION/SIGNIFICANCE: Stress and DTC may contribute to negative behaviors in children. An intervention designed to decrease stress and increase adaptive coping mechanism in parents could benefit health child socioemotional and behavioral development. Future analyses will examine third variable effects in the relationship between stress, coping, and child behaviors.

One of the main tasks of structural biology is comparing the structure of proteins. Comparisons of protein structure can determine their functional similarities. Multigraph alignment is a useful tool for identifying functional similarities based on structural analysis. This article proposes a new algorithm for aligning protein binding sites called ACOTS-MGA. This algorithm is based on the memetic scheme. It uses the ACO method to construct a set of solutions, then selects the best solution for implementing Tabu Search to improve the solution quality. Experimental results have shown that ACOTS-MGA outperforms state-of-the-art algorithms while producing alignments of better quality.KeywordsMultiple Graph Alignment, Tabu Search, Ant Colony Optimization, local search, memetic algorithm, SMMAS pheromone update rule, protein active sitesReferencesE. Todd, C. A. Orengo, and J. M. Thornton, “Evolution of function in protein superfamilies, from a structural perspective,” J. Mol. Biol., vol. 307, no. 4, pp. 1113–1143, Apr. 2001.S. F. Altschul et al., “Gapped BLAST and PSI-BLAST: a new generation of protein database search programs,” Nucleic Acids Res., vol. 25, pp. 3389–3402, 1997.R. C. Edgar, “MUSCLE: multiple sequence alignment with high accuracy and high throughput,” Nucleic Acids Res., vol. 32, no. 5, pp. 1792–1797, Mar. 2004.J. D. Thompson, D. G. Higgins, and T. J. Gibson, “CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice,” Nucleic Acids Res., vol. 22, no. 22, pp. 4673–4680, Nov. 1994.M. Larkin, G. Blackshields, N. Brown, … R. C.-, and undefined 2007, “Clustal W and Clustal X version 2.0,” academic.oup.com.C. Notredame, D. G. Higgins, and J. Heringa, “T-coffee: a novel method for fast and accurate multiple sequence alignment,” J. Mol. Biol., vol. 302, no. 1, pp. 205–217, Sep. 2000.K. Sjolander, “Phylogenomic inference of protein molecular function: advances and challenges,” Bioinformatics, vol. 20, no. 2, pp. 170–179, Jan. 2004.T. Fober, M. Mernberger, G. Klebe, and E. Hüllermeier, “Evolutionary construction of multiple graph alignments for the structural analysis of biomolecules,” Bioinformatics, vol. 25, no. 16, pp. 2110–2117, 2009.M. Mernberger, G. Klebe, and E. Hullermeier, “SEGA: Semiglobal Graph Alignment for Structure-Based Protein Comparison,” IEEE/ACM Trans. Comput. Biol. Bioinforma., vol. 8, no. 5, pp. 1330–1343, Sep. 2011.D. Shasha, J. T. L. Wang, and R. Giugno, “Algorithmics and applications of tree and graph searching,” in Proceedings of the twenty-first ACM SIGMOD-SIGACT-SIGART symposium on Principles of database systems - PODS ’02, 2002, p. 39.R. V. Spriggs, P. J. Artymiuk, and P. Willett, “Searching for Patterns of Amino Acids in 3D Protein Structures,” J. Chem. Inf. Comput. Sci., vol. 43, no. 2, pp. 412–421, Mar. 2003.D. Conte, P. Foggia, C. Sansone, And M. Vento, “Thirty years of graph matching in pattern recognition,” Int. J. Pattern Recognit. Artif. Intell., vol. 18, no. 3, pp. 265–298, May 2004.K. Kinoshita and H. Nakamura, “Identification of the ligand binding sites on the molecular surface of proteins,” Protein Sci., vol. 14, no. 3, pp. 711–718, Mar. 2005.O. Kuchaiev and N. Pržulj, “Integrative network alignment reveals large regions of global network similarity in yeast and human,” Bioinformatics, vol. 27, 2011.Xifeng Yan, Feida Zhu, Jiawei Han, and P. S. Yu, “Searching Substructures with Superimposed Distance,” in 22nd International Conference on Data Engineering (ICDE’06), 2006, pp. 88–88.X. Yan, P. S. Yu, and J. Han, “Substructure similarity search in graph databases,” in Proceedings of the 2005 ACM SIGMOD international conference on Management of data - SIGMOD ’05, 2005, p. 766.S. Zhang, M. Hu, and J. Yang, “TreePi: A Novel Graph Indexing Method,” in 2007 IEEE 23rd International Conference on Data Engineering, 2007, pp. 966–975.A. E. Aladag and C. Erten, “SPINAL: scalable protein interaction network alignment,” Bioinformatics, vol. 29, pp. 917–924, 2013.S. Schmitt, D. Kuhn, and G. Klebe, “A New Method to Detect Related Function Among Proteins Independent of Sequence and Fold Homology,” J. Mol. Biol., vol. 323, no. 2, pp. 387–406, Oct. 2002.M. Hendlich, A. Bergner, J. Günther, and G. Klebe, “Relibase: Design and Development of a Database for Comprehensive Analysis of Protein–Ligand Interactions,” J. Mol. Biol., vol. 326, no. 2, pp. 607–620, Feb. 2003.N. Weskamp, E. Hüllermeier, D. Kuhn, and G. Klebe, “Multiple graph alignment for the structural analysis of protein active sites,” IEEE/ACM Trans. Comput. Biol. Bioinforma., vol. 4, no. 2, pp. 310–320, 2007.T. N. Ha, D. D. Dong, and H. X. Huan, “An efficient ant colony optimization algorithm for Multiple Graph Alignment,” in 2013 International Conference on Computing, Management and Telecommunications (ComManTel), 2013, pp. 386–391. F. Neri, Handbook of memetic algorithms, vol. 379. Berlin, Heidelberg: Springer Berlin Heidelberg, 2011.M. Gong, Z. Peng, L. Ma, and J. Huang, “Global Biological Network Alignment by Using Efficient Memetic Algorithm,” IEEE/ACM Trans. Comput. Biol. Bioinforma., vol. 13, no. 6, pp. 1117–1129, Nov. 2016.J. M. Caldonazzo Garbelini, A. Y. Kashiwabara, and D. S. Sanches, “Sequence motif finder using memetic algorithm,” BMC Bioinformatics, vol. 19, 2018. L. Correa, B. Borguesan, C. Farfan, M. Inostroza-Ponta, and M. Dorn, “A Memetic Algorithm for 3-D Protein Structure Prediction Problem,” IEEE/ACM Trans. Comput. Biol. Bioinforma., pp. 1–1, 2016.H. Tran Ngoc, D. Do Duc, and H. Hoang Xuan, “A novel ant based algorithm for multiple graph alignment,” in 2014 International Conference on Advanced Technologies for Communications (ATC 2014), 2014, pp. 181–186. H. X. Huan, N. Linh-Trung, H.-T. Huynh, and others, “Solving the Traveling Salesman Problem with Ant Colony Optimization: A Revisit and New Efficient Algorithms,” REV J. Electron. Commun., vol. 2, no. 3–4, 2013. D. Do Duc, H. Q. Dinh, and H. Hoang Xuan, “On the Pheromone Update Rules of Ant Colony Optimization Approaches for the Job Shop Scheduling Problem,” 2008, pp. 153-160.

ABSTRACTThe purpose of this study was to characterize KOH based electrolytes and effects of additives on electro-chemical mechanical planarization. The electrochemical mechanical polisher was made to measure the potentiodynamic curve and removal rate of Cu. The potentiodynamic curves were measured in static and dynamic states in investigated electrolytes using a potentiostat. Cu disk of 2 inch was used as a working electrode and Pt electroplated platen was used as a counter electrode. KOH was used as the electrolyte. H2O2 and citric acid were used as additives for the ECMP of Cu. In static and dynamic potentiodynamic measurements, the corrosion potential decreased and corrosion current increased as a function of KOH concentration. In dynamic state, different potentiodynamic curve was obtained when compared to the static state. The current density did not decrease in passivation region by mechanical polishing effect. The static etch and removal rate were measured as function of KOH concentration and applied voltage. In ECMP system, polishing was performed at 30 rpm and 1 psi. The removal rate was about 60 nm/min at 0.3 V when 5 wt% KOH was used. Also, the effect of additive was investigated in KOH based electrolyte on removal rates. As a result, The removal rate was increased to 350 nm/min when 5wt% KOH, 5vol% H2O2, 0.3 M citric acid were used.

The general aim of the present dissertation was to participate in the progress of our understanding of how sensory input and sensory experience impact on how the human brain implements categorical knowledge. The goal was twofold: (1) understand whether there are brain regions that encode information about different categories regardless of input modality and sensory experience (study 1); (2) deepen the investigation of the mechanisms that drive cross-modal and intra-modal plasticity following early blindness and the way they express during the processing of different categories presented as real-world sounds (study 2). To address these fundamental questions, we used fMRI to characterize the brain responses to different conceptual categories presented acoustically in sighted and early blind individuals, and visually in a separate sighted group. In study 1, we observed that the right posterior middle temporal gyrus (rpMTG) is the region that most reliably decoded categories and selectively correlated with conceptual models of our stimuli space independently of input modality and visual experience. However, this region maintains separate the representational format from the different modalities, revealing a multimodal rather than an amodal nature. In addition, we observed that VOTC showed distinct functional profiles according to the hemispheric side. The left VOTC showed an involvement in the acoustical categorization processing at the same degree in sighted and in blind individuals. We propose that this involvement might reflect an engagement of the left VOTC in more semantic/linguistic processing of the stimuli potentially supported by its enhanced connection with the language system. However, paralleling our observation in rpMTG, the representations from different modalities are maintained segregated in VOTC, showing little evidence for sensory-abstraction. On the other side, the right VOTC emerged as a sensory-related visual region in sighted with the ability to rewires itself toward acoustical stimulation in case of early visual deprivation. In study 2, we observed opposite effects of early visual deprivation on auditory decoding in occipital and temporal regions. While occipital regions contained more information about sound categories in the blind, the temporal cortex showed higher decoding in the sighted. This unbalance effect was stronger in the right hemisphere where we, also, observed a negative correlation between occipital and temporal decoding of sound categories in EB. These last results suggest that the intramodal and crossmodal reorganizations might be inter-connected. We therefore propose that the extension of non-visual functions in the occipital cortex of EB may trigger a network-level reorganization that reduce the computational load of the regions typically coding for the remaining senses due to the extension of such computation in occipital regions.

The first part of my thesis presents an overview of the different approaches used in the past two decades in the attempt to forecast epileptic seizure on the basis of intracranial and scalp EEG. Past research could reveal some value of linear and nonlinear algorithms to detect EEG features changing over different phases of the epileptic cycle. However, their exact value for seizure prediction, in terms of sensitivity and specificity, is still discussed and has to be evaluated. In particular, the monitored EEG features may fluctuate with the vigilance state and lead to false alarms. Recently, such a dependency on vigilance states has been reported for some seizure prediction methods, suggesting a reduced reliability. An additional factor limiting application and validation of most seizure-prediction techniques is their computational load. For the first time, the reliability of permutation entropy [PE] was verified in seizure prediction on scalp EEG data, contemporarily controlling for its dependency on different vigilance states. PE was recently introduced as an extremely fast and robust complexity measure for chaotic time series and thus suitable for online application even in portable systems. The capability of PE to distinguish between preictal and interictal state has been demonstrated using Receiver Operating Characteristics (ROC) analysis. Correlation analysis was used to assess dependency of PE on vigilance states. Scalp EEG-Data from two right temporal epileptic lobe (RTLE) patients and from one patient with right frontal lobe epilepsy were analysed. The last patient was included only in the correlation analysis, since no datasets including seizures have been available for him. The ROC analysis showed a good separability of interictal and preictal phases for both RTLE patients, suggesting that PE could be sensitive to EEG modifications, not visible on visual inspection, that might occur well in advance respect to the EEG and clinical onset of seizures. However, the simultaneous assessment of the changes in vigilance showed that: a) all seizures occurred in association with the transition of vigilance states; b) PE was sensitive in detecting different vigilance states, independently of seizure occurrences. Due to the limitations of the datasets, these results cannot rule out the capability of PE to detect preictal states. However, the good separability between pre- and interictal phases might depend exclusively on the coincidence of epileptic seizure onset with a transition from a state of low vigilance to a state of increased vigilance. The finding of a dependency of PE on vigilance state is an original finding, not reported in literature, and suggesting the possibility to classify vigilance states by means of PE in an authomatic and objectic way. The second part of my thesis provides the description of a novel behavioral task based on motor imagery skills, firstly introduced (Bruzzo et al. 2007), in order to study mental simulation of biological and non-biological movement in paranoid schizophrenics (PS). Immediately after the presentation of a real movement, participants had to imagine or re-enact the very same movement. By key release and key press respectively, participants had to indicate when they started and ended the mental simulation or the re-enactment, making it feasible to measure the duration of the simulated or re-enacted movements. The proportional error between duration of the re-enacted/simulated movement and the template movement were compared between different conditions, as well as between PS and healthy subjects. Results revealed a double dissociation between the mechanisms of mental simulation involved in biological and non-biologial movement simulation. While for PS were found large errors for simulation of biological movements, while being more acurate than healthy subjects during simulation of non-biological movements. Healthy subjects showed the opposite relationship, making errors during simulation of non-biological movements, but being most accurate during simulation of non-biological movements. However, the good timing precision during re-enactment of the movements in all conditions and in both groups of participants suggests that perception, memory and attention, as well as motor control processes were not affected. Based upon a long history of literature reporting the existence of psychotic episodes in epileptic patients, a longitudinal study, using a slightly modified behavioral paradigm, was carried out with two RTLE patients, one patient with idiopathic generalized epilepsy and one patient with extratemporal lobe epilepsy. Results provide strong evidence for a possibility to predict upcoming seizures in RTLE patients behaviorally. In the last part of the thesis it has been validated a behavioural strategy based on neurobiofeedback training, to voluntarily control seizures and to reduce there frequency. Three epileptic patients were included in this study. The biofeedback was based on monitoring of slow cortical potentials (SCPs) extracted online from scalp EEG. Patients were trained to produce positive shifts of SCPs. After a training phase patients were monitored for 6 months in order to validate the ability of the learned strategy to reduce seizure frequency. Two of the three refractory epileptic patients recruited for this study showed improvements in self-management and reduction of ictal episodes, even six months after the last training session.

The first part of my thesis presents an overview of the different approaches used in the past two decades in the attempt to forecast epileptic seizure on the basis of intracranial and scalp EEG. Past research could reveal some value of linear and nonlinear algorithms to detect EEG features changing over different phases of the epileptic cycle. However, their exact value for seizure prediction, in terms of sensitivity and specificity, is still discussed and has to be evaluated. In particular, the monitored EEG features may fluctuate with the vigilance state and lead to false alarms. Recently, such a dependency on vigilance states has been reported for some seizure prediction methods, suggesting a reduced reliability. An additional factor limiting application and validation of most seizure-prediction techniques is their computational load. For the first time, the reliability of permutation entropy [PE] was verified in seizure prediction on scalp EEG data, contemporarily controlling for its dependency on different vigilance states. PE was recently introduced as an extremely fast and robust complexity measure for chaotic time series and thus suitable for online application even in portable systems. The capability of PE to distinguish between preictal and interictal state has been demonstrated using Receiver Operating Characteristics (ROC) analysis. Correlation analysis was used to assess dependency of PE on vigilance states. Scalp EEG-Data from two right temporal epileptic lobe (RTLE) patients and from one patient with right frontal lobe epilepsy were analysed. The last patient was included only in the correlation analysis, since no datasets including seizures have been available for him. The ROC analysis showed a good separability of interictal and preictal phases for both RTLE patients, suggesting that PE could be sensitive to EEG modifications, not visible on visual inspection, that might occur well in advance respect to the EEG and clinical onset of seizures. However, the simultaneous assessment of the changes in vigilance showed that: a) all seizures occurred in association with the transition of vigilance states; b) PE was sensitive in detecting different vigilance states, independently of seizure occurrences. Due to the limitations of the datasets, these results cannot rule out the capability of PE to detect preictal states. However, the good separability between pre- and interictal phases might depend exclusively on the coincidence of epileptic seizure onset with a transition from a state of low vigilance to a state of increased vigilance. The finding of a dependency of PE on vigilance state is an original finding, not reported in literature, and suggesting the possibility to classify vigilance states by means of PE in an authomatic and objectic way. The second part of my thesis provides the description of a novel behavioral task based on motor imagery skills, firstly introduced (Bruzzo et al. 2007), in order to study mental simulation of biological and non-biological movement in paranoid schizophrenics (PS). Immediately after the presentation of a real movement, participants had to imagine or re-enact the very same movement. By key release and key press respectively, participants had to indicate when they started and ended the mental simulation or the re-enactment, making it feasible to measure the duration of the simulated or re-enacted movements. The proportional error between duration of the re-enacted/simulated movement and the template movement were compared between different conditions, as well as between PS and healthy subjects. Results revealed a double dissociation between the mechanisms of mental simulation involved in biological and non-biologial movement simulation. While for PS were found large errors for simulation of biological movements, while being more acurate than healthy subjects during simulation of non-biological movements. Healthy subjects showed the opposite relationship, making errors during simulation of non-biological movements, but being most accurate during simulation of non-biological movements. However, the good timing precision during re-enactment of the movements in all conditions and in both groups of participants suggests that perception, memory and attention, as well as motor control processes were not affected. Based upon a long history of literature reporting the existence of psychotic episodes in epileptic patients, a longitudinal study, using a slightly modified behavioral paradigm, was carried out with two RTLE patients, one patient with idiopathic generalized epilepsy and one patient with extratemporal lobe epilepsy. Results provide strong evidence for a possibility to predict upcoming seizures in RTLE patients behaviorally. In the last part of the thesis it has been validated a behavioural strategy based on neurobiofeedback training, to voluntarily control seizures and to reduce there frequency. Three epileptic patients were included in this study. The biofeedback was based on monitoring of slow cortical potentials (SCPs) extracted online from scalp EEG. Patients were trained to produce positive shifts of SCPs. After a training phase patients were monitored for 6 months in order to validate the ability of the learned strategy to reduce seizure frequency. Two of the three refractory epileptic patients recruited for this study showed improvements in self-management and reduction of ictal episodes, even six months after the last training session.

This thesis was aimed at verifying the role of the superior colliculus (SC) in human spatial orienting. To do so, subjects performed two experimental tasks that have been shown to involve SC’s activation in animals, that is a multisensory integration task (Experiment 1 and 2) and a visual target selection task (Experiment 3). To investigate this topic in humans, we took advantage of neurophysiological finding revealing that retinal S-cones do not send projections to the collicular and magnocellular pathway. In the Experiment 1, subjects performed a simple reaction-time task in which they were required to respond as quickly as possible to any sensory stimulus (visual, auditory or bimodal audio-visual). The visual stimulus could be an S-cone stimulus (invisible to the collicular and magnocellular pathway) or a long wavelength stimulus (visible to the SC). Results showed that when using S-cone stimuli, RTs distribution was simply explained by probability summation, indicating that the redundant auditory and visual channels are independent. Conversely, with red long-wavelength stimuli, visible to the SC, the RTs distribution was related to nonlinear neural summation, which constitutes evidence of integration of different sensory information. We also demonstrate that when AV stimuli were presented at fixation, so that the spatial orienting component of the task was reduced, neural summation was possible regardless of stimulus color. Together, these findings provide support for a pivotal role of the SC in mediating multisensory spatial integration in humans, when behavior involves spatial orienting responses. Since previous studies have shown an anatomical asymmetry of fibres projecting to the SC from the hemiretinas, the Experiment 2 was aimed at investigating temporo-nasal asymmetry in multisensory integration. To do so, subjects performed monocularly the same task shown in the Experiment 1. When spatially coincident audio-visual stimuli were visible to the SC (i.e. red stimuli), the RTE depended on a neural coactivation mechanism, suggesting an integration of multisensory information. When using stimuli invisible to the SC (i.e. purple stimuli), the RTE depended only on a simple statistical facilitation effect, in which the two sensory stimuli were processed by independent channels. Finally, we demonstrate that the multisensory integration effect was stronger for stimuli presented to the temporal hemifield than to the nasal hemifield. Taken together, these findings suggested that multisensory stimulation can be differentially effective depending on specific stimulus parameters. The Experiment 3 was aimed at verifying the role of the SC in target selection by using a color-oddity search task, comprising stimuli either visible or invisible to the collicular and magnocellular pathways. Subjects were required to make a saccade toward a target that could be presented alone or with three distractors of another color (either S-cone or long-wavelength). When using S-cone distractors, invisible to the SC, localization errors were similar to those observed in the distractor-free condition. Conversely, with long-wavelength distractors, visible to the SC, saccadic localization error and variability were significantly greater than in either the distractor-free condition or the S-cone distractors condition. Our results clearly indicate that the SC plays a direct role in visual target selection in humans. Overall, our results indicate that the SC plays an important role in mediating spatial orienting responses both when required covert (Experiments 1 and 2) and overt orienting (Experiment 3).

This thesis was aimed at verifying the role of the superior colliculus (SC) in human spatial orienting. To do so, subjects performed two experimental tasks that have been shown to involve SC’s activation in animals, that is a multisensory integration task (Experiment 1 and 2) and a visual target selection task (Experiment 3). To investigate this topic in humans, we took advantage of neurophysiological finding revealing that retinal S-cones do not send projections to the collicular and magnocellular pathway. In the Experiment 1, subjects performed a simple reaction-time task in which they were required to respond as quickly as possible to any sensory stimulus (visual, auditory or bimodal audio-visual). The visual stimulus could be an S-cone stimulus (invisible to the collicular and magnocellular pathway) or a long wavelength stimulus (visible to the SC). Results showed that when using S-cone stimuli, RTs distribution was simply explained by probability summation, indicating that the redundant auditory and visual channels are independent. Conversely, with red long-wavelength stimuli, visible to the SC, the RTs distribution was related to nonlinear neural summation, which constitutes evidence of integration of different sensory information. We also demonstrate that when AV stimuli were presented at fixation, so that the spatial orienting component of the task was reduced, neural summation was possible regardless of stimulus color. Together, these findings provide support for a pivotal role of the SC in mediating multisensory spatial integration in humans, when behavior involves spatial orienting responses. Since previous studies have shown an anatomical asymmetry of fibres projecting to the SC from the hemiretinas, the Experiment 2 was aimed at investigating temporo-nasal asymmetry in multisensory integration. To do so, subjects performed monocularly the same task shown in the Experiment 1. When spatially coincident audio-visual stimuli were visible to the SC (i.e. red stimuli), the RTE depended on a neural coactivation mechanism, suggesting an integration of multisensory information. When using stimuli invisible to the SC (i.e. purple stimuli), the RTE depended only on a simple statistical facilitation effect, in which the two sensory stimuli were processed by independent channels. Finally, we demonstrate that the multisensory integration effect was stronger for stimuli presented to the temporal hemifield than to the nasal hemifield. Taken together, these findings suggested that multisensory stimulation can be differentially effective depending on specific stimulus parameters. The Experiment 3 was aimed at verifying the role of the SC in target selection by using a color-oddity search task, comprising stimuli either visible or invisible to the collicular and magnocellular pathways. Subjects were required to make a saccade toward a target that could be presented alone or with three distractors of another color (either S-cone or long-wavelength). When using S-cone distractors, invisible to the SC, localization errors were similar to those observed in the distractor-free condition. Conversely, with long-wavelength distractors, visible to the SC, saccadic localization error and variability were significantly greater than in either the distractor-free condition or the S-cone distractors condition. Our results clearly indicate that the SC plays a direct role in visual target selection in humans. Overall, our results indicate that the SC plays an important role in mediating spatial orienting responses both when required covert (Experiments 1 and 2) and overt orienting (Experiment 3).

Human brain is provided with a flexible audio-visual system, which interprets and guides responses to external events according to spatial alignment, temporal synchronization and effectiveness of unimodal signals. The aim of the present thesis was to explore the possibility that such a system might represent the neural correlate of sensory compensation after a damage to one sensory pathway. To this purpose, three experimental studies have been conducted, which addressed the immediate, short-term and long-term effects of audio-visual integration on patients with Visual Field Defect (VFD). Experiment 1 investigated whether the integration of stimuli from different modalities (cross-modal) and from the same modality (within-modal) have a different, immediate effect on localization behaviour. Patients had to localize modality-specific stimuli (visual or auditory), cross-modal stimulus pairs (visual-auditory) and within-modal stimulus pairs (visual-visual). Results showed that cross-modal stimuli evoked a greater improvement than within modal stimuli, consistent with a Bayesian explanation. Moreover, even when visual processing was impaired, cross-modal stimuli improved performance in an optimal fashion. These findings support the hypothesis that the improvement derived from multisensory integration is not attributable to simple target redundancy, and prove that optimal integration of cross-modal signals occurs in processing stage which are not consciously accessible. Experiment 2 examined the possibility to induce a short term improvement of localization performance without an explicit knowledge of visual stimulus. Patients with VFD and patients with neglect had to localize weak sounds before and after a brief exposure to a passive cross-modal stimulation, which comprised spatially disparate or spatially coincident audio-visual stimuli. After exposure to spatially disparate stimuli in the affected field, only patients with neglect exhibited a shifts of auditory localization toward the visual attractor (the so called Ventriloquism After-Effect). In contrast, after adaptation to spatially coincident stimuli, both neglect and hemianopic patients exhibited a significant improvement of auditory localization, proving the occurrence of After Effect for multisensory enhancement. These results suggest the presence of two distinct recalibration mechanisms, each mediated by a different neural route: a geniculo-striate circuit and a colliculus-extrastriate circuit respectively. Finally, Experiment 3 verified whether a systematic audio-visual stimulation could exert a long-lasting effect on patients’ oculomotor behaviour. Eye movements responses during a visual search task and a reading task were studied before and after visual (control) or audio-visual (experimental) training, in a group of twelve patients with VFD and twelve controls subjects. Results showed that prior to treatment, patients’ performance was significantly different from that of controls in relation to fixations and saccade parameters; after audiovisual training, all patients reported an improvement in ocular exploration characterized by fewer fixations and refixations, quicker and larger saccades, and reduced scanpath length. Similarly, reading parameters were significantly affected by the training, with respect to specific impairments observed in left and right hemisphere–damaged patients. The present findings provide evidence that a systematic audio-visual stimulation may encourage a more organized pattern of visual exploration with long lasting effects. In conclusion, results from these studies clearly demonstrate that the beneficial effects of audio-visual integration can be retained in absence of explicit processing of visual stimulus. Surprisingly, an improvement of spatial orienting can be obtained not only when a on-line response is required, but also after either a brief or a long adaptation to audio-visual stimulus pairs, so suggesting the maintenance of mechanisms subserving cross-modal perceptual learning after a damage to geniculo-striate pathway. The colliculus-extrastriate pathway, which is spared in patients with VFD, seems to play a pivotal role in this sensory compensation.

Human brain is provided with a flexible audio-visual system, which interprets and guides responses to external events according to spatial alignment, temporal synchronization and effectiveness of unimodal signals. The aim of the present thesis was to explore the possibility that such a system might represent the neural correlate of sensory compensation after a damage to one sensory pathway. To this purpose, three experimental studies have been conducted, which addressed the immediate, short-term and long-term effects of audio-visual integration on patients with Visual Field Defect (VFD). Experiment 1 investigated whether the integration of stimuli from different modalities (cross-modal) and from the same modality (within-modal) have a different, immediate effect on localization behaviour. Patients had to localize modality-specific stimuli (visual or auditory), cross-modal stimulus pairs (visual-auditory) and within-modal stimulus pairs (visual-visual). Results showed that cross-modal stimuli evoked a greater improvement than within modal stimuli, consistent with a Bayesian explanation. Moreover, even when visual processing was impaired, cross-modal stimuli improved performance in an optimal fashion. These findings support the hypothesis that the improvement derived from multisensory integration is not attributable to simple target redundancy, and prove that optimal integration of cross-modal signals occurs in processing stage which are not consciously accessible. Experiment 2 examined the possibility to induce a short term improvement of localization performance without an explicit knowledge of visual stimulus. Patients with VFD and patients with neglect had to localize weak sounds before and after a brief exposure to a passive cross-modal stimulation, which comprised spatially disparate or spatially coincident audio-visual stimuli. After exposure to spatially disparate stimuli in the affected field, only patients with neglect exhibited a shifts of auditory localization toward the visual attractor (the so called Ventriloquism After-Effect). In contrast, after adaptation to spatially coincident stimuli, both neglect and hemianopic patients exhibited a significant improvement of auditory localization, proving the occurrence of After Effect for multisensory enhancement. These results suggest the presence of two distinct recalibration mechanisms, each mediated by a different neural route: a geniculo-striate circuit and a colliculus-extrastriate circuit respectively. Finally, Experiment 3 verified whether a systematic audio-visual stimulation could exert a long-lasting effect on patients’ oculomotor behaviour. Eye movements responses during a visual search task and a reading task were studied before and after visual (control) or audio-visual (experimental) training, in a group of twelve patients with VFD and twelve controls subjects. Results showed that prior to treatment, patients’ performance was significantly different from that of controls in relation to fixations and saccade parameters; after audiovisual training, all patients reported an improvement in ocular exploration characterized by fewer fixations and refixations, quicker and larger saccades, and reduced scanpath length. Similarly, reading parameters were significantly affected by the training, with respect to specific impairments observed in left and right hemisphere–damaged patients. The present findings provide evidence that a systematic audio-visual stimulation may encourage a more organized pattern of visual exploration with long lasting effects. In conclusion, results from these studies clearly demonstrate that the beneficial effects of audio-visual integration can be retained in absence of explicit processing of visual stimulus. Surprisingly, an improvement of spatial orienting can be obtained not only when a on-line response is required, but also after either a brief or a long adaptation to audio-visual stimulus pairs, so suggesting the maintenance of mechanisms subserving cross-modal perceptual learning after a damage to geniculo-striate pathway. The colliculus-extrastriate pathway, which is spared in patients with VFD, seems to play a pivotal role in this sensory compensation.

The question of how we make, and how we should make judgments and decisions has occupied thinkers for many centuries. This thesis has the aim to add new evidences to clarify the brain’s mechanisms for decisions. The cognitive and the emotional processes of social actions and decisions are investigated with the aim to understand which brain areas are mostly involved. Four experimental studies are presented. A specific kind of population is involved in the first study (as well as in study III) concerning patients with lesion of ventromedial prefrontal cortex (vmPFC). This region is collocated in the ventral surface of frontal lobe, and it seems have an important role in social and moral decision in forecasting the negative emotional consequences of choice. In study I, it is examined whether emotions, specifically social emotions subserved by the vmPFC, affect people’s willingness to trust others. In study II is observed how incidental emotions could encourage trusting behaviour, especially when individuals are not aware of emotive stimulation. Study III has the aim to gather a direct psychophysiological evidence, both in healthy and neurologically impaired individuals, that emotions are crucially involved in shaping moral judgment, by preventing moral violations. Study IV explores how the moral meaning of a decision and its subsequent action can modulate the basic component of action such as sense of agency.

The question of how we make, and how we should make judgments and decisions has occupied thinkers for many centuries. This thesis has the aim to add new evidences to clarify the brain’s mechanisms for decisions. The cognitive and the emotional processes of social actions and decisions are investigated with the aim to understand which brain areas are mostly involved. Four experimental studies are presented. A specific kind of population is involved in the first study (as well as in study III) concerning patients with lesion of ventromedial prefrontal cortex (vmPFC). This region is collocated in the ventral surface of frontal lobe, and it seems have an important role in social and moral decision in forecasting the negative emotional consequences of choice. In study I, it is examined whether emotions, specifically social emotions subserved by the vmPFC, affect people’s willingness to trust others. In study II is observed how incidental emotions could encourage trusting behaviour, especially when individuals are not aware of emotive stimulation. Study III has the aim to gather a direct psychophysiological evidence, both in healthy and neurologically impaired individuals, that emotions are crucially involved in shaping moral judgment, by preventing moral violations. Study IV explores how the moral meaning of a decision and its subsequent action can modulate the basic component of action such as sense of agency.

The general aim of the thesis was to investigate how and to what extent the characteristics of action organization are reflected in language, and how they influence language processing and understanding. Even though a huge amount of research has been devoted to the study of the motor effects of language, this issue is very debated in literature. Namely, the majority of the studies have focused on low-level motor effects such as effector-relatedness of action, whereas only a few studies have started to systematically investigate how specific aspects of action organization are encoded and reflected in language. After a review of previous studies on the relationship between language comprehension and action (chapter 1) and a critical discussion of some of them (chapter 2), the thesis is composed by three experimental chapters, each devoted to a specific aspect of action organization. Chapter 3 presents a study designed with the aim to disentangle the effective time course of the involvement of the motor system during language processing. Three kinematics experiments were designed in order to determine whether and, at which stage of motor planning and execution effector-related action verbs influence actions executed with either the same or a different effector. Results demonstrate that the goal of an action can be linguistically re-activated, producing a modulation of the motor response. In chapter 4, a second study investigates the interplay between the role of motor perspective (agent) and the organization of action in motor chains. More specifically, this kinematics study aims at deepening how goal can be translated in language, using as stimuli simple sentences composed by a pronoun (I, You, He/She) and a verb. Results showed that the perspective activated by the pronoun You reflects the motor pattern of the “agent” combined with the chain structure of the verb. These data confirm an early involvement of the motor system in language processing, suggesting that it is specifically modulated by the activation of the agent’s perspective. In chapter 5, the issue of perspective is specifically investigated, focusing on its role in language comprehension. In particular, this study aimed at determining how a specific perspective (induced for example by a personal pronoun) modulates motor behaviour during and after language processing. A classical compatibility effect (the Action-sentence compatibility effect) has been used to this aim. In three behavioural experiments the authors investigated how the ACE is modulated by taking first or third person perspective. Results from these experiments showed that the ACE effect occurs only when a first-person perspective is activated by the sentences used as stimuli. Overall, the data from this thesis contributed to disentangle several aspects of how action organization is translated in language, and then reactivated during language processing. This constitutes a new contribution to the field, adding lacking information on how specific aspects such as goal and perspective are linguistically described. In addition, these studies offer a new point of view to understand the functional implications of the involvement of the motor system during language comprehension, specifically from the point of view of our social interactions.