Consensus paper: the role of the cerebellum in perceptual processes.

Various lines of evidence accumulated over the past 30 years indicate that the cerebellum, long recognized as essential for motor control, also has considerable influence on perceptual processes. In this paper, we bring together experts from psychology and neuroscience, with the aim of providing a succinct but comprehensive overview of key findings related to the involvement of the cerebellum in sensory perception. The contributions cover such topics as anatomical and functional connectivity, evolutionary and comparative perspectives, visual and auditory processing, biological motion perception, nociception, self-motion, timing, predictive processing, and perceptual sequencing. While no single explanation has yet emerged concerning the role of the cerebellum in perceptual processes, this consensus paper summarizes the impressive empirical evidence on this problem and highlights diversities as well as commonalities between existing hypotheses. In addition to work with healthy individuals and patients with cerebellar disorders, it is also apparent that several neurological conditions in which perceptual disturbances occur, including autism and schizophrenia, are associated with cerebellar pathology. A better understanding of the involvement of the cerebellum in perceptual processes will thus likely be important for identifying and treating perceptual deficits that may at present go unnoticed and untreated. This paper provides a useful framework for further debate and empirical investigations into the influence of the cerebellum on sensory perception.

Modalities and future prospects of gene therapy in heart transplantation.

Heart transplantation is the treatment of choice for many patients with end-stage heart failure. Its success, however, is limited by organ shortage, side effects of immunosuppressive drugs, and chronic rejection. Gene therapy is conceptually appealing for applications in transplantation, as the donor organ is genetically manipulated ex vivo before transplantation. Localised expression of immunomodulatory genes aims to create a state of immune privilege within the graft, which could eliminate the need for systemic immunosuppression. In this review, recent advances in the development of gene therapy in heart transplantation are discussed. Studies in animal models have demonstrated that genetic modification of the donor heart with immunomodulatory genes attenuates ischaemia-reperfusion injury and rejection. Alternatively, bone marrow-derived cells genetically engineered with donor-type major histocompatibility complex (MHC) class I or II promote donor-specific hyporesponsiveness. Genetic engineering of naïve T cells or dendritic cells may induce regulatory T cells and regulatory dendritic cells. Despite encouraging results in animal models, however, clinical gene therapy trials in heart transplantation have not yet been started. The best vector and gene to be delivered remain to be identified. Pre-clinical studies in non-human primates are needed. Nonetheless, the potential of gene therapy as an adjunct therapy in transplantation is essentially intact.

RECHERCHE TRANSLATIONNELLE EN NEUROSCIENCES PSYCHIATRIQUES: DE L'ANIMAL MODELE DE SCHIZOPHRENIE A LA DETECTION D'UNE DESORIENTATION SPATIALE, PRATIQUE OU SYMBOLIQUE CHEZ DES PATIENTS

La modélisation, chez l'animal, de maladies psychiatriques telles que la schizophrénie repose sur différentes démarches visant à induire des perturbations cérébrales similaires à celles observées dans la maladie. Nous avons cherché à étudier chez le rat les effets d'une diminution (50%) transitoire en glutathion (GSH) durant le développement (PND 5 à PND 16) à partir de l'implication, chez des adultes, des conséquences de cette perturbation dans des mécanismes fondamentaux de traitement de l'information sensorielle. Cette thèse évalue et documente les déficits de compétences de navigation spatiale dans ce modèle. Nous avons mis en évidence des effets comportementaux à partir de l'identification de différences particulières dans des tâches d'orientation: des difficultés, chez les rats ayant subi un déficit en GSH, à élaborer une représentation globale de l'environnement dans lequel ils se déplacent, difficultés compensées par une attention particulière aux détails visuels le composant. Cette stratégie réactive compensatoire est efficace lorsque les conditions permettent un ajustement continu aux repères visuels environnementaux. Elle ne permet cependant pas des prédictions et des attentes sur ce qui devrait être rencontré et perçu dans une certaine direction, dès qu'une partie des informations visuelles familières disparaît. Il faudrait pour cela une capacité fondée sur une représentation abstraite, à distance des modalités sensorielles qui en ont permis son élaboration. Notre thèse soutient que les déficits, supposés participer à l'émergence de certains symptômes de la maladie, auraient également des conséquences sur l'élaboration de la représentation spatiale nécessaire à des capacités d'orientation effectives et symboliques. - The study of a psychiatric disease such as schizophrenia in an animal model relies on different approaches attempting to replicate brain perturbations similar to those observed in the illness. In the present work, behavioural consequences of a functional deficit in brain connectivity and coordination were assessed in rats with a transitory glutathione (GSH) deficit induced during the postnatal development (PND 5-PND 16) with daily injections of BSO (1- buthionine-(S,R)- sulfoximine). We searched for a theoretical syndrome associating ecologically relevant behavioural adaptive deficits and resulting from the weakening of sensory integration processes. Our results revealed significant and specific deficit of BSO treated rats in spatial orientation tasks designed to test for cognitive mapping abilities. Treated rats behaved as if impaired in the proactive strategies supported by an abstract representation such as a cognitive map. In contrast their performances were preserved whenever the environmental conditions allowed for adaptative reactive strategies, an equivalent of the visual affordances described by Gibson (1958). This supports our thesis that BSO treated rats expressed difficulties in elaborating a global representation of the environment. This deficit was completely - or - partially compensated by the development of an increased attention to the environment's visual details. This compensatory reactive strategy requires a rich environment allowing for continuous adjustment to visual cues. However, such adjustment doesn't allow to predictions and expectancies about what should be met and perceived in a certain direction, when familiar visual spatial cues are missing. Such competencies require orientation based on the use of an abstract spatial representation, independent from the specific sensory modalities that have participated to its elaboration. The impairment of BSO rats such spatial representation could result from a deficit in the integration and organization of perceptual information. Our model leads to the hypothesis that these fundamental deficits might account for certain symptoms of schizophrenia. They would also interfere with in the capacity to elaborate spatial representation necessary for optimal orientation in natural, artificial or symbolic environment.

Therapeutic PD-1 pathway blockade augments with other modalities of immunotherapy T-cell function to prevent immune decline in ovarian cancer.

The tumor microenvironment mediates induction of the immunosuppressive programmed cell death-1 (PD-1) pathway, and targeted interventions against this pathway can help restore antitumor immunity. To gain insight into these responses, we studied the interaction between PD-1 expressed on T cells and its ligands (PD-1:PD-L1, PD-1:PD-L2, and PD-L1:B7.1), expressed on other cells in the tumor microenvironment, using a syngeneic orthotopic mouse model of epithelial ovarian cancer (ID8). Exhaustion of tumor-infiltrating lymphocytes (TIL) correlated with expression of PD-1 ligands by tumor cells and tumor-derived myeloid cells, including tumor-associated macrophages (TAM), dendritic cells, and myeloid-derived suppressor cells (MDSC). When combined with GVAX or FVAX vaccination (consisting of irradiated ID8 cells expressing granulocyte macrophage colony-stimulating factor or FLT3 ligand) and costimulation by agonistic α-4-1BB or TLR 9 ligand, antibody-mediated blockade of PD-1 or PD-L1 triggered rejection of ID8 tumors in 75% of tumor-bearing mice. This therapeutic effect was associated with increased proliferation and function of tumor antigen-specific effector CD8(+) T cells, inhibition of suppressive regulatory T cells (Treg) and MDSC, upregulation of effector T-cell signaling molecules, and generation of T memory precursor cells. Overall, PD-1/PD-L1 blockade enhanced the amplitude of tumor immunity by reprogramming suppressive and stimulatory signals that yielded more powerful cancer control.

Dynamic perceptual mapping

Perceptual maps have been used for decades by market researchers to illuminatethem about the similarity between brands in terms of a set of attributes, to position consumersrelative to brands in terms of their preferences, or to study how demographic and psychometricvariables relate to consumer choice. Invariably these maps are two-dimensional and static. Aswe enter the era of electronic publishing, the possibilities for dynamic graphics are opening up.We demonstrate the usefulness of introducing motion into perceptual maps through fourexamples. The first example shows how a perceptual map can be viewed in three dimensions,and the second one moves between two analyses of the data that were collected according todifferent protocols. In a third example we move from the best view of the data at the individuallevel to one which focuses on between-group differences in aggregated data. A final exampleconsiders the case when several demographic variables or market segments are available foreach respondent, showing an animation with increasingly detailed demographic comparisons.These examples of dynamic maps use several data sets from marketing and social scienceresearch.

The structural nature of perceptual experiences

Intuitively, we think of perception as providing us with direct cognitive access to physical objects and their properties. But this common sense picture of perception becomes problematic when we notice that perception is not always veridical. In fact, reflection on illusions and hallucinations seems to indicate that perception cannot be what it intuitively appears to be. This clash between intuition and reflection is what generates the puzzle of perception. The task and enterprise of unravelling this puzzle took, and still takes, centre stage in the philosophy of perception. The goal of my dissertation is to make a contribution to this enterprise by formulating and defending a new structural approach to perception and perceptual consciousness. The argument for my structural approach is developed in several steps. Firstly, I develop an empirically inspired causal argument against naïve and direct realist conceptions of perceptual consciousness. Basically, the argument says that perception and hallucination can have the same proximal causes and must thus belong to the same mental kind. I emphasise that this insight gives us good reasons to abandon what we are instinctively driven to believe - namely that perception is directly about the outside physical world. The causal argument essentially highlights that the information that the subject acquires in perceiving a worldly object is always indirect. To put it another way, the argument shows that what we, as perceivers, are immediately aware of, is not an aspect of the world but an aspect of our sensory response to it. A view like this is traditionally known as a Representative Theory of Perception. As a second step, emphasis is put on the task of defending and promoting a new structural version of the Representative Theory of Perception; one that is immune to some major objections that have been standardly levelled at other Representative Theories of Perception. As part of this defence and promotion, I argue that it is only the structural features of perceptual experiences that are fit to represent the empirical world. This line of thought is backed up by a detailed study of the intriguing phenomenon of synaesthesia. More precisely, I concentrate on empirical cases of synaesthetic experiences and argue that some of them provide support for a structural approach to perception. The general picture that emerges in this dissertation is a new perspective on perceptual consciousness that is structural through and through.

Perceptual mapping of practical ethics along the value chain: A multiple correspondence analysis with industry and cultural indices as supplementary variables

This paper presents findings from a study investigating a firm s ethical practices along the value chain. In so doing we attempt to better understand potential relationships between a firm s ethical stance with its customers and those of its suppliers within a supply chain and identify particular sectoral and cultural influences that might impinge on this. Drawing upon a database comprising of 667 industrial firms from 27 different countries, we found that ethical practices begin with the firm s relationship with its customers, the characteristics of which then influence the ethical stance with the firm s suppliers within the supply chain. Importantly, market structure along with some key cultural characteristics were also found to exert significant influence on the implementation of ethical policies in these firms.

Perceptual and semantic contributions to repetition priming of environmental sounds.

Repetition of environmental sounds, like their visual counterparts, can facilitate behavior and modulate neural responses, exemplifying plasticity in how auditory objects are represented or accessed. It remains controversial whether such repetition priming/suppression involves solely plasticity based on acoustic features and/or also access to semantic features. To evaluate contributions of physical and semantic features in eliciting repetition-induced plasticity, the present functional magnetic resonance imaging (fMRI) study repeated either identical or different exemplars of the initially presented object; reasoning that identical exemplars share both physical and semantic features, whereas different exemplars share only semantic features. Participants performed a living/man-made categorization task while being scanned at 3T. Repeated stimuli of both types significantly facilitated reaction times versus initial presentations, demonstrating perceptual and semantic repetition priming. There was also repetition suppression of fMRI activity within overlapping temporal, premotor, and prefrontal regions of the auditory "what" pathway. Importantly, the magnitude of suppression effects was equivalent for both physically identical and semantically related exemplars. That the degree of repetition suppression was irrespective of whether or not both perceptual and semantic information was repeated is suggestive of a degree of acoustically independent semantic analysis in how object representations are maintained and retrieved.

Diagnostic imaging modalities of osteoblastic metastases

Methods to quantify radiograph images are needed to improve the identification of metastases

Cognition and brain function in schizotypy : a selective review

Schizotypy refers to a set of personality traits thought to reflect the subclinical expression of the signs and symptoms of schizophrenia. Here, we review the cognitive and brain functional profile associated with high questionnaire scores in schizotypy. We discuss empirical evidence from the domains of perception, attention, memory, imagery and representation, language, and motor control. Perceptual deficits occur early and across various modalities. Whilst the neural mechanisms underlying visual impairments may be linked to magnocellular dysfunction, further effects may be seen downstream in higher cognitive functions. Cognitive deficits are observed in inhibitory control, selective and sustained attention, incidental learning and memory. In concordance with the cognitive nature of many of the aberrations of schizotypy, higher levels of schizotypy are associated with enhanced vividness and better performance on tasks of mental rotation. Language deficits seem most pronounced in higher-level processes. Finally, higher levels of schizotypy are associated with reduced performance on oculomotor tasks, resembling the impairments seen in schizophrenia. Some of these deficits are accompanied by reduced brain activation, akin to the pattern of hypoactivations in schizophrenia spectrum individuals. We conclude that schizotypy is a construct with apparent phenomenological overlap with schizophrenia and stable inter-individual differences that covary with performance on a wide range of perceptual, cognitive and motor tasks known to be impaired in schizophrenia. The importance of these findings lies not only in providing a fine-grained neurocognitive characterisation of a personality constellation known to be associated with real-life impairments, but also in generating hypotheses concerning the aetiology of schizophrenia.

Dosimetric comparison of different treatment modalities for stereotactic radiosurgery of arteriovenous malformations and acoustic neuromas.

PURPOSE: We investigated the influence of beam modulation on treatment planning by comparing four available stereotactic radiosurgery (SRS) modalities: Gamma-Knife-Perfexion, Novalis-Tx Dynamic-Conformal-Arc (DCA) and Dynamic-Multileaf-Collimation-Intensity-Modulated-radiotherapy (DMLC-IMRT), and Cyberknife. MATERIAL AND METHODS: Patients with arteriovenous malformation (n = 10) or acoustic neuromas (n = 5) were planned with different treatment modalities. Paddick conformity index (CI), dose heterogeneity (DH), gradient index (GI) and beam-on time were used as dosimetric indices. RESULTS: Gamma-Knife-Perfexion can achieve high degree of conformity (CI = 0.77 ± 0.04) with limited low-doses (GI = 2.59 ± 0.10) surrounding the inhomogeneous dose distribution (D(H) = 0.84 ± 0.05) at the cost of treatment time (68.1 min ± 27.5). Novalis-Tx-DCA improved this inhomogeneity (D(H) = 0.30 ± 0.03) and treatment time (16.8 min ± 2.2) at the cost of conformity (CI = 0.66 ± 0.04) and Novalis-TX-DMLC-IMRT improved the DCA CI (CI = 0.68 ± 0.04) and inhomogeneity (D(H) = 0.18 ± 0.05) at the cost of low-doses (GI = 3.94 ± 0.92) and treatment time (21.7 min ± 3.4) (p<0.01). Cyberknife achieved comparable conformity (CI = 0.77 ± 0.06) at the cost of low-doses (GI = 3.48 ± 0.47) surrounding the homogeneous (D(H) = 0.22 ± 0.02) dose distribution and treatment time (28.4min±8.1) (p<0.01). CONCLUSIONS: Gamma-Knife-Perfexion will comply with all SRS constraints (high conformity while minimizing low-dose spread). Multiple focal entries (Gamma-Knife-Perfexion and Cyberknife) will achieve better conformity than High-Definition-MLC of Novalis-Tx at the cost of treatment time. Non-isocentric beams (Cyberknife) or IMRT-beams (Novalis-Tx-DMLC-IMRT) will spread more low-dose than multiple isocenters (Gamma-Knife-Perfexion) or dynamic arcs (Novalis-Tx-DCA). Inverse planning and modulated fluences (Novalis-Tx-DMLC-IMRT and CyberKnife) will deliver the most homogeneous treatment. Furthermore, Linac-based systems (Novalis and Cyberknife) can perform image verification at the time of treatment delivery.

Auditory perceptual decision-making based on semantic categorization of environmental sounds.

Discriminating complex sounds relies on multiple stages of differential brain activity. The specific roles of these stages and their links to perception were the focus of the present study. We presented 250ms duration sounds of living and man-made objects while recording 160-channel electroencephalography (EEG). Subjects categorized each sound as that of a living, man-made or unknown item. We tested whether/when the brain discriminates between sound categories even when not transpiring behaviorally. We applied a single-trial classifier that identified voltage topographies and latencies at which brain responses are most discriminative. For sounds that the subjects could not categorize, we could successfully decode the semantic category based on differences in voltage topographies during the 116-174ms post-stimulus period. Sounds that were correctly categorized as that of a living or man-made item by the same subjects exhibited two periods of differences in voltage topographies at the single-trial level. Subjects exhibited differential activity before the sound ended (starting at 112ms) and on a separate period at ~270ms post-stimulus onset. Because each of these periods could be used to reliably decode semantic categories, we interpreted the first as being related to an implicit tuning for sound representations and the second as being linked to perceptual decision-making processes. Collectively, our results show that the brain discriminates environmental sounds during early stages and independently of behavioral proficiency and that explicit sound categorization requires a subsequent processing stage.

Estradiol levels in men with congenital hypogonadotropic hypogonadism and the effects of different modalities of hormonal treatment.

Objective: To evaluate the degree of E-2 deficiency in male congenital hypogonadotropic hypogonadism (CHH), and its response to different hormonal treatments.Design: Retrospective and prospective studies.Setting: Academic institution.Patient(s): Untreated or treated CHH, healthy men, untreated men with Klinefelter syndrome (KS). Intervention(s): Serum sex hormone-binding globulin (SHBG) and total E-2 (TE2) as well as bioavailable (BE2) and free (FE2) levels were measured and determined.Main Outcome Measure(s): Total, bioavailable, and free testosterone, TE2, BE2, FE2 were compared in normal men, untreated and treated CHH and in untreated KS.Result(s): TE2, BE2, and FE2 levels were very significantly lower in untreated patients with CHH (n = 91) than in controls (n = 63) and in patients with KS (n = 45). The TE2 correlated positively with serum total T in patients with CHH. The TE2 also correlated very positively with serum LH in the combined population of patients with CHH and healthy men, suggesting that low E-2 levels in CHH are due to severe LH-driven T deficiency. All fractions of circulating E-2 were very significantly higher in patients with CHH receiving T enanthate (n = 101) or the FSH-hCG combination (n = 88) than in untreated patients with CHH. Contrary to dihydrotestosterone (DHT), both T enanthate and combined FSH-hCGtherapy significantly and prospectively increased TE2 levels in patients with CHH.Conclusion(s): Contrary to KS, the male hypogonadism observed in CHH is associated with profound E-2 deficiency, which can be overcome by aromatizable androgen or combined gonadotropin therapy. (Fertil Steril (R) 2011; 95: 2324-29. (C) 2011 by American Society for Reproductive Medicine.)