Neural basis of visual deficits recovery: visual residual functions and multisensory integration.

The ability of integrating into a unified percept sensory inputs deriving from different sensory modalities, but related to the same external event, is called multisensory integration and might represent an efficient mechanism of sensory compensation when a sensory modality is damaged by a cortical lesion. This hypothesis has been discussed in the present dissertation. Experiment 1 explored the role of superior colliculus (SC) in multisensory integration, testing patients with collicular lesions, patients with subcortical lesions not involving the SC and healthy control subjects in a multisensory task. The results revealed that patients with collicular lesions, paralleling the evidence of animal studies, demonstrated a loss of multisensory enhancement, in contrast with control subjects, providing the first lesional evidence in humans of the essential role of SC in mediating audio-visual integration. Experiment 2 investigated the role of cortex in mediating multisensory integrative effects, inducing virtual lesions by inhibitory theta-burst stimulation on temporo-parietal cortex, occipital cortex and posterior parietal cortex, demonstrating that only temporo-parietal cortex was causally involved in modulating the integration of audio-visual stimuli at the same spatial location. Given the involvement of the retino-colliculo-extrastriate pathway in mediating audio-visual integration, the functional sparing of this circuit in hemianopic patients is extremely relevant in the perspective of a multisensory-based approach to the recovery of unisensory defects. Experiment 3 demonstrated the spared functional activity of this circuit in a group of hemianopic patients, revealing the presence of implicit recognition of the fearful content of unseen visual stimuli (i.e. affective blindsight), an ability mediated by the retino-colliculo-extrastriate pathway and its connections with amygdala. Finally, Experiment 4 provided evidence that a systematic audio-visual stimulation is effective in inducing long-lasting clinical improvements in patients with visual field defect and revealed that the activity of the spared retino-colliculo-extrastriate pathway is responsible of the observed clinical amelioration, as suggested by the greater improvement observed in patients with cortical lesions limited to the occipital cortex, compared to patients with lesions extending to other cortical areas, found in tasks high demanding in terms of spatial orienting. Overall, the present results indicated that multisensory integration is mediated by the retino-colliculo-extrastriate pathway and that a systematic audio-visual stimulation, activating this spared neural circuit, is able to affect orientation towards the blind field in hemianopic patients and, therefore, might constitute an effective and innovative approach for the rehabilitation of unisensory visual impairments.

Models for the study of neuronal activity during cognitive tasks

Assessment of brain connectivity among different brain areas during cognitive or motor tasks is a crucial problem in neuroscience today. Aim of this research study is to use neural mass models to assess the effect of various connectivity patterns in cortical EEG power spectral density (PSD), and investigate the possibility to derive connectivity circuits from EEG data. To this end, two different models have been built. In the first model an individual region of interest (ROI) has been built as the parallel arrangement of three populations, each one exhibiting a unimodal spectrum, at low, medium or high frequency. Connectivity among ROIs includes three parameters, which specify the strength of connection in the different frequency bands. Subsequent studies demonstrated that a single population can exhibit many different simultaneous rhythms, provided that some of these come from external sources (for instance, from remote regions). For this reason in the second model an individual ROI is simulated only with a single population. Both models have been validated by comparing the simulated power spectral density with that computed in some cortical regions during cognitive and motor tasks. Another research study is focused on multisensory integration of tactile and visual stimuli in the representation of the near space around the body (peripersonal space). This work describes an original neural network to simulate representation of the peripersonal space around the hands, in basal conditions and after training with a tool used to reach the far space. The model is composed of three areas for each hand, two unimodal areas (visual and tactile) connected to a third bimodal area (visual-tactile), which is activated only when a stimulus falls within the peripersonal space. Results show that the peripersonal space, which includes just a small visual space around the hand in normal conditions, becomes elongated in the direction of the tool after training, thanks to a reinforcement of synapses.

Il ruolo del collicolo superiore nell'orientamento spaziale

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).

Effetti dell'integrazione visuo-acustica in pazienti con disturbo di campo visivo

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.

Mathematical models of cognitive processes

The research activity carried out during the PhD course was focused on the development of mathematical models of some cognitive processes and their validation by means of data present in literature, with a double aim: i) to achieve a better interpretation and explanation of the great amount of data obtained on these processes from different methodologies (electrophysiological recordings on animals, neuropsychological, psychophysical and neuroimaging studies in humans), ii) to exploit model predictions and results to guide future research and experiments. In particular, the research activity has been focused on two different projects: 1) the first one concerns the development of neural oscillators networks, in order to investigate the mechanisms of synchronization of the neural oscillatory activity during cognitive processes, such as object recognition, memory, language, attention; 2) the second one concerns the mathematical modelling of multisensory integration processes (e.g. visual-acoustic), which occur in several cortical and subcortical regions (in particular in a subcortical structure named Superior Colliculus (SC)), and which are fundamental for orienting motor and attentive responses to external world stimuli. This activity has been realized in collaboration with the Center for Studies and Researches in Cognitive Neuroscience of the University of Bologna (in Cesena) and the Department of Neurobiology and Anatomy of the Wake Forest University School of Medicine (NC, USA). PART 1. Objects representation in a number of cognitive functions, like perception and recognition, foresees distribute processes in different cortical areas. One of the main neurophysiological question concerns how the correlation between these disparate areas is realized, in order to succeed in grouping together the characteristics of the same object (binding problem) and in maintaining segregated the properties belonging to different objects simultaneously present (segmentation problem). Different theories have been proposed to address these questions (Barlow, 1972). One of the most influential theory is the so called “assembly coding”, postulated by Singer (2003), according to which 1) an object is well described by a few fundamental properties, processing in different and distributed cortical areas; 2) the recognition of the object would be realized by means of the simultaneously activation of the cortical areas representing its different features; 3) groups of properties belonging to different objects would be kept separated in the time domain. In Chapter 1.1 and in Chapter 1.2 we present two neural network models for object recognition, based on the “assembly coding” hypothesis. These models are networks of Wilson-Cowan oscillators which exploit: i) two high-level “Gestalt Rules” (the similarity and previous knowledge rules), to realize the functional link between elements of different cortical areas representing properties of the same object (binding problem); 2) the synchronization of the neural oscillatory activity in the γ-band (30-100Hz), to segregate in time the representations of different objects simultaneously present (segmentation problem). These models are able to recognize and reconstruct multiple simultaneous external objects, even in difficult case (some wrong or lacking features, shared features, superimposed noise). In Chapter 1.3 the previous models are extended to realize a semantic memory, in which sensory-motor representations of objects are linked with words. To this aim, the network, previously developed, devoted to the representation of objects as a collection of sensory-motor features, is reciprocally linked with a second network devoted to the representation of words (lexical network) Synapses linking the two networks are trained via a time-dependent Hebbian rule, during a training period in which individual objects are presented together with the corresponding words. Simulation results demonstrate that, during the retrieval phase, the network can deal with the simultaneous presence of objects (from sensory-motor inputs) and words (from linguistic inputs), can correctly associate objects with words and segment objects even in the presence of incomplete information. Moreover, the network can realize some semantic links among words representing objects with some shared features. These results support the idea that semantic memory can be described as an integrated process, whose content is retrieved by the co-activation of different multimodal regions. In perspective, extended versions of this model may be used to test conceptual theories, and to provide a quantitative assessment of existing data (for instance concerning patients with neural deficits). PART 2. The ability of the brain to integrate information from different sensory channels is fundamental to perception of the external world (Stein et al, 1993). It is well documented that a number of extraprimary areas have neurons capable of such a task; one of the best known of these is the superior colliculus (SC). This midbrain structure receives auditory, visual and somatosensory inputs from different subcortical and cortical areas, and is involved in the control of orientation to external events (Wallace et al, 1993). SC neurons respond to each of these sensory inputs separately, but is also capable of integrating them (Stein et al, 1993) so that the response to the combined multisensory stimuli is greater than that to the individual component stimuli (enhancement). This enhancement is proportionately greater if the modality-specific paired stimuli are weaker (the principle of inverse effectiveness). Several studies have shown that the capability of SC neurons to engage in multisensory integration requires inputs from cortex; primarily the anterior ectosylvian sulcus (AES), but also the rostral lateral suprasylvian sulcus (rLS). If these cortical inputs are deactivated the response of SC neurons to cross-modal stimulation is no different from that evoked by the most effective of its individual component stimuli (Jiang et al 2001). This phenomenon can be better understood through mathematical models. The use of mathematical models and neural networks can place the mass of data that has been accumulated about this phenomenon and its underlying circuitry into a coherent theoretical structure. In Chapter 2.1 a simple neural network model of this structure is presented; this model is able to reproduce a large number of SC behaviours like multisensory enhancement, multisensory and unisensory depression, inverse effectiveness. In Chapter 2.2 this model was improved by incorporating more neurophysiological knowledge about the neural circuitry underlying SC multisensory integration, in order to suggest possible physiological mechanisms through which it is effected. This endeavour was realized in collaboration with Professor B.E. Stein and Doctor B. Rowland during the 6 months-period spent at the Department of Neurobiology and Anatomy of the Wake Forest University School of Medicine (NC, USA), within the Marco Polo Project. The model includes four distinct unisensory areas that are devoted to a topological representation of external stimuli. Two of them represent subregions of the AES (i.e., FAES, an auditory area, and AEV, a visual area) and send descending inputs to the ipsilateral SC; the other two represent subcortical areas (one auditory and one visual) projecting ascending inputs to the same SC. Different competitive mechanisms, realized by means of population of interneurons, are used in the model to reproduce the different behaviour of SC neurons in conditions of cortical activation and deactivation. The model, with a single set of parameters, is able to mimic the behaviour of SC multisensory neurons in response to very different stimulus conditions (multisensory enhancement, inverse effectiveness, within- and cross-modal suppression of spatially disparate stimuli), with cortex functional and cortex deactivated, and with a particular type of membrane receptors (NMDA receptors) active or inhibited. All these results agree with the data reported in Jiang et al. (2001) and in Binns and Salt (1996). The model suggests that non-linearities in neural responses and synaptic (excitatory and inhibitory) connections can explain the fundamental aspects of multisensory integration, and provides a biologically plausible hypothesis about the underlying circuitry.

Residual visual processing following real or virtual lesions to primary visual pathways

Lesions to the primary geniculo-striate visual pathway cause blindness in the contralesional visual field. Nevertheless, previous studies have suggested that patients with visual field defects may still be able to implicitly process the affective valence of unseen emotional stimuli (affective blindsight) through alternative visual pathways bypassing the striate cortex. These alternative pathways may also allow exploitation of multisensory (audio-visual) integration mechanisms, such that auditory stimulation can enhance visual detection of stimuli which would otherwise be undetected when presented alone (crossmodal blindsight). The present dissertation investigated implicit emotional processing and multisensory integration when conscious visual processing is prevented by real or virtual lesions to the geniculo-striate pathway, in order to further clarify both the nature of these residual processes and the functional aspects of the underlying neural pathways. The present experimental evidence demonstrates that alternative subcortical visual pathways allow implicit processing of the emotional content of facial expressions in the absence of cortical processing. However, this residual ability is limited to fearful expressions. This finding suggests the existence of a subcortical system specialised in detecting danger signals based on coarse visual cues, therefore allowing the early recruitment of flight-or-fight behavioural responses even before conscious and detailed recognition of potential threats can take place. Moreover, the present dissertation extends the knowledge about crossmodal blindsight phenomena by showing that, unlike with visual detection, sound cannot crossmodally enhance visual orientation discrimination in the absence of functional striate cortex. This finding demonstrates, on the one hand, that the striate cortex plays a causative role in crossmodally enhancing visual orientation sensitivity and, on the other hand, that subcortical visual pathways bypassing the striate cortex, despite affording audio-visual integration processes leading to the improvement of simple visual abilities such as detection, cannot mediate multisensory enhancement of more complex visual functions, such as orientation discrimination.