Funzioni di alto livello nella corteccia somatosensoriale secondaria (SII)

Le proprietà della corteccia somato-sensoriale secondaria (SII) sono state largamente discusse in molteplici studi sia nella scimmia, sia nell’uomo, suggerendo che quest’area assolva funzioni di alto livello nel processamento dello stimolo tattile, quali, ad esempio, l’apprendimento o la memoria. Recentemente, alcuni studi su scimmia hanno evidenziato che, oltre agli stimoli somato-sensoriali, SII risponde anche alla stimolazione dello spazio peri-personale, all’esecuzione di azioni, alla vista di oggetti in movimento ed all’osservazione di azioni, candidando SII ad essere un’area complessa, non limitata a sole funzioni somato-sensoriali. Partendo dallo studio delle risposte di SII agli stimoli tattili, lo scopo di questa tesi è di investigare la risposta di quest’area a stimoli complessi, con particolare attenzione a task di integrazione visuo-tattile e all’osservazione di azioni nell’uomo. Con queste finalità, gli esperimenti presentati sono stati condotti mediante elettroencefalografia stereotassica (stereo-EEG) su pazienti epilettici farmaco-resistenti, impiantati come parte della loro valutazione pre-chirurgica. In una prima fase, sono stati studiati la distribuzione spaziale ed il profilo temporale delle risposte intra-corticali alla stimolazione del nervo mediano controlaterale ed ipsilaterale. I risultati ottenuti indicano che mentre la corteccia somato-sensoriale primaria (SI), il giro precentrale ed il solco intra-parietale rispondono solo alla stimolazione controlaterale, la corteccia somato-sensoriale secondaria e l’insula posteriore sono attivate bilateralmente. Inoltre, queste ultime sono caratterizzate da una risposta tonica e duratura nel tempo. Questa potrebbe rappresentare un meccanismo di ritenzione temporale dell’informazione tattile ed essere l’espressione di funzioni di alto livello quali appunto la memoria e l’apprendimento degli stimoli. Nella seconda sezione della tesi, per testare il possibile coinvolgimento dell’opercolo parietale nell’integrazione visuo-tattile, la stimolazione del nervo mediano controlaterale è stata somministrata congiuntamente ad una stimolazione visiva (i.e. flash). I risultati ottenuti evidenziano un aumento in ampiezza della componente tonica, se comparato alla sola stimolazione tattile, localizzato nell’insula posteriore e nelle porzioni più rostrali dell’opercolo parietale mentre SII mostra un comportamento del tutto inalterato. Tuttavia, tenendo in considerazione che studi su primati non umani riportano risposte visiva in SII a stimoli biologici, sono necessarie ulteriori indagini per comprendere quale tipologia di stimolazione determina l’attivazione di quest’area. Infine, la terza parte della tesi mostra le risposte intra-corticali di SI e SII ad un task motorio che include compiti di afferramento e manipolazione di oggetti, e all’osservazione delle stesse azioni eseguite da un altro individuo. I risultati evidenziano un’attivazione bilaterale di SII, sia durante l’esecuzione sia durante l’osservazione di azioni, con un profilo temporale sincrono. Al contrario SI è attiva solo durante l’esecuzione: l’input a SI durante l’osservazione non ha dunque una natura somato-sensoriale ma piuttosto deve essere sostenuto da un circuito visuo-motorio capace di operare in maniera simultanea. In conclusione, questa tesi dimostra il ruolo cruciale di SII non solo nel processamento degli stimoli tattili ma anche nell’integrazione di stimoli visuo-motori.The somatosensory properties of the second somatosensory cortex (SII) have been largely described by many studies in both monkeys and humans, suggesting for this area a high-order role in tactile stimulation processing with functions including tactile learning and memory. More interestingly, recent studies on monkeys showed that beyond somatosensory stimuli, SII responds to a wider number of stimuli including peripersonal space stimulation, active movements, observation of objects displacement and action observation. Taking into account these results, SII is a candidate to be more than just a somatosensory area. Starting from its somatosensory properties, this thesis aims to disentangle the role of SII in more complex tasks with particular attention to visuo-tactile integration and action observation in humans. To this purpose, the experiments presented in this thesis are carried with stereotactic electroencephalography (stereo-EEG) on drug-resistant epileptic patients to take advantage of its high temporal and spatial resolution. Firstly, I investigated the spatial distribution and the temporal profile of the intracortical responses to both contralateral and ipsilateral median nerve stimulation. Results indicated that while the primary somatosensory area, precentral gyrus and intra-parietal sulcus respond only to the contralateral stimulation, the secondary somatosensory cortex and posterior insula are activated bilaterally. Furthermore, these regions exhibit a tonic long-lasting temporal profile, which might represent a mechanism of temporal retention of the tactile information, and thus be the signature of high-level somatosensory functions such as tactile memory and awareness. In a second stage of the thesis, to test the possible involvement of parietal operculum in visuo-tactile integration, we administered to patients contralateral median nerve stimulation jointly with visual stimulation (i.e. flash) to about 100 drug-resistant epileptic patients. Results underline an enhancement of the tonic components relative to tactile stimulation only, limited to posterior insula and to the rostral areas of parietal operculum, with SII maintaining an unaltered behavior. Considering previous findings in non-human primates, which reported visual responses in SII in response to biological stimuli, further researches are needed to understand which threshold in the stimulus might determine the eventual activation of this area. With this aim, the third part of this thesis presents the intracortical responses of both SI and SII to a motor task requiring reaching, grasping and manipulation, as well as to the observation of the same actions performed by another individual. The results obtained highlighted that SII activates bilaterally, both during the execution and the observation of actions, with a synchronous temporal profile. Conversely, SI activates only during the execution, leading to the conclusion that the input to SII during the observation condition has not a somatosensory nature, but rather that it is sustained by visuo-motor circuits operating simultaneously. Taking together all the evidence, this thesis demonstrates the pivotal role of SII not only in somatosensory functions, as largely reported in literature, but also in the integration of visuo-motor stimuli

C-tactile fibers mediate Affective Touch: from childhood to individual differences to neural correlates

The emotional aspect of touch has been called ‘Affective Touch’ (AT), a term capturing tactile processing with a hedonic, motivational and social significance (e.g. affiliative behaviors or mother-infant bonding). AT is driven by C-Tactile (CT) fibers that are mainly present in hairy skin and respond specifically to slow, gentle touch. CT fibers project to a neural network including the insular cortex and other areas involved in the social domain. In this thesis, the reader will find three distinct studies that, however, follow a temporal progression that reflects both the way they have been carried out and the logical sequence of the rationale underpinning my doctoral project. In the first study, we studied the development of somatosensation and Affective Touch as central role throughout childhood. In adults, these functions are driven by different, neuroanatomically and functionally segregated fibers. To date, very little is known about the basic features of these fibers in childhood and this lack of knowledge is mirrored in the Affective Touch domain, where there are no studies on the main physiological features of the tactile processes linked to the stimulation of the hairy skin, namely the only body part that modulates Affective Touch. Thus, our study aims to analyse: tactile sensitivity and tactile acuity of children’s hairy forearms; a possible separation between somatosensation and the Affective Touch; and the presence/absence of a mature Affective Touch system already in childhood. To these aims, participants (160 children, aged 6 to 14 years), were administered with the Von Frey (tactile sensitivity) and the 2 Point Discrimination (tactile acuity) tests. Affective Touch was measured following the classic protocol and pleasantness ratings were recorded. Our findings showed a correlation between age and somatosensation, suggesting a progressive reduction of sensitivity and acuity as age grows. Further, there was no overlap between Affective Touch and somatosensation, suggesting a behavioral separation. Lastly, we found higher pleasantness ratings for Affective vs. Neutral stimulations at all ages and an enhanced preference for Affective as age grows. We concluded that both somatosensation and Affective Touch are already present as two separate components of touch in childhood and change as a function of age. In the second and third studies, I investigated the perception of AT on the basis of individual differences. The perception and the neural processing of AT appear to be modulated by psychological and psychopathological factors such as autistic traits, anorexia disorder and attachment patterns. Despite this, nothing is known about the Disorganized attachment pattern which is the one with the highest difficulty in regulating emotions and social skills that are central aspects of the AT network. Our studies aim to compare the perception and brain responses to AT in a sample of adults classified as having a Organized (OA) or a Disorganized attachment (DA). 46 OA and 17 DA individuals (as coded via Adult Attachment Interview) underwent a behavioral tactile procedure for basic somatosensation (comprising Von Frey Monofilaments, 2PD, and thermal sensitivity) and a psychological assessment (including SCL-90-R and PID-5). AT perception was measured applying Affective (AS) and Neutral Stimulations (NS) with a watercolor brush on the forearm, respectively at 3 or 30 cm/s; pleasantness ratings for AS and NS and a index of preference (AT index) were collected. A randomly selected subset of 12 OA and 8 DA underwent also a fMRI block design, during affective and neutral tactile stimulations (four run of 5 repetitions of AS and 5 repetitions of NS each), in addition of two resting-state sessions for a functional connectivity analysis (fc-fMRI). No differences emerged for somatosensation and psychological scales. A MANOVA on AS and NS ratings showed that DA vs OA reported lower ratings for AS and no difference for NS. A t-test on AT index showed that DA vs OA preferred NS. A fMRI F omnibus contrast revealed the involvement of posterior insula (PI), somatosensory primary cortex (S1), supramarginal gyrus (SMG) and amygdala during AS and NS. A 2 (OA vs DA) x 2 (AS vs NS) mixed factorial ANOVA on hemodynamic responses showed an effect of stimulation, with higher activation for NS in PI, S1 and amygdala, and an effect of group, with DA showing higher activation in amygdala. An interaction in amygdala showed higher activation for NS vs AS in DA, but not in OA. fc-fMRI showed connectivity between PI and SMG and PI and S1. Results showed that DA perceived AT as less pleasant and preferred NS compared to OA, suggesting that adults who experience difficulties in the ways to relate to others in the affectivity domain, and, in particular, referring to attachment history, are specifically impaired in AT perception, but not in other basic functions of somatosensation. Altered AT perception appeared to be also mirrored by differences in brain mechanism for processing AT. In fact, we found a higher activation in amygdala for AS and NS in DA compared to OA, suggesting different mechanisms for coding motivational and hedonic aspect of AT. Further studies are needed to understand whether this atypical response to AT refers to attribution of a negative or positive value to these stimuli. The results from my three experiments have shown that it is worth investigating this construct in the future. From a personal point of view, it seems to me that this set of three experiments is a trait d'union between neurosciences, which we all know and fascinate us because of their ability to measure very complex phenomena, and other constructs associated with a more clinical perspective such as attachment. I therefore hope that my doctoral thesis will be a humble contribution to a wider view of clinical and neuroscientific phenomena

Caloric vestibular stimulation reduces pain and somatoparaphrenia in a severe chronic central post-stroke pain patient: a case study

Central post-stroke pain is a neuropathic syndrome characterized by intolerable contralesional pain and, in rare cases, somatic delusions. To date, there is limited evidence for the effective treatments of this disease. Here we used caloric vestibular stimulation to reduce pain and somatoparaphrenia in a 57-year-old woman suffering from central post-stroke pain. Resting-state functional magnetic resonance imaging was used to assess the neurological effects of this treatment. Following vestibular stimulation we observed impressive improvements in motor skills, pain, and somatic delusions. In the functional connectivity study before the vestibular stimulation, we observed differences in the patient's left thalamus functional connectivity, with respect to the thalamus connectivity of a control group (N = 20), in the bilateral cingulate cortex and left insula. After the caloric stimulation, the left thalamus functional connectivity with these regions, which are known to be involved in the cortical response to pain, disappeared as in the control group. The beneficial use of vestibular stimulation in the reduction of pain and somatic delusion in a CPSP patient is now documented by behavioral and imaging data. This evidence can be applied to theoretical models of pain and body delusions

Telemetry Controlled Brain Machine Interface To Train Cortical Circuits

The goal of this dissertation is to document functional reorganization in rat primary somatosensory (SI) cortex. This work proposes to strengthen the interhemispheric connection between homotopic sites in forelimb barrel cortex (FBC) through intracortical microstimulation (ICMS) and induce functional reorganization whereby neurons in the FBC respond to new input from the ipsilateral forelimb. Furthermore, a wireless microstimulation and recording device was developed for producing enhancement and functional reorganization of cortical circuits in FBC. The goal of Experiment One was to test the hypothesis that layer V neurons projected to homotopic sites in contralateral layer V FBC. Retrograde or anterograde neuronal tracer injections were made to characterize the distribution of callosal projecting neurons in contralateral SI that terminate in layer VFBC and where layer V callosal projecting neurons terminate in contralateral SI. The results showed a differential pattern of interhemispheric connectivity between homotopic forelimb representations in layer V FBC. The goal of Experiment Two was to test the hypothesis that ICMS enhances the interhemispheric pathway and leads to functional reorganization. ICMS was delivered in vivo to the interhemispheric pathway between homotopic layer V barrel cortices and multiunit recordings were made to assess changes in firing rate. The results showed ICMS strengthens interhemispheric connectivity and leads to functional reorganization in rat FBC. The goal of Experiment Three was to develop an interactive telemetry-based neural interface device for the controlled delivery of ICMS and recording response activity in rodent. The device successfully delivered microstimulation to a single electrode in SIand recorded evoked responses from a separate electrode in contralateral SI. Its performance was shown to be comparable to commercial stimulating and recording systems. This system serves as a prototype of a wearable compact device. The data suggest that neurons in rat FBC can be induced to respond to new input from the ipsilateral forelimb by enhancing the interhemispheric pathway with ICMS. An interactive system for the controlled delivery of telemetry-based microstimulation and real-time recordings has been demonstrated in vivo. These studies provide the framework for subsequent studies of interhemispheric pathway enhancement and functional reorganization in freely moving rats

Assessment and detection of pain in noncommunicative severely brain-injured patients.

peer reviewedDetecting pain in severely brain-injured patients recovering from coma represents a real challenge. Patients with disorders of consciousness are unable to consistently or reliably communicate their feelings and potential perception of pain. However, recent studies suggest that patients in a minimally conscious state can experience pain to some extent. Pain monitoring in these patients is hence of medical and ethical importance. In this article, we will focus on the possible use of behavioral scales for the assessment and detection of pain in noncommunicative patients

Acquisition of ownership illusion with self-disownership in neurological patients

The multisensory regions in frontoparietal cortices play a crucial role in the sense of body and self. Disrupting this sense may lead to a feeling of disembodiment, or more generally, a sense of disownership. Experimentally, this altered consciousness disappears during illusory own-body perceptions, increasing the intensity of perceived ownership for an external virtual limb. In many clinical conditions, particularly in individuals with a discontinuous or absent sense of bodily awareness, the brain may effortlessly create a convincing feeling of body ownership over a surrogate body or body part. The immediate visual input dominates the current bodily state and induces rapid plastic adaptation that reconfigures the dynamics of bodily representation, allowing the brain to acquire an alternative sense of body and self. Investigating strategies to deconstruct the lack of a normal sense of bodily ownership, especially after a neurological injury, may aid the selection of appropriate clinical treatment

Brain connectivity and sensory stimulation in patients with disorders of consciousness

This thesis explores brain connectivity and sensory stimulation in patients with disorders of consciousness (DOC). These are serious conditions where massive brain damage can lead to a dissociation between arousal and awareness (e.g., UWS and MCS). Part I explores brain connectivity. We highlight that brain function and structure are intimately related to each other, and to consciousness. The decrease in brain function can be used to distinguish between the clinically indicated states of consciousness. Part II evaluates passive sensory stimulations. Preferred stimuli may have the power to momentarily enhance brain function, and behavioral responses