Functional neuroanatomy of spatial sound processing in Alzheimer's disease.

Deficits of auditory scene analysis accompany Alzheimer's disease (AD). However, the functional neuroanatomy of spatial sound processing has not been defined in AD. We addressed this using a "sparse" fMRI virtual auditory spatial paradigm in 14 patients with typical AD in relation to 16 healthy age-matched individuals. Sound stimulus sequences discretely varied perceived spatial location and pitch of the sound source in a factorial design. AD was associated with loss of differentiated cortical profiles of auditory location and pitch processing at the prescribed threshold, and significant group differences were identified for processing auditory spatial variation in posterior cingulate cortex (controls > AD) and the interaction of pitch and spatial variation in posterior insula (AD > controls). These findings build on emerging evidence for altered brain mechanisms of auditory scene analysis and suggest complex dysfunction of network hubs governing the interface of internal milieu and external environment in AD. Auditory spatial processing may be a sensitive probe of this interface and contribute to characterization of brain network failure in AD and other neurodegenerative syndromes

Space, time and motion in a multisensory world

When interacting with environmental events, humans acquire information from different senses and combine these inputs within a coherent representation of the world. The present doctoral thesis aims at investigating how humans represent space, time, and motion through auditory and visual sensory modalities. It has been widely demonstrated a predisposition of different sensory systems towards the processing of different domains of representation, with hearing that prevails in representing the time domain and vision that is the most reliable sense for processing the space domain. Given this strong link between sensory modality and domain of representation, one objective of this thesis is to deepen the knowledge of the neural organization of multisensory spatial and temporal skills in healthy adults. In addition, by using blindness as a model to unravel the role of vision in the development of spatio-temporal abilities, this thesis explores the interaction of the spatial and temporal domains in the acoustic motion perception of early blind individuals. The interplay between space and time has also been explained as the result of humans performing actions in the surrounding environment since to carry out goal-directed motor behaviors it is useful for a person to associate the spatial and temporal information of one’s target into a shared mental map. In this regard, the present project also questions how the brain processes spatio-temporal cues of external events when it comes to manually intercepting moving objects with one hand. Finally, in light of the above results, this dissertation incorporates the development of a novel portable device, named MultiTab, for the behavioral evaluation of the processing of space, time, and motor responses, through the visual and acoustic sensory modality. For the purposes of this thesis, four methodological approaches have been employed: i) electroencephalogram (EEG) technique, to explore the cortical activation associated with multisensory spatial and temporal tasks; ii) psychophysical methods, to measure the relationship between stimuli in motion and the acoustic speed perception of blind and sighted individuals; iii) motion capture techniques, to measure indices of movements during an object’s interception task; iv) design and technical-behavioral validation of a new portable device. Studies of the present dissertation indicate the following results. First, this thesis highlights an early cortical gain modulation of sensory areas that depends on the domain of representation to process, with auditory areas mainly involved in the multisensory processing of temporal inputs, and visual areas of spatial inputs. Moreover, for the spatial domain specifically, the neural modulation of visual areas is also influenced by the kind of spatial layout representing multisensory stimuli. Second, this project shows that lack of vision influences the ability to process the speed of moving sounds by altering how blind individuals make use of the sounds’ temporal features. This result suggests that visual experience in the first years of life is a crucial factor when dealing with combined spatio-temporal information. Third, data of this thesis demonstrate that typically developing individuals manually intercepting a moving object with one hand take into consideration the item’s spatio-temporal cues, by adjusting their interceptive movements according to the object’s speed. Finally, the design and validation of MultiTab show its utility in the evaluation of multisensory processing such as the manual localization of audiovisual spatialized stimuli. Overall, findings from this thesis contribute to a more in-depth picture of how the human brain represents space, time, and motion through different senses. Moreover, they provide promising implications in exploring novel technological methods for the assessment and training of these dimensions in typical and atypical populations

Unbewusste Modulatoren der somatosensorischen Wahrnehmung

It is intriguing that perception of the same stimulus can vary profoundly from trial to trial. For example, it has been shown in many studies that weak, so-called “near-threshold stimuli” are sometimes consciously perceived and sometimes not. In my thesis, I have been investigating factors which underlie this profound perceptual variability in the somatosensory domain. Together with my colleagues, I performed three studies in which we tested three different types of presumed non-conscious modulators of somatosensory perception. In the first – behavioral - study, we investigated how the presence of subliminal noise during a peripheral somatosensory stimulation influences perception. Counter-intuitively, we found that peripheral noise can even improve perception of weak somatosensory stimuli. In our interpretation, this occurs most likely due to “stochastic resonance” effects (Study I: Iliopoulos et al. 2014). In the second – behavioral and EEG - study, we tested the effect of different forms of pulsed subliminal stimulation (single pulses versus pulse trains) on brain rhythms and somatosensory perception. Following-up on previous results of our group, we tested the hypothesis that subliminal pulsed stimulation impairs perception of subsequent stimuli via centrally enhanced Mu rhythm. Interestingly, the main result of this study was that trains of subliminal stimuli indeed inhibited subsequent somatosensory detection, however, - in contrast to our previous findings for single pulses – trains were associated with decreased Mu rhythm. We conclude that central rhythms most likely play a role in mediating the perceptual modulation of peripheral subliminal stimuli, however, the relationship is more complex than previously assumed (Study II: Iliopoulos et al. 2020). In the third study, we examined the influence of interoceptive signaling, especially from the heart, on somatosensory perception. The hypothesis was that the cardiac phase (systole versus diastole) and the so-called heart-evoked potential (HEP) would modulate somatosensory perception. Indeed, our study showed that somatosensory perception was better during diastole than during systole and detection performance declined as the amplitude of the HEP increased. Our interpretation of the former effect assumes that all events which occur simultaneously with the “pulse” are assumed by the brain to be pulse-synchronous peripheral noise and therefore suppressed. Our interpretation of the latter effect (HEP) assumes that HEP is a marker of the relative balance between interoception and exteroception (Study III: Al et al. 2020). In conclusion, in the studies which form the basis for my thesis, we have shown that somatosensory perception is modulated by peripheral effects (modes of peripheral stimulation, peripheral noise), central effects (Mu rhythm) and interoceptive signals from the heart. The precise interplay between these modulators is an exciting research topic for future studies.Interessanterweise kann die Wahrnehmung desselben Reizes von Augenblick zu Augenblick so stark variieren, dass dieser manchmal bewusst wahrgenommen wird und manchmal nicht. In meiner Dissertation habe ich Faktoren untersucht, die dieser Wahrnehmungsvariabilität im somatosensorischen (SS) System zugrunde liegen. Mit meinen Kollegen habe ich drei Studien durchgeführt, in denen wir verschiedene mutmaßlich unbewusste Modulatoren der SS-Wahrnehmung untersuchten. In der ersten Studie untersuchten wir, wie die Wahrnehmung peripherer SS-Reize durch unterschwelliges Rauschen beeinflusst wird. Wir konnten zeigen, dass peripheres Rauschen die Wahrnehmung schwacher Reize verbessert. Dies ist ein Hinweis auf das Vorliegen von "stochastischen Resonanzeffekten" (Studie I: Iliopoulos et al. 2014). In der zweiten Studie, die neben behavioralen Messungen auch elektroencephalographische (EEG) Messungen umfasste, testeten wir die Auswirkung verschiedener Formen gepulster unterschwelliger elektrischer Fingerstimulationen (Einzelpulse gegen Pulsserien) auf die Wahrnehmung und auf Hirn-rhythmen. Ausgehend von früheren Ergebnissen unserer Arbeitsgruppe überprüften wir, ob repetitive subliminale Stimulationen die Wahrnehmung nachfolgender Reize über einen zentral verstärkten Mu-Rhythmus beeinträchtigen. Das Ergebnis dieser Studie war, dass Serien unterschwelliger Reize tatsächlich die nachfolgende SS-Wahrnehmung hemmten, jedoch - im Gegensatz zu früheren Ergebnissen für Einzelimpulse – die Reizserien mit einem verringerten Mu-Rhythmus verbunden waren. Daraus schließen wir, dass zentrale Rhythmen höchstwahrscheinlich eine Rolle bei der Wahrnehmungsmodulation durch periphere unterschwellige Reize spielen, dass aber der Zusammenhang zwischen beiden komplexer ist als bisher vermutet (Studie II: Iliopoulos et al. 2020). In der dritten Studie untersuchten wir den Einfluss interozeptiver Signale aus dem Herzen auf die SS-Wahrnehmung. Die Hypothese war, dass die Herzphase und das so genannte Herz-evozierte Potenzial (HEP) die SS-Wahrnehmung modulieren. Wir zeigten, dass die SS-Wahrnehmung während der Diastole besser war als während der Systole und dass die Wahrnehmung in umgekehrtem Verhältnis zur Amplitude des vorausgehenden HEP stand. Für den ersten Effekt legen unsere Daten nahe, dass alle Ereignisse, die zusammen mit der Pulswelle auftreten, vom Gehirn als puls-synchrones peripheres Rauschen angenommen und daher unterdrückt werden. Der zweite Befund wird in Übereinstimmung mit der Literatur am besten dadurch erklärt, dass das HEP ein Marker für das relative Gleichgewicht zwischen Interozeption und Exterozeption darstellt (Studie III: Al et al. 2020). Zusammenfassend zeigen die Ergebnisse dieser Arbeit, wie die SS-Wahrnehmung durch periphere Effekte (Art der Stimulation, Rauschen), zentrale Effekte (Mu-Rhythmus) und interozeptive Signale des Herzens moduliert wird. Das genaue Zusammenspiel zwischen diesen Modulatoren ist ein spannendes Forschungsthema für zukünftige Studien

Electrostimulation Contingencies and Attention, Electrocortical Activity and Neurofeedback

There is a growing body of evidence for diverse ways of modulating neuronal processing to improve cognitive performance. These include brain-based feedback, self-regulation techniques such as EEG-neurofeedback, and stimulation strategies, alone or in combination. The thesis goal was to determine whether a combined strategy would have advantages for normal cognitive function; specifically operant control of EEG activity in combination with transcutaneous electro-acustimulation. In experiment one the association between transcutaneous electroacustimulation (EA) and improved perceptual sensitivity was demonstrated with a visual GO/NOGO attention task (Chen et al, 2011). Furthermore reduced commission errors were related to an electrocortical motor inhibition component during and after alternating high and low frequency EA, whereas habituation in the control group with sham stimulation was related to different independent components. Experiment two applied frequency-domain ICA to detect changes in EEG power spectra from the eyes-closed to the eyes-open state (Chen et al, 2012). A multiple step approach was provided for analysing the spatiotemporal dynamics of default mode and resting state networks of cerebral EEG sources, preferable to conventional scalp EEG data analysis. Five regions were defined, compatible with fMRI studies. In experiment three the EA approach of Exp I was combined with sensorimotor rhythm (SMR) neurofeedback. SMR training improved perceptual sensitivity, an effect not found in a noncontingent feedback group. However, non-significant benefits resulted from EA. With ICA spectral power analysis changes in frontal beta power were associated with contingent SMR training. Possible long-term effects on an attention network in the resting EEG were also found after SMR training, compared with mock SMR training. In conclusion, this thesis has supplied novel evidence for significant cognitive and electrocortical effects of neurofeedback training and transcutaneous electro-acustimulation in healthy humans. Possible implications of these findings and suggestions for future research are considered

Editorial: Executive function(s): Conductor, Orchestra or Symphony? Towards a Trans-Disciplinary Unification of Theory and Practice Across Development, in Normal and Atypical Groups

There are several theories of executive function(s) that tend to share some theoretical overlap yet are also conceptually distinct, each bolstered by empirical data (Norman and Shallice, 1986; Shallice & Burgess, 1991; Stuss and Alexander, 2007; Burgess, Gilbert, & Dumentheil, 2007; Burgess & Shallice, 1996; Miyake et al., 2000). The notion that executive processes are supervisory, and most in demand in novel situations was an early conceptualization of executive function that has been adapted and refined over time (Norman & Shallice, 1986; Shallice, 2001; Burgess, Gilbert & Dumentheil, 2007). Presently there is general consensus that executive functions are multi-componential (Shallice, 2001), and are supervisory only in the sense that attention in one form or another is key to the co-ordination of other hierarchically organized ‘lower’ cognitive processes. Attention in this sense is defined as (i) independent but interrelated attentional control processes (Stuss & Alexander, 2007); (ii) automatic orientation towards stimuli in the environment or internally–driven thought (Burgess, Gilbert & Dumontheil, 2007); (iii) the automatically generated interface between tacit processes and strategic conscious thought (Barker, Andrade, Romanowski, Morton and Wasti, 2006; Morton and Barker, 2010); and (iv) distinct but interrelated executive processes that maintain, update and switch across different sources of information (Miyake et al., 2000). One problem is that executive dysfunction or dysexecutive syndrome (Baddeley & Wilson, 1988) after brain injury typically produces a constellation of deficits across social, cognate, emotional and motivational domains that rarely map neatly onto theoretical frameworks (Barker, Andrade & Romanowski, 2004). As a consequence there is debate that conceptual theories of executive function do not always correspond well to the clinical picture (Manchester, Priestley & Jackson, 2004). Several studies have reported cases of individuals with frontal lobe pathology and impaired daily functioning despite having little detectable impairment on traditional tests of executive function (Shallice & Burgess, 1991; Eslinger & Damasio, 1985; Barker, Andrade & Romanowski, 2004; Andrés & Van der Linden, 2002; Chevignard et al., 2000; Cripe, 1998; Fortin, Godbout & Braun, 2003). There is also some suggestion that weak ecological validity limits predictive and clinical utility of many traditional measures of executive function (Burgess et al, 2006; Lamberts, Evans & Spikman, 2010; Barker, Morton, Morrison, McGuire, 2011). Complete elimination of environmental confounds runs the risk of generating results that cannot be generalized beyond constrained circumstances of the test environment (Barker, Andrade & Romanowski, 2004). Several researchers have concluded that a new approach is needed that is mindful of the needs of the clinician yet also informed by the academic debate and progress within the discipline (McFarquhar & Barker, 2012; Burgess et al., 2006). Finally, translational issues also confound executive function research across different disciplines (psychiatry, cognitive science, and developmental psychology) and across typically developing and clinical populations (including Autism Spectrum Disorders, Head Injury and Schizophrenia – Blakemore & Choudhury, 2006; Taylor, Barker, Heavey & McHale, 2013). Consequently, there is a need for unification of executive function approaches across disciplines and populations and narrowing of the conceptual gap between theoretical positions, clinical symptoms and measurement

Ain't no rest for the brain: Neuroimaging and neuroethics in dialogue for patients with disorders of consciousness

The sheer amount of different opinions about what consciousness is highlights its multifaceted character. The clinical study of consciousness in coma survivors provides unique opportunities, not only to better comprehend normal conscious functions, but also to confront clinical and medico-ethical challenges. For example, pain in vegetative state/unresponsive wakefulness syndrome patients (VS/UWS; i.e. awaken, but unconscious) and patients in minimally conscious states (MCS; awaken, with fluctuating signs of awareness) cannot be communicated and needs to be inferred. Behaviorally, we developed the Nociception Coma Scale, a clinical tool which measures patients’ motor, verbal, visual, and facial responsiveness to noxious stimulation. Importantly, the absence of proof of a behavioral response cannot be taken as proof of absence of pain. Functional neuroimaging studies show that patients in VS/UWS exhibit no evidence of control-like brain activity, when painfully stimulated, in contrast to patients in MCS. Similarly, the majority of clinicians ascribe pain perception in MCS patients. Interestingly, their opinions appear less congruent with regards to pain perception in VS/UWS patients, due to personal and cultural differences. The imminent bias in clinical practice due to personal beliefs becomes more ethically salient in complex clinical scenarios, such as end-of-life decisions. Surveys among clinicians show that the majority agrees with treatment withdrawal for VS/UWS, but fewer respondents would do so for MCS patients. For the issue of pain in patients with disorders of consciousness, the more the respondents ascribed pain perception in these states the less they supported treatment withdraw from these patients. Such medico-ethical controversies require an objective and valid assessment of pain (and eventually of consciousness) in noncommunicating patients. Functional neuroimaging during “resting state” (eyes closed, no task performance) is an ideal paradigm to investigate residual cognition in noncommunicating patients, because it does not require sophisticated technical support or subjective input on patients’ behalf. With the ultimate intention to use this paradigm in patients, we first aimed to validate it in controls. We initially found that, in controls, fMRI “resting state” activity correlated with subjective reports of “external” (perception of the environment through the senses) or “internal” awareness (self-related mental processes). Then, using hypnosis, we showed that there was reduced fMRI connectivity in the “external network”, reflecting decreased sensory awareness. When more cerebral networks were tested, increased functional connectivity was observed for most of the studied networks (except the visual). These results indicate that resign state fMRI activity reflects, at least partially, ongoing conscious cognition, which changes under different conditions. Using the resting state paradigm in patients with disorders of consciousness, we vi showed intra- and inter-network connectivity breakdown in sensorysensorimotor and “higher-order” networks, possibly accounting for patients’ limited capacities for conscious cognition. We have further observed positive correlation between the Nociception Coma Scale scores and the pain-related (salience) network connectivity, potentially reflecting nociception-related processes in these patients, measured in the absence of an external stimulus. These results highlight the utility of resting state analyses in clinical settings, where short and simple setups are preferable to activation protocols with somatosensory, visual, and auditory stimulation devices. Especially for neuroimaging studies, it should be stressed that such experimental investigations tackle the necessary conditions supporting conscious processing. The sufficiency of the identified neural correlates accounting for conscious awareness remains to be identified via dynamic and causal information flow investigations. Importantly, the quest of subjectivity in non-communicating patients can be better understood by adopting an interdisciplinary biopsychosocial approach, combining basic neuroscience (bio), psychological-cognitive-emotional processing (psycho), and the influence of different socioeconomic, cultural, and technological factors (social)