NON INVASIVE INVESTIGATION OF SENSORIMOTOR CONTROL FOR FUTURE DEVELOPMENT OF BRAIN-MACHINE-INTERFACE (BMI)

My thesis focuses on describing novel functional connectivity properties of the sensorimotor system that are of potential interest in the field of brain-machine interface. In particular, I have investigated how the connectivity changes as a consequence of either pathologic conditions or spontaneous fluctuations of the brain's internal state. An ad-hoc electronic device has been developed to implement the appropriate experimental settings. First, the functional communication among sensorimotor primary nodes was investigated in multiple sclerosis patients afflicted by persistent fatigue. I selected this condition, for which there is no effective pharmacological treatment, since existing literature links this type of fatigue to the motor control system. In this study, electroencephalographic (EEG) and electromyographic (EMG) traces were acquired together with the pressure exerted on a bulb during an isometric hand grip. The results showed a higher frequency connection between central and peripheral nervous systems (CMC) and an overcorrection of the exerted movement in fatigued multiple sclerosis patients. In fact, even though any fatigue-dependent brain and muscular oscillatory activity alterations were absent, their connectivity worked at higher frequencies as fatigue increased, explaining 67% of the fatigue scale (MFIS) variance (p=.002). In other terms, the functional communication within the central-peripheral nervous systems, namely involving primary sensorimotor areas, was sensitive to tiny alterations in neural connectivity leading to fatigue, well before the appearance of impairments in single nodes of the network. The second study was about connectivity intended as propagation of information and studied in dependence on spontaneous fluctuations of the sensorimotor system triggered by an external stimulus. Knowledge of the propagation mechanisms and of their changes is essential to extract significant information from single trials. The EEG traces were acquired during transcranial magnetic stimulation (TMS) to yield to a deeper knowledge about the response to an external stimulation while the cortico-spinal system passes through different states. The results showed that spontaneous increases of the excitation of the node originating the transmission within the hand control network gave rise to dynamic recruitment patterns with opposite behaviors, weaker in homotopic and parietal circuits, stronger in frontal ones. As probed by TMS, this behavior indicates that the effective connectivity within bilateral circuits orchestrating hand control are dynamically modulated in time even in resting state. The third investigation assessed the plastic changes in the sensorimotor system after stroke induced by 3 months of robotic rehabilitation in chronic phase. A functional source extraction procedure was applied on the acquired EEG data, enabling the investigation of the functional connectivity between homologous areas in the resting state. The most significant result was that the clinical ameliorations were associated to a ‘normalization’ of the functional connectivity between homologous areas. In fact, the brain connectivity did not necessarily increase or decrease, but it settled within a ‘physiological’ range of connectivity. These studies strengthen our knowledge about the behavioral role of the functional connectivity among neuronal networks’ nodes, which will be essential in future developments of enhanced rehabilitative interventions, including brain-machine interfaces. The presented research also moves the definition of new indices of clinical state evaluation relevant for compensating interventions, a step forward

Influence of Focal Activity on Macroscale Brain Dynamics in Health and Disease

Macroscopic recordings of brain activity (e.g. fMRI, EEG) are a sensitive biomarker of the neural networks supporting neurocognitive function. However, it remains largely unclear what mechanisms mediate changes in macroscale networks after focal brain injuries like stroke, seizure, and TBI. Recently, optical neuroimaging in animal models has emerged as a powerful tool to begin addressing these questions. Using widefield imaging of cortical calcium dynamics in mice, this dissertation investigates the mechanisms by which focal disruptions in activity alter brain-wide functional dynamics. In two chapters, I demonstrate 1) that focal sensory stimulation elicits state-dependent, global slow waves propagating from primary somatosensory cortex (S1). Using a focal ischemic stroke model, I show that bilateral activation of somatosensory cortices is required for initiating global SWs, while spontaneous SWs are generated independent of S1. 2) That regional disruption of cortical excitability induces widespread changes across cortical networks, using chemogenetic manipulation of parvalbumin interneurons to model focal epileptiform activity in S1. We further show that local imbalances in excitability propagate differentially through intra- and interhemispheric connections, and can induce plasticity in large-scale networks. These studies begin to define the mechanisms of macro-scale network disruption after focal injuries, adding to our understanding of how local cortical circuits modulate global brain networks

Neural mechanisms of treatment for mental disorders

“Cognitive control” refers to the ability to regulate thoughts and actions in the service of goals or plans (Braver, 2012). Coordination between the central and peripheral autonomic nervous systems (ANS) maintains arousal and attention levels, which are essential for effective cognitive control. Diamond (2013) proposed a cognitive control model that builds on three core cognitive functions: cognitive flexibility, inhibitory control, and working memory. Abnormality in active inhibitory cognitive control is implicated in a broad range of psychiatric and personality disorders, including schizophrenia, attention deficit hyperactivity disorder (ADHD), impulsivity, and substance abuse, among many others. Transcranial direct current stimulation (tDCS) and cognitive training are two neuromodulation techniques which have the potential to modulate cortical functions to introduce long-lasting neuronal plasticity. The antisaccade task is a visual inhibitory control task frequently used to assess cognitive control. It requires the participant to suppress an automatic stimulus-driven saccadic eye movement and instead make a goal-driven saccade in the opposite direction. In this thesis, by conducting two separate studies, we used the antisaccade task to examine the effect of tDCS and computerised cognitive training on inducing neuroplastic changes for the oculomotor control network (OCN). ‎Chapter 1¢introduces relevant concepts to the subject of this thesis with a technical account of the methods used. The details of the first study are discussed in ‎Chapter 2 - ‎Chapter 4, where we used eye-tracking during antisaccade performance with the continuous assessment of cortical activity using Magnetoencephalography (MEG). Chapter 2 will discuss the short-term neuroplastic changes introduced by the tDCS on the functional connectivity within the resting state networks assessed using MEG. We found evidence of increased connectivity following the engagement in the antisaccade task for both active tDCS and sham conditions, but with different spatial patterns. Following tDCS delivered over the frontal cortex, there was increased connectivity with the frontal cortex. In contrast, in the sham condition there was increased connectivity with the posterior cortex. The effects of tDCS stimulation on the ANS activity during the task performance were further assessed via pupillometry as a measure of Locus Coeruleus (LC) activity in ‎Chapter 3. Our results showed that faster pupil dilation, reflecting increased arousal and sympathetic activity, was associated with faster saccade reaction times. In ‎Chapter 4, we investigated the immediate effects of tDCS stimulation on the cerebral cortex during active cognitive inhibition followed by a correct saccadic response. The tDCS introduced neuromodulatory changes in the putative Alpha and low-Beta band during the anticipatory and post-stimulus periods, reflecting enhanced cortical engagement in a task-beneficial pattern. ‎Chapter 5 reports on the second study in which we used functional magnetic resonance imaging (fMRI) to evaluate the neuromodulatory effects of prolonged computerised cognitive training games (RECOGNeyes) on the resting state functional connectivity of the OCN and pupil dilation. Following gaze-control training, the connectivity within the left hemisphere was strengthened, while the intra-right hemisphere and the interhemispheric connectivity were diminished. ‎Chapter 6 provides a summary of the findings and concluding remarks. Our result furthers our knowledge of the processes involved in the performance of the antisaccade task, the mechanisms of action and the neuroplastic effects of two neuromodulation techniques. However, the exact mechanisms underlying these methods' beneficial effects demand further exploration

Neural mechanisms of treatment for mental disorders

“Cognitive control” refers to the ability to regulate thoughts and actions in the service of goals or plans (Braver, 2012). Coordination between the central and peripheral autonomic nervous systems (ANS) maintains arousal and attention levels, which are essential for effective cognitive control. Diamond (2013) proposed a cognitive control model that builds on three core cognitive functions: cognitive flexibility, inhibitory control, and working memory. Abnormality in active inhibitory cognitive control is implicated in a broad range of psychiatric and personality disorders, including schizophrenia, attention deficit hyperactivity disorder (ADHD), impulsivity, and substance abuse, among many others. Transcranial direct current stimulation (tDCS) and cognitive training are two neuromodulation techniques which have the potential to modulate cortical functions to introduce long-lasting neuronal plasticity. The antisaccade task is a visual inhibitory control task frequently used to assess cognitive control. It requires the participant to suppress an automatic stimulus-driven saccadic eye movement and instead make a goal-driven saccade in the opposite direction. In this thesis, by conducting two separate studies, we used the antisaccade task to examine the effect of tDCS and computerised cognitive training on inducing neuroplastic changes for the oculomotor control network (OCN). ‎Chapter 1¢introduces relevant concepts to the subject of this thesis with a technical account of the methods used. The details of the first study are discussed in ‎Chapter 2 - ‎Chapter 4, where we used eye-tracking during antisaccade performance with the continuous assessment of cortical activity using Magnetoencephalography (MEG). Chapter 2 will discuss the short-term neuroplastic changes introduced by the tDCS on the functional connectivity within the resting state networks assessed using MEG. We found evidence of increased connectivity following the engagement in the antisaccade task for both active tDCS and sham conditions, but with different spatial patterns. Following tDCS delivered over the frontal cortex, there was increased connectivity with the frontal cortex. In contrast, in the sham condition there was increased connectivity with the posterior cortex. The effects of tDCS stimulation on the ANS activity during the task performance were further assessed via pupillometry as a measure of Locus Coeruleus (LC) activity in ‎Chapter 3. Our results showed that faster pupil dilation, reflecting increased arousal and sympathetic activity, was associated with faster saccade reaction times. In ‎Chapter 4, we investigated the immediate effects of tDCS stimulation on the cerebral cortex during active cognitive inhibition followed by a correct saccadic response. The tDCS introduced neuromodulatory changes in the putative Alpha and low-Beta band during the anticipatory and post-stimulus periods, reflecting enhanced cortical engagement in a task-beneficial pattern. ‎Chapter 5 reports on the second study in which we used functional magnetic resonance imaging (fMRI) to evaluate the neuromodulatory effects of prolonged computerised cognitive training games (RECOGNeyes) on the resting state functional connectivity of the OCN and pupil dilation. Following gaze-control training, the connectivity within the left hemisphere was strengthened, while the intra-right hemisphere and the interhemispheric connectivity were diminished. ‎Chapter 6 provides a summary of the findings and concluding remarks. Our result furthers our knowledge of the processes involved in the performance of the antisaccade task, the mechanisms of action and the neuroplastic effects of two neuromodulation techniques. However, the exact mechanisms underlying these methods' beneficial effects demand further exploration

Exploring the role of interhemispheric inhibition in musculoskeletal pain

The overarching aim of this thesis was to determine whether: i) interhemispheric inhibition (IHI) is altered in response to unilateral musculoskeletal pain; and ii) a relationship exists between altered IHI (if any) and the development of bilateral sensorimotor dysfunction. To achieve this, three studies were conducted. These studies provided novel insight into IHI in experimentally induced acute muscle pain and chronic lateral elbow pain. The body of work in this thesis provides an original contribution to the field of musculoskeletal pain that deepens our understanding of IHI, and its potential association with changes in sensorimotor function in the unaffected limb, in unilateral conditions. Study 1 demonstrated a reduction in IHI from the affected to unaffected M1 but no change in IHI from the affected to unaffected S1 was observed in Study 2. In both studies, increased sensitivity to pressure was observed on the affected and unaffected sides. No change in IHI between M1s, and no differences in sensorimotor function were observed between individuals with chronic LE and healthy controls in Study 3. Taken together, the findings presented in this thesis suggest that IHI between M1s is reduced in response to acute muscle pain and altered IHI could contribute to the development of bilateral sensorimotor symptoms soon after pain onset. Conversely, IHI between S1s is preserved in response to acute muscle pain. In a clinical chronic musculoskeletal pain population, IHI is also preserved. However, further research is needed to determine whether the degree of change in IHI is related to various features of clinical pain such as pain severity, or the severity of bilateral sensorimotor dysfunction. The studies in this thesis are amongst the first to investigate: i) IHI in response to musculoskeletal pain of varying durations; and ii) the relationship between altered IHI and the development of bilateral sensorimotor dysfunction. Longitudinal studies that follow individuals from an initial episode of acute musculoskeletal pain to recovery, or to the development of chronic musculoskeletal pain, are required to further explore the relationship between IHI and the development of bilateral sensorimotor symptoms in unilateral musculoskeletal pain conditions

Neural and behavioral plasticity in olfactory sensory deprivation

The human brain has a remarkable ability to reorganize as a consequence of altered demands. This ability is particularly noticeable when studying the neural effects of complete sensory deprivation. Both structural and functional cerebral reorganization have repeatedly been demonstrated in individuals with sensory deprivation, most evident in cortical regions associated with the processing of the absent sensory modality. Furthermore, sensory deprivation has been linked to altered abilities in remaining sensory modalities, often of a compensatory character. Although anosmia, complete olfactory sensory deprivation, is our most common sensory deprivation, estimated to affect around 5 % of the population, the effects of anosmia on brain and behavior are still poorly understood. The overall aim of this thesis was to investigate how the human brain and behavior are affected by anosmia, with a focus on individuals with congenital (lifelong) sensory deprivation. Specifically, Study I and Study IV assessed potential behavioral and neural multisensory compensatory abilities whereas Study II and Study III assessed potential reorganization beyond the processing of specific stimuli; the latter by determining morphological and resting-state functional connectivity alterations. Integration of information from different sensory modalities leads to a more accurate perception of the world around us, given that our senses provide complementary information. Although an improved ability to extract multisensory information would be of particular relevance to individuals deprived of one sensory modality, multisensory integration has been sparsely studied in relation to sensory deprivation. In Study I, multisensory integration of audio-visual stimuli was assessed in individuals with anosmia using two different experimental tasks. First, individuals with anosmia were better than matched controls in detecting multisensory temporal asynchronies in a simultaneity judgement task. Second, individuals with congenital, but not acquired, anosmia demonstrated indications of an enhanced ability to utilize multisensory information in an object identification task with degraded stimuli. Based on these results, the neural correlates of audio-visual processing and integration were assessed in individuals with congenital anosmia in Study IV. Relative to matched normosmic individuals, individuals with congenital anosmia demonstrated increased activity in established multisensory regions when integrating degraded audio-visual stimuli; however, no compensatory cross-modal processing in olfactory regions was demonstrated. Together, Study I and IV suggest that complete olfactory sensory deprivation is linked to enhanced audio-visual integration performance that might be facilitated by increased processing in multisensory regions. In Study II, whole-brain gray matter morphology was assessed in individuals with congenital anosmia. Both increases and decreases in the orbitofrontal cortex, a region associated with olfaction and sometimes referred to as secondary olfactory cortex, were observed in individuals with congenital anosmia in relation to matched controls. However, in contrast to our expectations, no sensory deprivation-dependent effects were demonstrated in piriform cortex, a region commonly referred to as primary olfactory cortex. Furthermore, Study III revealed an absence of differences in resting-state functional connectivity between individuals withcongenital anosmia and normosmic individuals within the primary olfactory cortex (including piriform cortex) as well as between core olfactory processing regions. In conclusion, the studies presented within this thesis suggest the existence of a potential multisensory compensatory mechanism in individuals with anosmia, but demonstrate a striking lack of morphological and functional alterations in piriform (primary olfactory) cortex. These results demonstrate that complete olfactory deprivation is associated with a distinct neural and behavioral reorganization in some regions but also a clear lack of effects in other regions; the latter underline the clear differences between our senses and suggest that extrapolating from individual senses should be done cautiously

Analysis of resting-state neurovascular coupling and locomotion-associated neural dynamics using wide-field optical mapping

Understanding the relationship between neural activity and cortical hemodynamics, or neurovascular coupling is the foundation to interpret neuroimaging signals such as functional magnetic resonance imaging (fMRI) which measure local changes in hemodynamics as a proxy for underlying neural activity. Even though the stereotypical stimulus-evoked hemodynamic response pattern with increased concentration of oxy- and total-hemoglobin and decrease in concentration of deoxy-hemoglobin has been well-recognized, the linearity of neurovascular coupling and its variances depending on brain state and tasks haven’t been thoroughly evaluated. To directly assess the cortical neurovascular coupling, simultaneous recordings of neural and hemodynamic activity were imaged by wide-field optical mapping (WFOM) over the bilateral dorsal surface of the mouse brain through a bilateral thinned-skull cranial window. Neural imaging is achieved through wide-field fluorescence imaging in animals expressing genetically encoded calcium sensor (Thy1-GCaMP). Hemodynamics are recorded via simultaneous imaging of multi-spectral reflectance. Significant hemodynamic crosstalk was found in the detected fluorescence signal and the physical model of the contamination, methods of correction as well as electrophysiological verification are presented. A linear model between neural and hemodynamic signals was used to fit spatiotemporal hemodynamics can be predicted by convolving local fluorescence changes with hemodynamic response functions derived through both deconvolution and gamma-variate fitting. Beyond confirming that the resting-state hemodynamics in the awake and anesthetized brain are coupled to underlying neural activity, the patterns of bilaterally symmetric spontaneous neural activity observed by WFOM emulate the functionally connected networks detected by fMRI. This result provides reassurance that resting-state functional connectivity has neural origins. With the access to cortical neural activity at mesoscopic level, we further explore the cortical neural representations preceding and during spontaneous locomotion

Modern Developments in Transcranial Magnetic Stimulation (TMS) – Applications and Perspectives in Clinical Neuroscience

Transcranial magnetic stimulation (TMS) is being increasingly used in neuroscience and clinics. Modern advances include but are not limited to the combination of TMS with precise neuronavigation as well as the integration of TMS into a multimodal environment, e.g., by guiding the TMS application using complementary techniques such as functional magnetic resonance imaging (fMRI), electroencephalography (EEG), diffusion tensor imaging (DTI), or magnetoencephalography (MEG). Furthermore, the impact of stimulation can be identified and characterized by such multimodal approaches, helping to shed light on the basic neurophysiology and TMS effects in the human brain. Against this background, the aim of this Special Issue was to explore advancements in the field of TMS considering both investigations in healthy subjects as well as patients

Transcranial magnetic stimulation of the brain: What is stimulated? – A consensus and critical position paper

Copyright © 2022 The Author(s) and International Federation of Clinical Neurophysiology. Transcranial (electro)magnetic stimulation (TMS) is currently the method of choice to non-invasively induce neural activity in the human brain. A single transcranial stimulus induces a time-varying electric field in the brain that may evoke action potentials in cortical neurons. The spatial relationship between the locally induced electric field and the stimulated neurons determines axonal depolarization. The induced electric field is influenced by the conductive properties of the tissue compartments and is strongest in the superficial parts of the targeted cortical gyri and underlying white matter. TMS likely targets axons of both excitatory and inhibitory neurons. The propensity of individual axons to fire an action potential in response to TMS depends on their geometry, myelination and spatial relation to the imposed electric field and the physiological state of the neuron. The latter is determined by its transsynaptic dendritic and somatic inputs, intrinsic membrane potential and firing rate. Modeling work suggests that the primary target of TMS is axonal terminals in the crown top and lip regions of cortical gyri. The induced electric field may additionally excite bends of myelinated axons in the juxtacortical white matter below the gyral crown. Neuronal excitation spreads ortho- and antidromically along the stimulated axons and causes secondary excitation of connected neuronal populations within local intracortical microcircuits in the target area. Axonal and transsynaptic spread of excitation also occurs along cortico-cortical and cortico-subcortical connections, impacting on neuronal activity in the targeted network. Both local and remote neural excitation depend critically on the functional state of the stimulated target area and network. TMS also causes substantial direct co-stimulation of the peripheral nervous system. Peripheral co-excitation propagates centrally in auditory and somatosensory networks, but also produces brain responses in other networks subserving multisensory integration, orienting or arousal. The complexity of the response to TMS warrants cautious interpretation of its physiological and behavioural consequences, and a deeper understanding of the mechanistic underpinnings of TMS will be critical for advancing it as a scientific and therapeutic tool.Aman S. Aberra was supported by a U. S. A. National Science Foundation Graduate Research Fellowship (No. DGF 1106401). Andrea Antal has been supported by a grant of the Federal Ministry of Education and Research (BMBF) of Germany (Grant 01GP2124B) and by a grant of the Lower Saxony Ministry of Science and Culture (Grant 76251-12-7/19 ZN 3456). Marco Davare has been supported by a BBSRC responsive mode grant. Klaus Funke has been supported by a grant of the Federal Ministry of Education and Research (BMBF) of Germany (Grant 01EE1403B) as part of the German Center for Brain Stimulation (GCBS) and by the Deutsche Forschungsgemeinschaft (DFG) (Grants FU256/3-2; 122679504–SFB874). Mark Hallett is supported by the NINDS Intramural Program. Anke N. Karabanov holds a 4-year Sapere Aude Fellowship which is sponsored by the Independent Research Fund Denmark (Grant Nr. 0169-00027B). The sponsor had no direct involvement in the collection, analysis and interpretation of data and in the writing of the manuscript. Giacomo Koch has been supported by na EU grant H2020-EU.1.2.2. - FET Proactive (Neurotwin ID: 101017716). Sabine Meunier is Emeritus Research Director at INSERM, this has no direct involvement in the collection, analysis and interpretation of data and in the writing of the manuscript. Carlo Miniussi has been supported by a grant of the Caritro Foundation, Italy. Walter Paulus received grants from the Deutsche Forschungsgemeinschaft and BMBF. Angel V. Peterchev was supported by grants from the U. S. A. National Institutes of Health (Grants Nos. R01NS117405, R01NS088674, RF1MH114268, R01MH111865). Traian Popa has been supported by the Defitech Foundation and NIBS-iCog grant from the Swiss National Science Foundation. Hartwig R. Siebner holds a 5-year professorship in precision medicine at the Faculty of Health Sciences and Medicine, University of Copenhagen which is sponsored by the Lundbeck Foundation (Grant Nr. R186-2015-2138). The salary for Janine Kesselheim (PhD project) has been covered by a project grant “Biophysically adjusted state-informed cortex stimulation” (BASICS) funded by a synergy grant from Novo Nordisk Foundation (PI: Hartwig R Siebner, Interdisciplinary Synergy Program 2014; grant number NNF14OC001). Axel Thielscher has been supported by grants of the Lundbeck foundation (R118-A11308, R244-2017-196 and R313-2019-622). Yoshikazu Ugawa has been supported in part by grants from the Research Project Grant-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology (Grants 15H05881, 16H05322, 19H01091, 20K07866). Ulf Ziemann received grants from the German Ministry of Education and Research (BMBF), European Research Council (ERC), and German Research Foundation (DFG)