Nonlinear and factorization methods for the non-invasive investigation of the central nervous system

This thesis focuses on the functional study of the Central Nervous System (CNS) with non-invasive techniques. Two different aspects are investigated: nonlinear aspects of the cerebrovascular system, and the muscle synergies model for motor control strategies. The main objective is to propose novel protocols, post-processing procedures or indices to enhance the analysis of cerebrovascular system and human motion analysis with noninvasive devices or wearable sensors in clinics and rehabilitation. We investigated cerebrovascular system with Near-infrared Spectroscopy (NIRS), a technique measuring blood oxygenation at the level of microcirculation, whose modification reflects cerebrovascular response to neuronal activation. NIRS signal was analyzed with nonlinear methods, because some physiological systems, such as neurovascular coupling, are characterized by nonlinearity. We adopted Empirical Mode Decomposition (EMD) to decompose signal into a finite number of simple functions, called Intrinsic Mode Functions (IMF). For each IMF, we computed entropy-based features to characterize signal complexity and variability. Nonlinear features of the cerebrovascular response were employed to characterize two treatments. Firstly, we administered a psychotherapy called eye movement desensitization and reprocessing (EMDR) to two groups of patients. The first group performed therapy with eye movements, the second without. NIRS analysis with EMD and entropy-based features revealed a different cerebrovascular pattern between the two groups, that may indicate the efficacy of the psychotherapy when administered with eye movements. Secondly, we administered ozone autohemotherapy to two groups of subjects: a control group of healthy subjects and a group of patients suffering by multiple sclerosis (MS). We monitored the microcirculation with NIRS from oxygen-ozone injection up 1.5 hours after therapy, and 24 hours after therapy. We observed that, after 1.5 hours after the ozonetherapy, oxygenation levels improved in both groups, that may indicate that ozonetherapy reduced oxidative stress level in MS patients. Furthermore, we observed that, after ozonetherapy, autoregulation improved in both groups, and that the beneficial effects of ozonetherapy persisted up to 24 hours after the treatment in MS patients. Due to the complexity of musculoskeletal system, CNS adopts strategies to efficiently control the execution of motor tasks. A model of motor control are muscle synergies, defined as functional groups of muscles recruited by a unique central command. Human locomotion was the object of investigation, due to its importance for daily life and the cyclicity of the movement. Firstly, by exploiting features provided from statistical gait analysis, we investigated consistency of muscle synergies. We demonstrated that synergies are highly repeatable within-subjects, reinforcing the hypothesis of modular control in motor performance. Secondly, in locomotion, we distinguish principal from secondary activations of electromyography. Principal activations are necessary for the generation of the movement. Secondary activations generate supplement movements, for instance slight balance correction. We investigated the difference in the motor control strategies underlying muscle synergies of principal (PS) and secondary (SS) activations. We found that PS are constituted by a few modules with many muscles each, whereas SS are described by more modules than PS with one or two muscles each. Furthermore, amplitude of activation signals of PS is higher than SS. Finally, muscle synergies were adopted to investigate the efficacy of rehabilitation of stiffed-leg walking in lower back pain (LBP). We recruited a group of patients suffering from non-specific LBP stiffening the leg at initial contact. Muscle synergies during gait were extracted before and after rehabilitation. Our results showed that muscles recruitment and consistency of synergies improved after the treatment, showing that the rehabilitation may affect motor control strategies

Investigating Phantom Motor Execution as treatment of Phantom Limb Pain

Phantom Limb Pain (PLP) is commonly suffered by people with amputations and even though it has been studied for centuries, it remains a mysterious object of debate among researchers. For one thing, despite the vast number of proposed PLP treatments, no therapy has so far proved to be reliably effective. For another, studies attempting to provide a mechanistic explanation of the condition have produced mixed and inconsistent results, thus providing unreliable guidance for devising new treatment approaches. Phantom Motor Execution (PME) – exertion of voluntary phantom limb movements – aims at restoring control over the phantom limb and the exercise of such control has been hypothesized to reverse neural changes implicated in PLP. Preliminary evidence supporting this hypothesis has been provided by clinical investigations on upper limb amputees. The main purpose of this doctoral thesis was to provide high quality and unbiased evidence for the use of PME as a treatment of PLP, by probing its efficacy with a Randomized Controlled Trial (RCT) on both upper and lower limb amputees. However, the implementation of this clinical investigation required of additional technology development related the extraction of motor volition via Myoelectric Pattern Recognition (MPR). In practice, this doctoral work consisted in the extension of PME technology to lower limb amputations by proposing and validating a new and more user-friendly recording method to acquire myoelectric signals. The use of PME was then shown to be efficacious in relieving PLP even in the lower limb population with a case study.Another necessity for providing unbiased evidence was to ensure that the highest standards were met when designing, conducting, analysing and reporting the results of the RCT. For this reason, the protocol for the RCT and the prospective Statistical Analysis Plan (SAP) were designed and published. The RCT was established as an international, multi-center effort in 2017 and it is expected to reach its conclusion in September 2021. Preliminary results of the RCT regarding the primary outcome showed reduction of PLP above what is considered clinically relevant, and whereas a higher reduction was obtained with PME, this was not statistically significant over the control treatment. The available evidence at this stage indicates that the RCT will not be able to rule out the role of contextual factors other than PME in providing pain relief. Having at hand a way to alleviate PLP provided a unique opportunity to investigate and identify its neural correlates, therefore this became a secondary aim of this thesis. In particular, patients suffering from PLP were followed regarding their pain trajectory through the therapy and brain imaging studies with functional Magnetic Resonance Imaging (fMRI) and electroencephalography (EEG) were performed. The present doctoral thesis reports part of this work by showing the early results of a cross-sectional study on the EEG correlates of PLP. The results show that it is possible to use machine-learning techniques to discriminate EEG recorded from patients with and without PLP. The findings further point to this technique as a promising target for future longitudinal research aiming at elucidating the neural mechanisms underlying PLP

The influence of peripheral neuropathy on walking kinematics and physical function

The 108th Congress (2005) has reported that 20 million U.S. citizens suffer from Peripheral Neuropathy (PN). Characterized by sensory nerve deterioration, PN reduces somatosensation (Padua et al., 2005) and increases the risk of fall-related injury (Richardson et al., 1992). The purpose of this dissertation was to provide insight into 1) the effects of acute loss of foot sole sensation on locomotor system health, 2) the effects of PN on locomotor system health, and 3) the underlying impairments associated with reduced physical function within the older adult and PN populations. Locomotor system health was assessed by the magnitude of stride-to-stride variability and local instability contained in the kinematics of treadmill walking. In healthy young adults, ice-induced reduction of foot sole sensation did not alter the magnitude of stride-to-stride variability during treadmill walking. It did, however, increase lower-extremity joint local instability, or the sensitivity to small scale perturbations. Compared to controls, individuals with PN walked with similar local instability yet increased variability, at relatively slow speeds. When walking at relatively fast speeds, individuals with PN exhibited exaggerated increases in local instability. In healthy older adults, locomotion-based physical function (LBPF), as defined by 6-minute walk and Timed Up-and-Go performance, was correlated to leg strength and measures of locomotor system health. However, only measures of locomotor system health provided independent predictive information of LBPF. The PN group exhibited reduced LBPF. As opposed to healthy old adults, correlates of LBPF were not leg strength but instead standing balance variables. Multiple variables of leg strength, standing balance, and locomotor system health provided independently predictive information regarding each test of LBPF. The opposing effects of ice-induced reduction in foot sole sensation and PN on locomotor system health suggest that the chronic nature of PN allows for the implementation of partially effective compensatory strategies. Yet, the inability to adapt to relatively fast speeds suggests that falls likely occur during challenging situations. The fundamentally different correlates and predictors of LBPF between older adults and those with PN highlight the uniqueness of the movement disorder associated with PN

Reproducing tactile and proprioception based on the human-in-the-closed-loop conceptual approach

Prosthetic limb embodiment remains a significant challenge for many amputees due to traditional designs' lack of sensory feedback. To address this challenge, the effectiveness of non-invasive neuromuscular electrical stimulation (NMES) controlled by a hybrid proportional-differential (PD)-Fuzzy logic system was evaluated for providing real-time proprioception and tactile feedback. The study used a human-in-the-closed-loop approach with ten participants: five upper limb amputees and five non-disabled individuals as the control group. An applied force, the joint angle of a prosthetic hand's finger, and surface electromyography signals generated by the biceps muscle all regulate the intensity of sensory feedback. Additionally, the C6 and C7 myotomes were selected as elicitation sites. The average threshold for detecting action motion and force was around 21° and 1.524N, respectively. The participants successfully reproduced desired joint angles within the range of 0°-110° at five separate intervals. In the weight recognition experiment, the amputee participant's minimum number of false predictions was four. The highest accuracy achieved was 80.66% in detecting object size and stiffness. Additionally, unpaired t-tests were performed for the means of the results of the experiments to determine statistically significant differences between groups. The results suggest that stimulation of myotomes by NMES is an effective non-invasive method for delivering rich multimodal sensation information to individuals with disabilities, including upper limb amputees, without needing visual or auditory cues. These findings contribute to the development of non-invasive sensory substitution in prostheses

Afferent information modulates spinal network activity in vitro and in preclinical animal models

Primary afferents are responsible for the transmission of peripheral sensory information to the spinal cord. Spinal circuits involved in sensory processing and in motor activity are directly modulated by incoming input conveyed by afferent fibres. Current neurorehabilitation exploits primary afferent information to induce plastic changes within lesioned spinal circuitries. Plasticity and neuromodulation promoted by activity-based interventions are suggested to support both the functional recovery of locomotion and pain relief in subjects with sensorimotor disorders. The present study was aimed at assessing spinal modifications mediated by afferent information. At the beginning of my PhD project, I adopted a simplified in vitro model of isolated spinal cord from the newborn rat. In this preparation, dorsal root (DR) fibres were repetitively activated by delivering trains of electrical stimuli. Responses of dorsal sensory-related and ventral motor-related circuits were assessed by extracellular recordings. I demonstrated that electrostimulation protocols able to activate the spinal CPG for locomotion, induced primary afferent hyperexcitability, as well. Thus, evidence of incoming signals in modulating spinal circuits was provided. Furthermore, a robust sensorimotor interplay was reported to take place within the spinal cord. I further investigated hyperexcitability conditions in a new in vivo model of peripheral neuropathic pain. Adult rats underwent a surgical procedure where the common peroneal nerve was crushed using a calibrated nerve clamp (modified spared nerve injury, mSNI). Thus, primary afferents of the common peroneal nerve were activated through the application of a noxious compression, which presumably elicited ectopic activity constitutively generated in the periphery. One week after surgery, animals were classified into two groups, with (mSNI+) and without (mSNI-) tactile hypersensitivity, based on behavioral tests assessing paw withdrawal threshold. Interestingly, the efficiency of the mSNI in inducing tactile hypersensitivity was halved with respect to the classical SNI model. Moreover, mSNI animals with tactile hypersensitivity (mSNI+) showed an extensive neuroinflammation within the dorsal horn, with activated microglia and astrocytes being significantly increased with respect to mSNI animals without tactile hypersensitivity (mSNI-) and to sham-operated animals. Lastly, RGS4 (regulator of G protein signaling 4) was reported to be enhanced in lumbar dorsal root ganglia (DRGs) and dorsal horn ipsilaterally to the lesion in mSNI+ animals. Thus, a new molecular marker was demonstrated to be involved in tactile hypersensitivity in our preclinical model of mSNI. Lastly, we developed a novel in vitro model of newborn rat, where hindlimbs were functionally connected to a partially dissected spinal cord and passively-driven by a robotic device (Bipedal Induced Kinetic Exercise, BIKE). I aimed at studying whether spinal activity was influenced by afferent signals evoked during passive cycling. I first demonstrated that BIKE could actually evoke an afferent feedback from the periphery. Then, I determined that spinal circuitries were differentially affected by training sessions of different duration. On one side, a short exercise session could not directly activate the locomotor CPG, but was able to transiently facilitate an electrically-induced locomotor-like activity. Moreover, no changes in reflex or spontaneous activity of dorsal and ventral networks were promoted by a short training. On the other side, a long BIKE session caused a loss in facilitation of spinal locomotor networks and a depression in the area of motor reflexes. Furthermore, activity in dorsal circuits was long-term enhanced, with a significant increase in both electrically-evoked and spontaneous antidromic discharges. Thus, the persistence of training-mediated effects was different, with spinal locomotor circuits being only transiently modulated, whereas dorsal activity being strongly and stably enhanced. Motoneurons were also affected by a prolonged training, showing a reduction in membrane resistance and an increase in the frequency of post-synaptic currents (PSCs), with both fast- and slow-decaying synaptic inputs being augmented. Changes in synaptic transmission onto the motoneuron were suggested to be responsible for network effects mediated by passive training. In conclusion, I demonstrated that afferent information might induce changes within the spinal cord, involving both neuronal and glial cells. In particular, spinal networks are affected by incoming peripheral signals, which mediate synaptic, cellular and molecular modifications. Moreover, a strong interplay between dorsal and ventral spinal circuits was also reported. A full comprehension of basic mechanisms underlying sensory-mediated spinal plasticity and bidirectional interactions between functionally different spinal networks might lead to the development of neurorehabilitation strategies which simultaneously promote locomotor recovery and pain relief

Social and Affective Neuroscience of Everyday Human Interaction

This Open Access book presents the current state of the art knowledge on social and affective neuroscience based on empirical findings. This volume is divided into several sections first guiding the reader through important theoretical topics within affective neuroscience, social neuroscience and moral emotions, and clinical neuroscience. Each chapter addresses everyday social interactions and various aspects of social interactions from a different angle taking the reader on a diverse journey. The last section of the book is of methodological nature. Basic information is presented for the reader to learn about common methodologies used in neuroscience alongside advanced input to deepen the understanding and usability of these methods in social and affective neuroscience for more experienced readers

Neurophysiologic diagnosis, clinical symptoms and neuropathologic findings in polyneuropathies

Tausta: Polyneuropatia (PNP) on ääreishermoston sairaus, joka aiheuttaa laaja-alaisia, yleensä symmetrisiä vaurioita ääreishermostossa. PNP:aan johtavia syitä on satoja. Tavoitteet: Löytää parhaat neurofysiologiset menetelmät uremian, myelooman hoidossa käytettävän talidomidin sekä Fabryn taudin aiheuttaman PNP:n diagnosoimiseksi. Fabryn taudissa tutkin lisäksi ohutsäieneuropatian aiheuttamia neuropatologisia löydöksiä iholta otetusta koepalasta. Tutkimuksissa kartoitettiin lisäksi PNP:n aiheuttamien subjektiivisten oireiden korrelaatio neurofysiologisten ja neuropatologisten löydösten kanssa. Munuaisten vajaatoimintaa sairastavilla potilailla tavoitteena oli tutkia dialyysihoidon tehon vaikutusta autonomisen hermoston toimintaan sekä yhden dialyysikerran vaikutusta neurofysiologisiin löydöksiin. Aineisto ja menetelmät: I: Tutkittiin 21 uremiapotilaan sensoristen ja motoristen hermojen vasteet, värinä- sekä lämpötuntokynnykset ennen ja jälkeen hemodialyysin. Subjektiiviset PNP oireet kartoitettiin PNP oireita kysyvillä kaavakkeella. II:12 talidomidi hoitoa saavaa myeloomapotilasta, tutkimuksen menetelmät olivat samat kuin tutkimuksessa I. III: 12 Fabryn tautia sairastavaa potilasta, edellä mainittujen neurofysiologisten tutkimusten lisäksi potilailta otettiin ihobiopsia säären alueelta. Ihobiopsiasta laskettiin ohuiden hermosyiden määrä koepalan värjäyksen jälkeen. Subjektiiviset PNP oireet kartoitettiin kyselykaavakkeella. Sydämen sykevaihtelu tutkittiin levossa taajuustason analyysillä. IV: 32 uremiapotilaan autonomisen hermoston toimintaa tutkittiin sydämen sykevaihtelun aikatason analysillä, paksujen myelinoituneiden säikeiden toimintaa tutkittiin perifeeristen sensoristen hermojen mittauksilla toistetusti noin 2.9 vuoden aikana. Tulokset: Ureemisen PNP:n diagnostiikassa herkimmät tutkimukset ovat F-aaltojen parametrit alaraajojen motorisista hermoista, värinätuntokynnys alaraajoista sekä suralishermon amplitudi. Positiiviset PNP oireet uremiassa korreloivat värinätunto-kynnyksen sekä sensoristen hermojen neurografialöydösten kanssa. Neurofysiologisten tutkimusten ajankohdalla dialyysiajankohtaan nähden ei ole merkitystä. Talidomidi-PNP on pääasiassa sensorinen, mutta motoriset syyt ovat lievästi vaurioituneet. Talidomidi PNP:ssa subjektiiviset oireet korreloivat huonosti neurofysiologisten löydösten kanssa. Fabryn taudissa naisilla on oletettua enemmän ohutsäieneuropatian aiheuttamia oireita ja löydöksiä. Paksujen säikeiden löydöksiä ei tullut esiin. Ohutsäieneuropatian diagnostiikassa ihobiopsia ja kvantitatiiviset tuntokynnysmittaustestit täydentävät toisiaan. Tehokas dialyysi parantaa autonomisen hermoston toimintaa uremiapotilailla. Päätelmät: Erityyppisten polyneuropatioiden diagnostiikassa pitää etukäteen valita PNP tyypille oikeat tutkimusmenetelmät raskaiden tutkimuspatterien vähentämiseksi sekä diagnostiikan parantamiseksi. PNP:n aiheuttamat oireet ja kliiniset löydökset pitää aina tutkia, mutta yksin ne eivät ole herkkiä PNP:n diagnostiikassa.Backround: Polyneuropathy (PNP) is a disorder of the peripheral nervous system that causes widespread, usually symmetric, abnormalities of peripheral nerves. Numerous underlying conditions can cause PNP. Aims: To evaluate the subjective PNP symptoms and the most useful neurophysiologic tests for the diagnosis of uremic PNP, thalidomide induced PNP in myeloma patients, and PNP in Fabry disease. Another aspect of the study was to determine the correlation between subjective symptoms and neurophysiologic and neuropathologic findings in patients with PNP. In uremic patients, the aim was also to study the effect of one dialysis session on neurophysiologic parameters. Also the effect of dialysis on the function of autonomic nervous system was evaluated. Subjects and methods: (I) 21 uremic patients, sensory and motor conduction studies, vibratory- and thermal detection thresholds before and after dialysis. The clinical findings and subjective symptoms were studied using a standardized questionnaire. (II) 12 myeloma patients with thalidomide therapy, the methods were the same as in study I. (III) 12 patients with Fabry disease, same methods as in studies I and II, also skin biopsy for the detection of intraepidermal nerve fibre density. (IV) 32 uremic patients, autonomic nervous system was studied with time-domain measures, thick myelinated fibers were studied with sensory neurography. Results: The F- wave parameters, vibratory perception threshold from lower limbs, and the sural amplitude were the best parameters in the diagnosis of uremic PNP. Positive PNP symptoms in uremic patients correlated with vibratory perception threshold and sensory neurography. The neurophysiologic test can be done either before or after dialysis. Thalidomide PNP is predominantly sensory, but motor fibers are also slightly affected. The subjective sensory PNP symptoms did not correlate with neurophysiologic findings. In Fabry disease, women had more PNP symptoms than expected. Thick myelinated fibers are not affected in Fabry disease. In the diagnosis of small-fibre PNP, the skin biopsy and quantitative sensory tests complement each other. Effective dialysis therapy had a positive effect to cardiac autonomic function. Conclusions: When diagnosing PNP, it is important to use standardized neurophysiologic tests that reflect the function of different types of nerve fibres. These tests should have proper reference values and they should be sensitive in detecting the particular type of PNP that is suspected. The patient’s subjective symptoms, family history and clinical findings give valuable information, and should always be evaluated together with the neurophysiologic tests.Siirretty Doriast