Multichannel EEG : towards applications in clinical neurology.

Electroencephalogram (EEG) measures the electric activity produced by the brain with electrodes placed on the scalp. It is used for monitoring or as diagnostic tool for neurological disorders. In practice a maximum of 21 electrodes are generally used for a clinical EEG recording. However, EEG systems with 128 and 256 electrodes are also available and used for fundamental research. In this thesis we investigate whether the extra information obtained with 128-channel recordings is clinically relevant. We have focused on evoked potentials (EPs). EP is the electric activity of the brain caused by a stimulus (e.g. a flashlight). We showed that a measure often used for evoked potentials, the peak amplitude, can be estimated more accurately by using 128 channels recordings than by conventional recordings. Therefore this technique might be more sensitive to pathological changes. In addition, we developed a new technique to estimate EP symmetry (similarity of EPs generated in left and right hemisphere). This technique might be useful for diagnosis of neurological disorders with brain damage in one hemisphere. Both methods have been applied to a group of patients with parkinsonism; neurological symptoms typical for Parkinson’s disease. No differences could be observed in amplitude or symmetry between patients with different parkinsonian disorders. Therefore, (so far) these methods cannot be used as diagnostic tool for neurological disorders. Future research will show whether small adaptations to the stimulation method or analysis technique will result in an improvement of the diagnostic value and whether these methods are useful for other neurological disorders.

Sensorimotor integration in dystonia: pathophysiology and possible non-invasive approaches to therapy

Dystonia is a condition characterized by excessive and sustained muscle contractions causing abnormal postures and involuntary movements. The pathophysiology of dystonia includes loss of inhibition and abnormal plasticity in the somatosensory and motor systems; however, their contribution to the phenomenology of dystonia is still uncertain, and the possibility to target these abnormalities in an attempt to devise new treatments has not been thoroughly explored. This thesis describes how abnormal inhibition and plasticity in the somatosensory system of dystonic patients can be manipulated to ameliorate motor symptoms by means of peripheral stimulation. First, we characterized electrophysiological and behavioural markers of inhibition in the primary somatosensory cortex in a group of patients with idiopathic cervical dystonia (CD). Outcome measures included a) somatosensory temporal discrimination threshold (STDT); b) paired-pulse somatosensory evoked potentials (PP-SEP) tested with interstimulus intervals (ISIs) of 5, 20 and 40 ms; c) spatial somatosensory inhibition ratio (SIR) by measuring SEP interaction between simultaneous stimulation of the digital nerves in thumb and index finger; d) high-frequency oscillations (HFO) extracted from SEP obtained with stimulation of digital nerves of the index finger. This first investigation demonstrated that increased STDT in dystonia is related to reduced activity of inhibitory circuits within the primary somatosensory cortex, as reflected by reduced PP-SEP inhibition at ISI of 5 ms and reduced area of the late part of the HFO (l-HFO). In a second set of experiments, we applied high frequency repetitive somatosensory stimulation (HF-RSS), a patterned electric stimulation applied to the skin through surface electrodes, to the index finger in a sample of healthy subjects, with the aim to manipulate excitability and inhibition of the primary somatosensory (S1) and motor (M1) cortices. The former was assessed by the same methods used before (STDT, PP-SEP, HFO), with the addition of two psychophysical tasks designed to assess tactile spatial discrimination (grating orientation and bumps tests). Assessment of physiology of M1 was performed by means of short intracortical inhibition (SICI) assessed with TMS; this was performed with multiple conditioning stimulus (CS) intensities (70%, 80%, 90% of the active motor threshold) and with a insterstimulus interval (ISI) between conditioning and test stimulus of 3 ms. It was found that HF-RSS increased inhibition in S1 tested by PP-SEP and HFO; these changes were correlated with improvement in STDT. HF-RSS also enhanced bumps detection, while there was no change in grating orientation test. Finally, there was an increase in SICI, suggesting widespread changes in cortical sensorimotor interactions. Overall, these findings demonstrated that HF-RSS is able to modify the effectiveness of inhibitory circuitry in S1 and M1. The results obtained so far led us to hypothesize that HF-RSS could restore inhibition in dystonic patients, similar to what observed in healthy subjects. To test this, we applied HF-RSS on the index finger in a sample of patients with CD, and tested its effects with some of the outcome measures used before (STDT, PP-SEP, HFO, SIR, SICI). Unexpectedly, the results were opposite to what was predicted. Patients with CD showed a consistent, paradoxical response: after HF-RSS, they had reduced suppression of PP-SEP, as well as decreased HFO area and SICI, and increased SIR. STDT deteriorated after the stimulation protocol, and correlated with reduced measures of inhibition within S1 (PP-SEP at 5 ms ISI, l-HFO area). It was hypothesized that patients with CD have abnormal homeostatic inhibitory plasticity within the sensorimotor cortex and that this is responsible for their abnormal response to HF-RSS. Interestingly, this alteration in plasticity seems to be specific to idiopathic dystonia: when the same protocol was applied to patients with dystonia caused by lesions in the basal ganglia, the response was similar to healthy controls. This result suggests that reduced somatosensory inhibition and abnormal cortical plasticity are not strictly required for the clinical expression of dystonia, and that the abnormalities reported in idiopathic dystonia are not necessarily linked to basal ganglia damage. We then directed our attention to another form of peripheral electrical stimulation, delivered at low frequency (LF-RSS). Previous literature demonstrated that this pattern of stimulation had effects opposite to HF-RSS on tactile performance in healthy subjects; therefore, given the previous findings of abnormal response to HF-RSS in CD, we hypothesized that an inverse response might occur in these patients following LF-RSS as well. Our hypothesis was confirmed by the observation that LF-RSS, applied to the fingers in patients with CD, induced an increase in inhibition in the primary somatosensory and motor cortices. This was reflected by an improvement of STDT and an increase in PP-SEP suppression, HFO area and SICI. With this in mind, in the final project of the thesis, we tested the effects of HF-RSS and LF-RSS applied directly over two affected muscles in different groups of patients with focal hand dystonia (FHD), in an attempt to modulate involuntary muscle activity and, consequently, to ameliorate motor symptoms. Whereas HF-RSS was delivered synchronously over the two muscles, LF-RSS was given either synchronously or asynchronously. Outcome measures included a) PP-SEP obtained by direct stimulation of affected muscles, with ISIs of 5 and 30 ms; b) quantification of electromyographic (EMG) activity from tested muscles; c) SICI recorded from the affected muscles, with CS intensities ranging from 50% to 100% RMT and with an ISI of 3 ms; d) evaluation of hand function, assessed by the box and blocks test (BBT) and the nine-hole peg test (NHPT); e) SIR by measuring SEP interaction between simultaneous stimulation of the two muscles receiving repetitive stimulation. We confirmed the paradoxical response of dystonic patients to HF-RSS, which was reflected in decreased PP-SEP suppression and SICI and increased SIR. Importantly, this was paralleled by an increase in involuntary EMG activity and worse scores at the BBT and NHPT. This results were opposite when LF-RSS was delivered, either in its synchronous or asynchronous version, the latter being slightly more effective. Thus, LF-RSS was able to increase PP-SEP suppression and SICI, decrease SIR and reduce involuntary EMG activity, with consequent improvement in performance in the BBT and NHPT. Overall, our data provide novel insight into the neural mechanisms underlying loss of inhibition and deranged somatosensory plasticity in idiopathic dystonia and bring preliminary evidence that peripheral electrical stimulation can be used as a treatment in idiopathic focal hand dystonia

Conscious and unconscious somatosensory perception and its modulation by attention

Our brains handle vast amounts of information incoming through our senses. Continuously exposed to sensory input, the sense of touch, however, may miss tactile stimuli, no matter how much attention we pay to them. In four empirical studies, this thesis tested (1) the feasibility of investigating undetectable stimulation by electrical finger nerve pulses, (2) how its neural correlates dissociate from detectable stimulation and (3) whether and how selective somatosensory attention nevertheless affects the neural representation of undetectable stimuli. The first two studies showed that there is a natural range of electrical stimulation intensities that cannot be detected. A rigorous statistical evaluation with Bayes factor analysis indicated that the evidence of chance performance after undetectable stimulation reliably outweighed evidence of above-chance performance. A subsequent study applying electroencephalography (EEG) revealed qualitative differences between the processing of detectable and undetectable stimulation, which is evident in altered event-related potentials (ERP). Specifically, undetectable stimulation evokes a single component that is not predictive of stimulus detectability but lacks a subsequent component, which correlates with upcoming stimulus detection. The final study showed that attention nevertheless affects neural processing of undetectable stimuli in a top-down manner as it does for detectable stimuli and fosters the view of attention and awareness being two separate and mostly independent mechanisms. The influence of the pre-stimulus oscillatory (~10 Hz) alpha amplitude—a putative marker of attentional deployment—on the ERP depended on the current attentional state and indicates that both processes are interacting but not functionally matching.:1 Touch, Consciousness, And Attention – Theoretical Considerations ........ 1-11 1.1 A Neural Account To (Un-) Consciousness ............................................ 1-12 1.2 Controlling detectability of external stimulation ...................................... 1-14 1.3 Thresholds in the light of signal detection theory ................................... 1-17 1.4 Selective attention in touch .................................................................... 1-19 1.5 Research questions ............................................................................... 1-21 2 Empirical Evidence .................................................................................... 2-25 2.1 General methods .................................................................................... 2-25 2.1.1 Stimulation ........................................................................................... 2-25 2.1.2 Threshold assessment procedure ....................................................... 2-25 2.1.3 Behavioral analysis .............................................................................. 2-26 2.1.4 Electrophysiological measurement ...................................................... 2-28 2.1.5 Analysis of event-related potentials ..................................................... 2-30 2.1.6 Spectral Analysis resolved over time ................................................... 2-30 2.2 Psychophysical assessment of subthreshold stimulation ........................ 2-33 2.2.1 A method for assessing the individual absolute detection threshold (ADTH) ......................................................................................................... 2-33 2.2.2 Validation of absolute detection threshold assessment by signal detection theory measures and Bayesian Null-Hypothesis testing ................ 2-39 2.3 Non-invasive neural markers of unconscious perception ....................... 2-47 2.3.1 Neural Correlates of Undetectable Somatosensory Stimulation in EEG and fMRI ...................................................................................................... 2-47 2.3.2 Prediction of stimulus perception by features of the evoked potential for different stimulation intensities along the psychometric function ................. 2-51 2.4 The role of Rolandic Alpha Activity in Somatosensation and its Relation to Attention ................................................................................................. 2-75 3 General Discussion and Conclusions ...................................................... 3-101 3.1 Summary of empirical results ................................................................ 3-101 3.2 Neural processing of undetectable stimulation ..................................... 3-102 3.3 Attention, awareness and neural oscillatory activity ............................. 3-104 3.4 Limits of the current studies and future perspectives ........................... 3-109 References .................................................................................................... 113 Summary ....................................................................................................... 137 Zusammenfassung ........................................................................................ 143 Curriculum Vitae ............................................................................................ 151 Selbständigkeitserklärung ............................................................................. 155 Nachweis über die Anteile der Co-Autoren .................................................... 15

Signal processing methods for EEG data classification

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Electroencephalographic Responses to Frictional Stimuli: Measurement Setup and Processing Pipeline

Tactility is a key sense in the human interaction with the environment. The understanding of tactile perception has become an exciting area in industrial, medical and scienti c research with an emphasis on the development of new haptic technologies. Surprisingly, the quanti cation of tactile perception has, compared to other senses, only recently become a eld of scienti c investigation. The overall goal of this emerging scienti c discipline is an understanding of the causal chain from the contact of the skin with materials to the brain dynamics representing recognition of and emotional reaction to the materials. Each link in this chain depends on individual and environmental factors ranging from the in uence of humidity on contact formation to the role of attention for the perception of touch. This thesis reports on the research of neural correlates to the frictional stimulation of the human ngertip. Event-related electroencephalographic potentials (ERPs) upon the change in ngertip friction are measured and studied, when pins of a programmable Braille-display were brought into skin contact. In order to contribute to the understanding of the causal chain mentioned above, this work combines two research areas which are usually not connected to each other, namely tribology and neuroscience. The goal of the study is to evaluate contributions of friction to the process of haptic perception. Key contributions of this thesis are: 1) Development of a setup to simultaneously record physical forces and ERPs upon tactile stimulation. 2) Implementation of a dedicated signal processing pipeline for the statistical analysis of ERP -amplitudes, -latencies and -instantaneous phases. 3) Interpretation of skin friction data and extraction of neural correlates with respect to varying friction intensities. The tactile stimulation of the ngertip upon raising and lowering of di erent lines of Braille-pins (one, three and ve) caused pronounced N50 and P100 components in the event-related ERPsequences, which is in line with the current literature. Friction between the ngertip and the Braille-system exhibited a characteristic temporal development which is attributed to viscoelastic skin relaxation. Although the force stimuli varied by a factor of two between the di erent Braillepatterns, no signi cant di erences were observed between the amplitudes and latencies of ERPs after standard across-trial averaging. Thus, for the rst time a phase measure for estimating singletrial interactions of somatosensory potentials is proposed. Results show that instantaneous phase coherency is evoked by friction, and that higher friction induces stronger and more time-localized phase coherencyDie Taktilität ist ein zentraler Sinn in der Interaktion mit unserer Umwelt. Das Bestreben, fundierte Erkenntnisse hinsichtlich der taktilenWahrnehmung zu gewinnen erhält groÿen Zuspruch in der industriellen, medizinischen und wissenschaftlichen Forschung, meist mit einem Fokus auf der Entwicklung von haptischen Technologien. Erstaunlicherweise ist jedoch die wissenschaftliche Quanti zierung der taktilen Wahrnehmung, verglichen mit anderen Sinnesmodalitäten, erst seit kurzem ein sich entwickelnder Forschungsbereich. Fokus dieser Disziplin ist es, die kognitive und emotionale Reaktion nach physischem Kontakt mit Materialien zu beschreiben, und die kausale Wirkungskette von der Berührung bis zur Reaktion zu verstehen. Dabei unterliegen die einzelnen Faktoren dieser Kette sowohl individuellen als auch externen Ein üssen, welche von der Luftfeuchtigkeit während des Kontaktes bis hin zur Rolle der Aufmerksamkeit für die Wahrnehmung reichen. Die vorliegende Arbeit beschäftigt sich mit der Untersuchung von neuronalen Korrelaten nach Reibungsstimulation des menschlichen Fingers. Dazu wurden Reibungsänderungen, welche durch den Kontakt der menschlichen Fingerspitze mit schaltbaren Stiften eines Braille-Display erzeugt wurden, untersucht und die entsprechenden neuronalen Korrelate aufgezeichnet. Um zu dem Verst ändnis der oben erwähnten Wirkungskette beizutragen, werden Ansätze aus zwei für gewöhnlich nicht zusammenhängenden Forschungsbereichen, nämlich der Tribologie und der Neurowissenschaft, kombiniert. Folgende Beiträge sind Hauptbestandteile dieser Arbeit: 1) Realisierung einer Messumgebung zur simultanen Ableitung von Kräften und ereigniskorrelierten Potentialen nach taktiler Stimulation der Fingerspitze. 2) Aufbau einer speziellen Signalverarbeitungskette zur statistischen Analyse von stimulationsabh ängigen EEG -Amplituden, -Latenzen und -instantanen Phasen. 3) Interpretation der erhobenen Reibungsdaten und Extraktion neuronaler Korrelate hinsichtlich variierender Stimulationsintensitäten. Unsere Resultate zeigen, dass die taktile Stimulation der Fingerspitze nach Anheben und Senken von Braille-Stiften zu signi kanten N50 und P100 Komponenten in den ereigniskorrelierten Potentialen führt, im Einklang mit der aktuellen Literatur. Die Reibung zwischen der Fingerspitze und dem Braille-System zeigte einen charakteristischen Signalverlauf, welcher auf viskoelastische Hautrelaxation zurückzuführen ist. Trotz der um einen Faktor zwei verschiedenen Intensit ätsunterschiede zwischen den Stimulationsmustern zeigten sich keine signi kanten Unterschiede zwischen den einfach gemittelten Amplituden der evozierten Potentialen. Erstmalig wurde ein Phasen-Maÿ zur Identi zierung von Unterschieden zwischen somatosensorischen "single-trial" Interaktionen angewandt. Diese Phasenanalyse zeigte, im Gegensatz zur Amplituden- und Latenzanalyse, deutlichere und signi kantere Unterschiede zwischen den Stimulationsparadigmen. Es wird gefolgert, dass Kohärenz zwischen den Momentanphasen durch Reibungsereignisse herbeigef ührt wird und dass durch stärkere Reibung diese Kohärenz, im zeitlichen Verlauf, stärker und lokalisierter wird

Neurophysiological correlates of preparation for action measured by electroencephalography

The optimal performance of an action depends to a great extend on the ability of a person to prepare in advance the appropriate kinetic and kinematic parameters at a specific point in time in order to meet the demands of a given situation and to foresee its consequences to the surrounding environment. In the research presented in this thesis, I employed high-density electroencephalography in order to study the neural processes underlying preparation for action. A typical way for studying preparation for action in neuroscience is to divide it in temporal preparation (when to respond) and event preparation (what response to make). In Chapter 2, we identified electrophysiological signs of implicit temporal preparation in a task where such preparation was not essential for the performance of the task. Electrophysiological traces of implicit timing were found in lateral premotor, parietal as well as occipital cortices. In Chapter 3, explicit temporal preparation was assessed by comparing anticipatory and reactive responses to periodically or randomly applied external loads, respectively. Higher (pre)motor preparatory activity was recorded in the former case, which resulted in lower post-load motor cortex activation and consequently to lower long-latency reflex amplitude. Event preparation was the theme of Chapter 4, where we introduced a new method for studying (at the source level) the generator mechanisms of lateralized potentials related to response selection, through the interaction with steady-state somatosensory responses. Finally, in Chapter 5 we provided evidence for the existence of concurrent and mutually inhibiting representations of multiple movement options in premotor and primary motor areas.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

A Subspace Method for Dynamical Estimation of Evoked Potentials

It is a challenge in evoked potential (EP) analysis to incorporate prior physiological knowledge for estimation. In this paper, we address the problem of single-channel trial-to-trial EP characteristics estimation. Prior information about phase-locked properties of the EPs is assesed by means of estimated signal subspace and eigenvalue decomposition. Then for those situations that dynamic fluctuations from stimulus-to-stimulus could be expected, prior information can be exploited by means of state-space modeling and recursive Bayesian mean square estimation methods (Kalman filtering and smoothing). We demonstrate that a few dominant eigenvectors of the data correlation matrix are able to model trend-like changes of some component of the EPs, and that Kalman smoother algorithm is to be preferred in terms of better tracking capabilities and mean square error reduction. We also demonstrate the effect of strong artifacts, particularly eye blinks, on the quality of the signal subspace and EP estimates by means of independent component analysis applied as a prepossessing step on the multichannel measurements

The utility of latency and spectral analysis methods in evoked potential recordings from patients with hepatic encephalopathy

Evoked potentials (EPs) are small phasic potentials that are elicited in conjunction with sensory, motor and cognitive events. EP variables have been assessed in patients with cirrhosis but in general, methods were inadequately standardized and study populations incompletely characterized, leading to some studies questioning the validity of EP’s in diagnosing and monitoring hepatic encephalopathy, while other studies indicated that there is only a low positive yield with these investigations. Few studies have attempted tri-modal sensory and cognitive recordings. Recorded waveforms may demonstrate altered morphology while possessing broadly normal latencies. Since EP analysis is usually performed solely in the time domain, latency measurements do not therefore highlight morphological changes to the waveform and so abnormalities may go unreported. The aim of this study was twofold (i) to measure sensory and cognitive EPs in patients with cirrhosis in relation to their neuropsychiatric status and (ii) to address frequency content in relation to neuropsychiatric status by examining EPs with two spectral techniques, the Fourier Transform (FT) and the Power Spectral Density Estimate (PSD). Seventy patients with biopsy–proven cirrhosis were classified using clinical, psychometric and EEG criteria as unimpaired or as having minimal or overt hepatic encephalopathy (HE). Forty-eight healthy individuals served as controls. Visual (VEPs), brainstem auditory (BAEPs) somatosensory (SSEPs) and cognitive auditory (P300) EPs were recorded under standardized conditions. Significant latency differences were observed in sensory EPs between patients and controls with patient subgroups differences being less significant. The cognitive auditory P300 however, distinguished the patient subpopulations from one another. Frequency shifts are observed in all EP modalities with significant differences also occurring between patient groups. The sensitivity and specificity of the frequency-domain is comparable to that of the time-domain. Paired EP investigations analysed by latency indicate BAEP and P300 best discriminate any degree of encephalopathy; in the frequency domain it is the VEP combined with SEP and in the time-frequency domain it is the SEP. These findings suggest that EPs, when performed as a bank of multimodal tests and with spectral analysis, could provide a sensitive and specific method for the diagnosis and monitoring of hepatic encephalopathy