Electrophysiological characterization of the hyperdirect pathway and its functional relevance for subthalamic deep brain stimulation

The subthalamic nucleus (STN) receives input from various cortical areas via hyperdirect pathway (HDP) which bypasses the basal-ganglia loop. Recently, the HDP has gained increasing interest, because of its relevance for STN deep brain stimulation (DBS). To understand the HDP's role cortical responses evoked by STN-DBS have been investigated. These responses have short (<2 ms), medium (2–15 ms), and long (20–70 ms) latencies. Medium-latency responses are supposed to represent antidromic cortical activations via HDP. Together with long-latency responses the medium responses can potentially be used as biomarker of DBS efficacy as well as side effects. We here propose that the activation sequence of the cortical evoked responses can be conceptualized as high frequency oscillations (HFO) for signal analysis. HFO might therefore serve as marker for antidromic activation. Using existing knowledge on HFO recordings, this approach allows data analyses and physiological modeling to advance the pathophysiological understanding of cortical DBS-evoked high-frequency activity

Neural excitability and sensory input determine intensity perception with opposing directions in initial cortical responses

Perception of sensory information is determined by stimulus features (e.g., intensity) and instantaneous neural states (e.g., excitability). Commonly, it is assumed that both are reflected similarly in evoked brain potentials, that is, larger amplitudes are associated with a stronger percept of a stimulus. We tested this assumption in a somatosensory discrimination task in humans, simultaneously assessing (i) single-trial excitatory post-synaptic currents inferred from short-latency somatosensory evoked potentials (SEPs), (ii) pre-stimulus alpha oscillations (8-13 Hz), and (iii) peripheral nerve measures. Fluctuations of neural excitability shaped the perceived stimulus intensity already during the very first cortical response (at ~20 ms) yet demonstrating opposite neural signatures as compared to the effect of presented stimulus intensity. We reconcile this discrepancy via a common framework based on the modulation of electro-chemical membrane gradients linking neural states and responses, which calls for reconsidering conventional interpretations of brain potential magnitudes in stimulus intensity encoding

Analysis of the structure of time-frequency information in electromagnetic brain signals

This thesis encompasses methodological developments and experimental work aimed at revealing information contained in time, frequency, and time–frequency representations of electromagnetic, specifically magnetoencephalographic, brain signals. The work can be divided into six endeavors. First, it was shown that sound slopes increasing in intensity from undetectable to audible elicit event-related responses (ERRs) that predict behavioral sound detection. This provides an opportunity to use non-invasive brain measures in hearing assessment. Second, the actively debated generation mechanism of ERRs was examined using novel analysis techniques, which showed that auditory stimulation did not result in phase reorganization of ongoing neural oscillations, and that processes additive to the oscillations accounted for the generation of ERRs. Third, the prerequisites for the use of continuous wavelet transform in the interrogation of event-related brain processes were established. Subsequently, it was found that auditory stimulation resulted in an intermittent dampening of ongoing oscillations. Fourth, information on the time–frequency structure of ERRs was used to reveal that, depending on measurement condition, amplitude differences in averaged ERRs were due to changes in temporal alignment or in amplitudes of the single-trial ERRs. Fifth, a method that exploits mutual information of spectral estimates obtained with several window lengths was introduced. It allows the removal of frequency-dependent noise slopes and the accentuation of spectral peaks. Finally, a two-dimensional statistical data representation was developed, wherein all frequency components of a signal are made directly comparable according to spectral distribution of their envelope modulations by using the fractal property of the wavelet transform. This representation reveals noise buried processes and describes their envelope behavior. These examinations provide for two general conjectures. The stability of structures, or the level of stationarity, in a signal determines the appropriate analysis method and can be used as a measure to reveal processes that may not be observable with other available analysis approaches. The results also indicate that transient neural activity, reflected in ERRs, is a viable means of representing information in the human brain.reviewe

Non-invasive multi-channel electrophysiology of the human spinal cord: Assessing somatosensory processing from periphery to cortex

The spinal cord is of fundamental importance for somatosensory processing and plays a significant role in various pathologies, such as chronic pain. However, knowledge on spinal cord processing in humans is limited due to the vast technical challenges involved in its investigation via non-invasive recording approaches. Here, we aim to address these challenges by developing an electrophysiological approach – based on a high-density electrode-montage – that allows for characterizing spinal cord somatosensory evoked potentials (SEPs) and combining this with concurrent recordings of the spinal cord’s input (peripheral nerve action potentials) and output (SEPs in brainstem and cortex). In two separate experiments, we first methodologically validate the approach (including replication and robustness analyses) and then assess its application in the context of a neuroscientific question (integrative processes along the neural hierarchy). Critically, we demonstrate the benefits of multi-channel recordings in terms of enhancing sensitivity via spatial filtering, which also allows for obtaining spinal cord SEPs at the single-trial level. We make use of this approach to demonstrate the feasibility of recording spinal cord SEPs in low-signal scenarios (single-digit stimulation) and – most importantly – to provide evidence for bottom-up signal integration already at the level of the spinal cord. Taken together, our approach of concurrent multi-channel recordings of evoked responses along the neural hierarchy allows for a comprehensive assessment of the functional architecture of somatosensory processing at a millisecond timescale

Power-law dynamics in cortical excitability as probed by early somatosensory evoked responses

While it is well-established that instantaneous changes in neuronal networks’ states lead to variability in brain responses and behavior, the mechanisms causing this variability are poorly understood. Insights into the organization of underlying system dynamics may be gained by examining the temporal structure of network state fluctuations, such as reflected in instantaneous cortical excitability. Using the early part of single-trial somatosensory evoked potentials in the human EEG, we non-invasively tracked the magnitude of excitatory post-synaptic potentials in the primary somatosensory cortex (BA 3b) in response to median nerve stimulation. Fluctuations in cortical excitability demonstrated long-range temporal dependencies decaying according to a power-law across trials. As these dynamics covaried with pre-stimulus alpha oscillations, we establish a functional link between ongoing and evoked activity and argue that the co-emergence of similar temporal power-laws may originate from neuronal networks poised close to a critical state, representing a parsimonious organizing principle of neural variability

Magnetoencephalography

This is a practical book on MEG that covers a wide range of topics. The book begins with a series of reviews on the use of MEG for clinical applications, the study of cognitive functions in various diseases, and one chapter focusing specifically on studies of memory with MEG. There are sections with chapters that describe source localization issues, the use of beamformers and dipole source methods, as well as phase-based analyses, and a step-by-step guide to using dipoles for epilepsy spike analyses. The book ends with a section describing new innovations in MEG systems, namely an on-line real-time MEG data acquisition system, novel applications for MEG research, and a proposal for a helium re-circulation system. With such breadth of topics, there will be a chapter that is of interest to every MEG researcher or clinician

Inhibition and oscillatory activity in human motor cortex

Using transcranial magnetic stimulation (TMS) important information can be obtained about the function of motor cortical circuitry during performance of voluntary movements by conscious human subjects. In particular, pairs of TMS pulses can probe inhibitory pathways projecting onto corticospinal neurones, which themselves project to motoneurones innervating hand muscles. This allows investigation of inhibitory circuitry involved in the performance of specific motor tasks, such as the precision grip. Previous studies have shown that pronounced synchronous oscillatory activity within the hand motor system is present at both cortical and muscular level when subjects maintain steady grasp of an object in a precision grip. The origin of this synchronous activity is unknown. However modelling studies have suggested that inhibitory pathways are likely to play an important role in the generation of cortical oscillations, and therefore TMS was used in this Thesis to investigate the origin of synchrony present during the precision grip task. In the first study, parameters of the paired-pulse test used to measure intracortical inhibition were examined. It was found that by modifying the intensities of the stimuli, and the interval between the paired-pulses, different phases of inhibition could be measured. This enabled specific use of TMS to investigate inhibitory pathways. Both single and paired-pulse TMS were then delivered to the motor cortex of subjects performing a precision grip task. It was found that low intensity TMS could reset the phase of muscle oscillatory activity, consistent with corticospinal neurones being part of the circuitry that generates the oscillatory rhythm. When, in the paired-pulse test, a low intensity stimulus was followed a few milliseconds later with a larger TMS stimulus, in the paired-pulse test, strong intracortical inhibition could be measured. This suggested that inhibitory interneurones activated by low intensity TMS could play an important role in the rhythm-generating network. An additional study looked at the importance of cutaneous receptor feedback on synchrony, by studying the effects of local anaesthesia of the index finger and thumb. Whereas low intensity TMS was shown to enhance synchronous activity between muscle pairs, suppression of cutaneous feedback from the digits reduced it. Results in this Thesis suggest that inhibitory interneurones within the motor cortex are important in the generation of synchronous activity within the hand motor system. This synchrony is also under the influence of cutaneous afferent input

Decoding Electrophysiological Correlates of Selective Attention by Means of Circular Data

Sustaining our attention to a relevant sensory input in a complex listening environment, is of great importance for a successful auditory communication. To avoid the overload of the auditory system, the importance of the stimuli is estimated in the higher levels of the auditory system. Based on these information, the attention is drifted away from the irrelevant and unimportant stimuli. Long-term habituation, a gradual process independent from sensory adaptation, plays a major role in drifting away our attention from irrelevant stimuli. A better understanding of attention-modulated neural activity is important for shedding light on the encoding process of auditory streams. For instance, these information can have a direct impact on developing smarter hearing aid devices in which more accurate objective measures can be used to re ect the hearing capabilities of patients with hearing pathologies. As an example, an objective measures of long-term habituation with respect to di erent level of sound stimuli can be used more accurately for adjustment of hearing aid devices in comparison to verbal reports. The main goal of this thesis is to analyze the neural decoding signatures of long-term habituation and neural modulations of selective attention by exploiting circular regularities in electrophysiological (EEG) data, in which we can objectively measure the level of attentional-binding to di erent stimuli. We study, in particular, the modulations of the instantaneous phase (IP) in event related potentials (ERPs) over trials for di erent experimental settings. This is in contrast to the common approach where the ERP component of interest is computed through averaging a su ciently large number of ERP trials. It is hypothesized that a high attentional binding to a stimulus is related to a high level of IP cluster. As the attention binding reduces, IP is spread more uniformly on a unit circle. This work is divided into three main parts. In the initial part, we investigate the dynamics of long-term habituation with di erent acoustical stimuli (soft vs. loud) over ERP trials. The underlying temporal dynamics in IP and the level of phase cluster of the ERPs are assessed by tting circular probability functions (pdf) over data segments. To increase the temporal resolution of detecting times at which a signi cant change in IP occurs, an abrupt change point model at di erent pure-tone stimulations is used. In a second study, we improve upon the results and methodology by relaxing some of the constrains in order to integrate the gradual process of long-term habituation into the model. For this means, a Bayesian state-space model is proposed. In all of the aforementioned studies, we successfully classi ed between di erent stimulation levels, using solely the IP of ERPs over trials. In the second part of the thesis, the experimental setting is expanded to contain longer and more complex auditory stimuli as in real-world scenarios. Thereby, we study the neural-correlates of attention in spontaneous modulations of EEG (ongoing activity) which uses the complete temporal resolution of the signal. We show a mapping between the ERP results and the ongoing EEG activity based on IP. A Markov-based model is developed for removing spurious variations that can occur in ongoing signals. We believe the proposed method can be incorporated as an important preprocessing step for a more reliable estimation of objective measures of the level of selective attention. The proposed model is used to pre-process and classify between attending and un-attending states in a seminal dichotic tone detection experiment. In the last part of this thesis, we investigate the possibility of measuring a mapping between the neural activities of the cortical laminae with the auditory evoked potentials (AEP) in vitro. We show a strong correlation between the IP of AEPs and the neural activities at the granular layer, using mutual information.Die Aufmerksamkeit auf ein relevantes auditorisches Signal in einer komplexen H orumgebung zu lenken ist von gro er Bedeutung f ur eine erfolgreiche akustische Kommunikation. Um eine Uberlastung des H orsystems zu vermeiden, wird die Bedeutung der Reize in den h oheren Ebenen des auditorischen Systems bewertet. Basierend auf diesen Informationen wird die Aufmerksamkeit von den irrelevanten und unwichtigen Reizen abgelenkt. Dabei spielt die sog. Langzeit- Habituation, die einen graduellen Prozess darstellt der unabh angig von der sensorischen Adaptierung ist, eine wichtige Rolle. Ein besseres Verst andnis der aufmerksamkeits-modulierten neuronalen Aktivit at ist wichtig, um den Kodierungsprozess von sog. auditory streams zu beleuchten. Zum Beispiel k onnen diese Informationen einen direkten Ein uss auf die Entwicklung intelligenter H orsysteme haben bei denen genauere, objektive Messungen verwendet werden k onnen, um die H orf ahigkeiten von Patienten mit H orpathologien widerzuspiegeln. So kann beispielsweise ein objektives Ma f ur die Langzeit- Habituation an unterschiedliche Schallreize genutzt werden um - im Vergleich zu subjektiven Selbsteinsch atzungen - eine genauere Anpassung der H orsysteme zu erreichen. Das Hauptziel dieser Dissertation ist die Analyse neuronaler Dekodierungssignaturen der Langzeit- Habituation und neuronaler Modulationen der selektiver Aufmerksamkeit durch Nutzung zirkul arer Regularit aten in elektroenzephalogra schen Daten, in denen wir objektiv den Grad der Aufmerksamkeitsbindung an verschiedene Reize messen k onnen. Wir untersuchen insbesondere die Modulation der Momentanphase (engl. Instantaneous phase, IP) in ereigniskorrelierten Potenzialen (EKPs) in verschiedenen experimentellen Settings. Dies steht im Gegensatz zu dem traditionellen Ansatz, bei dem die interessierenden EKP-Komponenten durch Mittelung einer ausreichend gro en Anzahl von Einzelantworten im Zeitbereich ermittelt werden. Es wird vermutet, dass eine hohe Aufmerksamkeitsbindung an einen Stimulus mit einem hohen Grad an IP-Clustern verbunden ist. Nimmt die Aufmerksamkeitsbindung hingegen ab, so ist die Momentanphase uniform auf dem Einheitskreis verteilt. Diese Arbeit gliedert sich in drei Teile. Im ersten Teil untersuchen wir die Dynamik der Langzeit-Habituation mit verschiedenen akustischen Reizen (leise vs. laut) in EKP-Studien. Die zugrundeliegende zeitliche Dynamik der Momentanphase und die Ebene des Phasenclusters der EKPs werden durch die Anpassung von zirkul aren Wahrscheinlichkeitsfunktionen (engl. probability density function, pdf) uber Datensegmente bewertet. Mithilfe eines sog. abrupt change-point Modells wurde die zeitliche Au osung der Daten erh oht, sodass signi kante Anderungen in der Momentanphase bei verschiedenen Reintonstimulationen detektierbar sind. In einer zweiten Studie verbessern wir die Ergebnisse und die Methodik, indem wir einige der Einschr ankungen lockern, um den gradualen Prozess der Langzeit-Habituation in das abrupt changepoint Modell zu integrieren. Dazu wird ein bayes`sches Zustands-Raum-Modell vorgeschlagen. In den zuvor genannten Studien konnte erfolgreich mithilfe der Momentanphase zwischen verschiedenen Stimulationspegeln unterschieden werden. Im zweiten Teil der Arbeit wird der experimentelle Rahmen erweitert, um komplexere auditorische Reize wie in realen H orsituationen untersuchen zu k onnen. Dabei analysieren wir die neuronalen Korrelate der Aufmerksamkeit anhand spontaner Modulationen der kontinuierlichen EEG-Aktivit at, die eine zeitliche Au osung erm oglicht. Wir zeigen eine Abbildung zwischen den EKP-Ergebnissen und der kontinuierlichen EEG-Aktivit at auf Basis der Momentanphase. Ein Markov-basiertes Modell wird entwickelt, um st orende Variationen zu entfernen, die in kontinuierlichen EEG-Signalen auftreten k onnen. Wir glauben, dass die vorgeschlagene Methode als wichtiger Vorverarbeitungsschritt zur soliden objektiven Absch atzung des Aufmerksamkeitsgrades mithilfe von EEG-Daten verwendet werden kann. In einem dichotischen Tonerkennungsexperiment wird das vorgeschlagene Modell zur Vorverarbeitung der EEG-Daten und zur Klassi zierung zwischen gerichteten und ungerichteten Aufmerksamkeitszust anden erfolgreich verwendet. Im letzten Teil dieser Arbeit untersuchen wir den Zusammenhang zwischen den neuronalen Aktivit aten der kortikalen Laminae und auditorisch evozierten Potentialen (AEP) in vitro im Tiermodell. Wir zeigen eine starke Korrelation zwischen der Momentanphase der AEPs und den neuronalen Aktivit aten in der Granularschicht unter Verwendung der Transinformation

The role of somatosensory afferences in Parkinson's disease

Parkinson’s disease (PD) is the second most common neurodegenerative disorder in the world. The primary motor symptom of PD is bradykinesia, a slowing and reduction in amplitude of voluntary movement. Here, I aim to test some neurophysiological aspects of PD. Furthermore, I explored the possibility to develop non-invasive treatment for this group of patients. The first two studies tested the contribution of a specific phenomenon labelled sensory attenuation or sensory gating in the motor symptoms of PD, especially bradykinesia. I found that the sensory attenuation is abnormal in this group of patients. Especially, PD patients OFF medications showed a reduced sensory attenuation measured as the amplitude of the somatosensory evoked potentials. Interestingly, I found that the sensory attenuation was equal to the healthy age matched controls when the patients were tested in ON pharmacological state. Additionally, this research tested a theory of the functional role of sensorimotor beta oscillations that could explain beta power modulations in healthy subjects and the increase in beta power observed in PD patients. My results were in line with the previous data presented in the literature. Indeed, I found the increase beta power in both my two cohorts of PD patients. Finally, I tested a potential correlation between the abnormalities of these two phenomena in PD: reduced sensory attenuation and increased beta oscillations. I did not find any significant correlation between the two phenomena. They might be two different neurophysiological mechanisms 5 underlying this disease. However, further studies are necessary to investigate this hypothesis. Having tested the influence of the somatosensory signal in some motor symptoms, the second part of the thesis was focused on the development of non-invasive treatments of bradykinesia in PD. I tested the impact of vibratory stimuli to improve these motor signs. In particular, several frequencies of vibration have been tested through different devices applied to the wrist. The device was called “Emma watch” and I found that the application of vibration with the modulation of 60 bpm improved the bradykinesia in PD patients Finally, I presented a case study regarding the benefit of vibratory stimulation on the freezing of gait thought shoe insoles generating vibration. The tested patient showed an improvement of the frequency of the freezing episodes after a week wearing the insoles, which generated vibration at 200 Hz