Neuromagnetic investigations of mechanisms and effects of STN-DBS and medication in Parkinson's disease

Parkinson’s disease (PD) is a neurodegenerative disorder cardinally marked by motor symptoms, but also sensory symptoms and several other non-motor symptoms. PD patients are typically treated with dopaminergic medication for several years. Many patients eventually experience bouts of periods where medication might not be able to effectively control symptoms as well as experience side-effects of long-term dopaminergic treatments. Deep brain stimulation (DBS) is an option as the next therapeutic recourse for such patients. DBS treatment essentially involves placement of stimulating electrodes in the subthalamic nucleus (STN) or the globus pallidus internum (GPi) along with an implanted pulse generator (IPG) in the sub-clavicular space. STN-DBS alleviates motor symptoms and leads to substantial improvements in quality of life for PD patients. Although DBS is known to improve several classes of symptoms, the effect mechanism of DBS is still not clear. While there is a lack of electrophysiological investigation of sensory processing and the effects of treatments in PD altogether, the electrophysiological studies of the cortical dynamics during motor tasks and at rest lack consensus.We recorded magnetoencephalography (MEG) and electromyography (EMG) from PD patients in three studies: (i) at rest, (ii) during median nerve stimulation, and (iii) while performing phasic contractions (hand gripping). The three studies focused on cortical oscillatory dynamics at rest, during somatosensory processing and during movement, respectively. The measurements were conducted in DBS-treated, untreated (DBS washout) and dopaminergic-medicated states. While both treatments (DBS and dopaminergic medication) ameliorated motor symptoms similarly in all studies, they showed differentiated effects on: (i) increased sensorimotor cortical low-gamma spectral power (31-45 Hz) (but no changes in beta power (13-30 Hz)) at rest only during DBS, (ii) somatosensory processing with higher gamma augmentation (31-45 Hz, 20-60 ms) in the dopaminergic-medicated state compared to DBS-treated and untreated states, and (iii) hand gripping with increased motor-related beta corticomuscular coherence (CMC, 13-30 Hz) during dopaminergic medication in contrast to increased gamma power (31-45 Hz) during DBS.Firstly, we infer from the three studies that DBS and dopaminergic medication employ partially different anatomo-functional pathways and functional strategies when improving PD symptoms. Secondly, we suggest that treatments act on pathological oscillatory dynamics differently at cortical and sub-cortical levels and may do so through more sophisticated mechanisms than mere suppression of the pathological spectral power in a particular band. And thirdly, we urge exploring effect mechanisms of PD treatments beyond the motor system. The effects of dopaminergic medication on early somatosensory processing has opened the door for exploring the effects of treatments and studying their mechanisms using electrophysiology, especially in higher order sensory deficits. Integration of such research findings into a holistic view on mechanisms of treatments could pave way for better disease management paradigms. 

Cortico-muscular coherence in sensorimotor synchronisation

This thesis sets out to investigate the neuro-muscular control mechanisms underlying the ubiquitous phenomenon of sensorimotor synchronisation (SMS). SMS is the coordination of movement to external rhythms, and is commonly observed in everyday life. A large body of research addresses the processes underlying SMS at the levels of behaviour and brain. Comparatively, little is known about the coupling between neural and behavioural processes, i.e. neuro-muscular processes. Here, the neuro-muscular processes underlying SMS were investigated in the form of cortico-muscular coherence measured based on Electroencephalography (EEG) and Electromyography (EMG) recorded in human healthy participants. These neuro-muscular processes were investigated at three levels of engagement: passive listening and observation of rhythms in the environment, imagined SMS, and executed SMS, which resulted in the testing of three hypotheses: (i) Rhythms in the environment, such as music, spontaneously modulate cortico-muscular coupling, (ii) Movement intention modulates cortico-muscular coupling, and (iii) Cortico-muscular coupling is dynamically modulated during SMS time-locked to the stimulus rhythm. These three hypotheses were tested through two studies that used Electroencephalography (EEG) and Electromyography (EMG) recordings to measure Cortico-muscular coherence (CMC). First, CMC was tested during passive music listening, to test whether temporal and spectral properties of music stimuli known to induce groove, i.e., the subjective experience of wanting to move, can spontaneously modulate the overall strength of the communication between the brain and the muscles. Second, imagined and executed movement synchronisation was used to investigate the role of movement intention and dynamics on CMC. The two studies indicate that both top-down, and somatosensory and/or proprioceptive processes modulate CMC during SMS tasks. Although CMC dynamics might be linked to movement dynamics, no direct correlation between movement performance and CMC was found. Furthermore, purely passive auditory or visual rhythmic stimulation did not affect CMC. Together, these findings thus indicate that movement intention and active engagement with rhythms in the environment might be critical in modulating CMC. Further investigations of the mechanisms and function of CMC are necessary, as they could have important implications for clinical and elderly populations, as well as athletes, where optimisation of motor control is necessary to compensate for impaired movement or to achieve elite performance

Sensor Approach for Brain Pathophysiology of Freezing of Gait in Parkinson\u27s Disease Patients

Parkinson\u27s Disease (PD) affects over 1% of the population over 60 years of age and is expected to reach 1 million in the USA by the year 2020, growing by 60 thousand each year. It is well understood that PD is characterized by dopaminergic loss, leading to decreased executive function causing motor symptoms such as tremors, bradykinesia, dyskinesia, and freezing of gait (FoG) as well as non-motor symptoms such as loss of smell, depression, and sleep abnormalities. A PD diagnosis is difficult to make since there is no worldwide approved test and difficult to manage since its manifestations are widely heterogeneous among subjects. Thus, understanding the patient subsets and the neural biomarkers that set them apart will lead to improved personalized care. To explore the physiological alternations caused by PD on neurological pathways and their effect on motor control, it is necessary to detect the neural activity and its dissociation with healthy physiological function. To this effect, this study presents a custom ultra-wearable sensor solution, consisting of electroencephalograph, electromyograph, ground reaction force, and symptom measurement sensors for the exploration of neural biomarkers during active gait paradigms. Additionally, this study employed novel de-noising techniques for dealing with the motion artifacts associated with active gait EEG recordings and compared time-frequency features between a group of PD with FoG and a group of age-matched controls and found significant differences between several EEG frequency bands during start and end of normal walking (with a p\u3c0.05)

Neuroimaging of human motor control in real world scenarios: from lab to urban environment

The main goal of this research programme was to explore the neurophysiological correlates of human motor control in real-world scenarios and define mechanism-specific markers that could eventually be employed as targets of novel neurorehabilitation practice. As a result of recent developments in mobile technologies it is now possible to observe subjects' behaviour and monitor neurophysiological activity whilst they perform natural activities freely. Investigations in real-world scenarios would shed new light on mechanisms of human motor control previously not observed in laboratory settings and how they could be exploited to improve rehabilitative interventions for the neurologically impaired. This research programme was focussed on identifying cortical mechanisms involved in both upper- (i.e. reaching) and lower-limb (i.e. locomotion) motor control. Complementary results were obtained by the simultaneous recordings of kinematic, electromyographic and electrocorticographic signals. To study motor control of the upper-limb, a lab­based setup was developed, and the reaching movement of healthy young individuals was observed in both stable and unstable (i.e. external perturbation) situations. Robot-mediated force-field adaptation has the potential to be employed in rehabilitation practice to promote new skills learning and motor recovery. The muscular (i.e. intermuscular couplings) and neural (i.e. spontaneous oscillations and cortico­muscular couplings) indicators of the undergoing adaptation process were all symbolic of adaptive strategies employed during early stages of adaptation. The medial frontal, premotor and supplementary motor regions appeared to be the principal cortical regions promoting adaptive control and force modulation. To study locomotion control, a mobile setup was developed and daily life human activities (i.e. walking while conversing, walking while texting with a smartphone) were investigated outside the lab. Walking in hazardous environments or when simultaneously performing a secondary task has been demonstrated to be challenging for the neurologically impaired. Healthy young adults showed a reduced motor performance when walking in multitasking conditions, during which whole-brain and task-specific neural correlates were observed. Interestingly, the activity of the left posterior parietal cortex was predictive of the level of gait stability across individuals, suggesting a crucial role of this area in gait control and determination of subject specific motor capabilities. In summary, this research programme provided evidence on different cortical mechanisms operative during two specific scenarios for "real­world" motor behaviour in and outside the laboratory-setting in healthy subjects. The results suggested that identification of neuro-muscular indicators of specific motor control mechanisms could be exploited in future "real-world" rehabilitative practice

Proceedings of the 3rd International Mobile Brain/Body Imaging Conference : Berlin, July 12th to July 14th 2018

The 3rd International Mobile Brain/Body Imaging (MoBI) conference in Berlin 2018 brought together researchers from various disciplines interested in understanding the human brain in its natural environment and during active behavior. MoBI is a new imaging modality, employing mobile brain imaging methods like the electroencephalogram (EEG) or near infrared spectroscopy (NIRS) synchronized to motion capture and other data streams to investigate brain activity while participants actively move in and interact with their environment. Mobile Brain / Body Imaging allows to investigate brain dynamics accompanying more natural cognitive and affective processes as it allows the human to interact with the environment without restriction regarding physical movement. Overcoming the movement restrictions of established imaging modalities like functional magnetic resonance tomography (MRI), MoBI can provide new insights into the human brain function in mobile participants. This imaging approach will lead to new insights into the brain functions underlying active behavior and the impact of behavior on brain dynamics and vice versa, it can be used for the development of more robust human-machine interfaces as well as state assessment in mobile humans.DFG, GR2627/10-1, 3rd International MoBI Conference 201

Proceedings XXII Congresso SIAMOC 2022

Il congresso annuale della Società Italiana di Analisi del Movimento in Clinica dà l’occasione a tutti i professionisti, dell’ambito clinico e ingegneristico, di incontrarsi, presentare le proprie ricerche e rimanere aggiornati sulle più recenti innovazioni nell’ambito dell’applicazione clinica dei metodi di analisi del movimento, al fine di promuoverne lo studio e le applicazioni cliniche per migliorare la valutazione dei disordini motori, aumentare l’efficacia dei trattamenti attraverso l’analisi quantitativa dei dati e una più focalizzata pianificazione dei trattamenti, ed inoltre per quantificare i risultati delle terapie correnti

Multimodal characterisation of sensorimotor oscillations

The studies in this project have investigated the ongoing neuronal network oscillatory activity found in the sensorimotor cortex using two modalities: magnetoencephalography (MEG) and in vitro slice recordings. The results have established that ongoing sensorimotor oscillations span the mu and beta frequency region both in vitro and in MEG recordings, with distinct frequency profiles for each recorded laminae in vitro, while MI and SI show less difference in humans. In addition, these studies show that connections between MI and SI modulate the ongoing neuronal network activity in these areas. The stimulation studies indicate that specific frequencies of stimulation affect the ongoing activity in the sensorimotor cortex. The continuous theta burst stimulation (cTBS) study demonstrates that cTBS predominantly enhances the power of the local ongoing activity. The stimulation studies in this project show limited comparison between modalities, which is informative of the role of connectivity in these effects. However, independently these studies provide novel information on the mechanisms on sensorimotor oscillatory interaction. The pharmacological studies reveal that GABAergic modulation with zolpidem changes the neuronal oscillatory network activity in both healthy and pathological MI. Zolpidem enhances the power of ongoing oscillatory activity in both sensorimotor laminae and in healthy subjects. In contrast, zolpidem attenuates the “abnormal” beta oscillatory activity in the affected hemisphere in Parkinsonian patients, while restoring the hemispheric beta power ratio and frequency variability and thereby improving motor symptomatology. Finally we show that independent signals from MI laminae can be integrated in silico to resemble the aggregate MEG MI oscillatory signals. This highlights the usefulness of combining these two methods when elucidating neuronal network oscillations in the sensorimotor cortex and any interventions

Exploring the combined use of electrical and hemodynamic brain activity to investigate brain function

This thesis explored the relationship between electrical and metabolic aspects of brain functioning in health and disease, measured with QEEG and NIRS, in order to evaluate its clinical potential. First the limitations of NIRS were investigated, depicting its susceptibility to different types of motion artefacts and the inability of the CBSI-method to remove them from resting state data. Furthermore, the quality of the NIRS signals was poor in a significant portion of the investigated sample, reducing clinical potential. Different analysis methods were used to explore both EEG and NIRS, and their coupling in an eyes open eyes closed paradigm in healthy participants. It could be reproduced that during eyes closed blocks less HbO2 (p = 0.000), more Hbb (p = 0.008), and more alpha activity (p = 0.000) was present compared to eyes open blocks. Furthermore, dynamic cross correlation analysis reproduced a positive correlation between alpha and Hbb (r: 0.457 and 0.337) and a negative correlation between alpha and HbO2 (r: -0.380 and -0.366) with a delayed hemodynamic response (7 to 8s). This was only possible when removing all questionable and physiological illogical data, suggesting that an 8s hemodynamic delay might not be the golden standard. Also the inability of the cross correlation to take non-linear relationships into account may distort outcomes. Therefore, In chapter 5 non-linear aspects of the relationship were evaluated by introducing the measure of relative cross mutual information. A newly suggested approach and the most valuable contribution of the thesis since it broadens knowledge in the fields of EEG, NIRS and general time series analysis. Data of two stroke patients then showed differences from the healthy group between the coupling of EEG and NIRS. The differences in long range temporal correlations (p= 0.000 for both cases), entropy (p< 0.040 and p =0.000), and relative cross mutual information (p < 0.003 and p < 0.013) provide the proof of principle that these measures may have clinical utility. Even though more research is necessary before widespread clinical use becomes possible

Assessing Neuronal Synchrony and Brain Function Through Local Field Potential and Spike Analysis

Studies of neuronal network oscillations and rhythmic neuronal synchronization have led to a number of important insights in recent years, giving us a better understanding of the temporal organization of neuronal activity related to essential brain functions like sensory processing and cognition. Important principles and theories have emerged from these findings, including the communication through coherence hypothesis, which proposes that synchronous oscillations render neuronal communication effective, selective, and precise. The implications of such a theory may be universal for brain function, as the determinants of neuronal communication inextricably shape the neuronal representation of information in the brain. However, the study of communication through coherence is still relatively young. Since its articulation in 2005, the theory has predominantly been applied to assess cortical function and its communication with downstream targets in different sensory and behavioral conditions. The results herein are intended to bolster this hypothesis and explore new ways in which oscillations coordinate neuronal communication in distributed regions. This includes the development of new analytic tools for interpreting electrophysiological patterns, inspired by phase synchronization and spike train analysis. These tools aim to offer fast results with clear statistical and physiological interpretation

State-Dependent Cortical Network Dynamics

Neuropsychiatric illness represents a major health burden in the United States with a paucity of effective treatment. Many neuropsychiatric illnesses are network disorders, exhibiting aberrant organization of coordinated activity within and between brain areas. Cortical oscillations, arising from the synchronized activity of groups of neurons, are important in mediating both local and long-range communication in the brain and are particularly affected in neuropsychiatric diseases. A promising treatment approach for such network disorders entails ‘correcting’ abnormal oscillatory activity through non-invasive brain stimulation. However, we lack a clear understanding of the functional role of oscillatory activity in both health and disease. Thus, basic science and translational work is needed to elucidate the role of oscillatory activity and other network dynamics in neuronal processing and behavior. Organized activity in the brain occurs at many spatial and temporal scales, ranging from the millisecond duration of individual action potentials to the daily circadian rhythm. The studies comprising this dissertation focused on organization in cortex at the time scale of milliseconds, assessing local field potential and spiking activity, and contribute to understanding (1) the effects of non-invasive brain stimulation on behavioral responses, (2) network dynamics within and across cortical areas during different states, and (3) how oscillatory activity organizes spiking activity locally and long-range during sustained attention. Taken together, this work provides insight into the physiological organization of network dynamics and can provide the basis for future rational design of non-invasive brain stimulation treatments.Doctor of Philosoph