Cross-Frequency Coupling and Intelligent Neuromodulation.

Cross-frequency coupling (CFC) reflects (nonlinear) interactions between signals of different frequencies. Evidence from both patient and healthy participant studies suggests that CFC plays an essential role in neuronal computation, interregional interaction, and disease pathophysiology. The present review discusses methodological advances and challenges in the computation of CFC with particular emphasis on potential solutions to spurious coupling, inferring intrinsic rhythms in a targeted frequency band, and causal interferences. We specifically focus on the literature exploring CFC in the context of cognition/memory tasks, sleep, and neurological disorders, such as Alzheimer's disease, epilepsy, and Parkinson's disease. Furthermore, we highlight the implication of CFC in the context and for the optimization of invasive and noninvasive neuromodulation and rehabilitation. Mainly, CFC could support advancing the understanding of the neurophysiology of cognition and motor control, serve as a biomarker for disease symptoms, and leverage the optimization of therapeutic interventions, e.g., closed-loop brain stimulation. Despite the evident advantages of CFC as an investigative and translational tool in neuroscience, further methodological improvements are required to facilitate practical and correct use in cyborg and bionic systems in the field

Characterization of cortico-subthalamic networks during deep brain stimulation surgery in Parkinson’s disease

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a well-established symptomatic treatment for Parkinson’s diseases (PD). However, knowledge on local electrophysiological biomarkers within the STN and their cortical connectivity profile is still scarce. Such information would be necessary for optimal positioning of the DBS leads based on PD network pathophysiology. This thesis describes the introduction and exploration of a novel technique for electrophysiological measurements during DBS surgery. Combined electroencephalography (EEG) with stepwise local field potentials recordings during insertion of the DBS lead was performed intraoperatively, thereby, allowing to capture local STN and cortico-subthalamic physiology with high speactral and spatial specificity. Our results revealed that strong beta oscillatory activity in the STN was located more dorsally than the STN-ipsilateral motor network phase coupling; the respective frequency bands were in the low and high beta-band, respectively. Moreover, the spot within the STN, where this STN-cortical phase coupling occurred, correlated highly with the STN spot where the phase of beta oscillations modulated the amplitude of high-frequency oscillations. This STN location was furthermore, characterized by information flowed from the ipsilateral motor cortex to the STN in the high beta-band suggesting a pathologically synchronized network with a direct STN-motor cortex connection via the hyperdirect pathway. Interestingly, the very same STN spot showed a resonance like responses to electrical stimulation suggesting a decoupling of pathologically synchronized STN-motor cortex connectivity during therapeutic DBS. In conclusion, this PhD thesis provides first evidence that macroelectrode recordings with the chronic electrode concurrent with EEG recordings are a reliable method for STN localization during DBS surgery. Additionally, combining LFP and EEG recordings during mapping of STN offered a new way of DBS targeting on the basis of pathological local biomarkers and network activity

Comparison of oscillatory activity in subthalamic nucleus in Parkinson's disease and dystonia

OBJECTIVES: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been successfully used to treat both Parkinson's disease (PD) and dystonia. Local field potentials (LFPs) recorded from the STN of PD patients demonstrate prominent beta frequency band activity. It is unclear whether such activity occurs in the STN in dystonia, and, if not, whether dystonia has another distinctive neural population activity in the STN. METHODS: Twelve patients with PD, and eight patients with dystonia underwent DBS electrode implantation targeting the STN. Seven dystonia patients were off medication and one was on aripiprazole and clonazepam. LFPs were recorded from the DBS electrodes in PD in the on/off medication states and in dystonia. Power spectra and temporal dynamics measured by the with Lempel-Ziv complexity of the LFPs were compared among these states. RESULTS: Normalised power spectra and Lempel-Ziv complexity of subthalamic LFPs differed between dystonia off and PD on/off, and between PD off and on over the low frequency, beta and high gamma bands. Patients with dystonia and off medication had lower beta power but higher low frequency and high gamma power than PD. Spectral power in the low beta frequency (11-20Hz) range was attenuated in medicated PD. CONCLUSION: The results suggest that dystonia and PD are characterized by different patterns of oscillatory activities even within the same nucleus, and exaggerated beta activity may relate to hypo-dopaminergic status

Advances in closed-loop deep brain stimulation devices

BACKGROUND: Millions of patients around the world are affected by neurological and psychiatric disorders. Deep brain stimulation (DBS) is a device-based therapy that could have fewer side-effects and higher efficiencies in drug-resistant patients compared to other therapeutic options such as pharmacological approaches. Thus far, several efforts have been made to incorporate a feedback loop into DBS devices to make them operate in a closed-loop manner. METHODS: This paper presents a comprehensive investigation into the existing research-based and commercial closed-loop DBS devices. It describes a brief history of closed-loop DBS techniques, biomarkers and algorithms used for closing the feedback loop, components of the current research-based and commercial closed-loop DBS devices, and advancements and challenges in this field of research. This review also includes a comparison of the closed-loop DBS devices and provides the future directions of this area of research. RESULTS: Although we are in the early stages of the closed-loop DBS approach, there have been fruitful efforts in design and development of closed-loop DBS devices. To date, only one commercial closed-loop DBS device has been manufactured. However, this system does not have an intelligent and patient dependent control algorithm. A closed-loop DBS device requires a control algorithm to learn and optimize the stimulation parameters according to the brain clinical state. CONCLUSIONS: The promising clinical effects of open-loop DBS have been demonstrated, indicating DBS as a pioneer technology and treatment option to serve neurological patients. However, like other commercial devices, DBS needs to be automated and modernized

The role of oscillation population activity in cortico-basal ganglia circuits.

The basal ganglia (BG) are a group of subcortical brain nuclei that are anatomically situated between the cortex and thalamus. Hitherto, models of basal ganglia function have been based solely on the anatomical connectivity and changes in the rate of neurons mediated by inhibitory and excitatory neurotransmitter interactions and modulated by dopamine. Depletion of striatal dopamine as occurs in Parkinson's Disease (PD) however, leads primarily to changes in the rhythmicity of basal ganglia neurons. The general aim of this thesis is to use frontal electrocorticogram (ECoG) and basal ganglia local field potential (LFP) recordings in the rat to further investigate the putative role for oscillations and synchronisation in these structures in the healthy and dopamine depleted brain. In the awake animal, lesion of the SNc lead to a dramatic increase in the power and synchronisation of P-frequency band oscillations in the cortex and subthalamic nucleus (STN) compared to the sham lesioned animal. These results are highly similar to those in human patients and provide further evidence for a direct pathophysological role for p-frequency band oscillations in PD. In the healthy, anaesthetised animal, LFPs recorded in the STN, globus pallidus (GP) and substantia nigra pars reticulata (SNr) were all found to be coherent with the ECoG. A detailed analysis of the interdependence and direction of these activities during two different brain states, prominent slow wave activity (SWA) and global activation, lead to the hypothesis that there were state dependant changes in the dominance of the cortico-subthalamic and cortico-striatal pathways. Multiple LFP recordings in the striatum and GP provided further evidence for this hypothesis, as coherence between the ECoG and GP was found to be dependent on the striatum. Together these results suggest that oscillations and synchronisation may mediate information flow in cortico-basal ganglia networks in both health and disease

Experimental and Model-based Approaches to Directional Thalamic Deep Brain Stimulation

University of Minnesota Ph.D. dissertation. September 2016. Major: Biomedical Engineering. Advisor: Matthew Johnson. 1 computer file (PDF); xii, 181 pages.Deep brain stimulation (DBS) is an effective surgical procedure for the treatment of several brain disorders. However, the clinical successes of DBS hinges on several factors. Here, we describe the development of tools and methodologies in the context of thalamic DBS for essential tremor (ET) to address three key challenges: 1) accurate localization of nuclei and fiber pathways for stimulation, 2) model-based programming of high-density DBS electrode arrays (DBSA) and 3) in vivo assessment of computational DBS model predictions. We approached the first challenge through a multimodal imaging approach, utilizing high-field (7T) susceptibility-weighted imaging and diffusion-weighted imaging data. A nonlinear image deformation algorithm was used in conjunction with probabilistic fiber tractography to segment individual thalamic sub-nuclei and reconstruct their afferent fiber pathways. We addressed the second challenge by developing subject-specific computational model-based algorithms built on maximizing population activating function values within a target region using convex optimization principles. The algorithms converged within seconds and only required as many finite-element simulations as the number of electrodes on the DBSA being modeled. For the third challenge, we recorded (in two non-human primates) unit-spike data from neurons in the vicinity of chronically implanted thalamic DBSAs before, during and after high-frequency stimulation. A novel entropy-based method was developed to quantify the degree and significance of stimulation-induced changes in neuronal firing pattern. Results indicated that neurons modulated by thalamic DBS were distributed and not confined to the immediate proximity of the active electrode. For those that were modulated by DBS, their responses increasingly shifted from firing rate modulation to firing pattern modulation with increased stimulation amplitude. Additionally, strong low-pass filtering effect was observed where <4% of DBS pulses produced phase-locked spikes in cells exhibiting significant excitatory firing pattern modulation. Finally, we quantified the spatial distribution of neurons modulated by DBS by developing a novel spherical statistical framework for analysis. Together, these tools and methodologies are poised to improve our understanding of DBS mechanisms and improve the efficacy and efficiency of DBS therapy

An entropy-based investigation of underpinnings and impact of oscillations in a model of PD

The involvement of the basal ganglia in motor control has been highlighted in studies of Parkinson’s disease (PD) and other movement disorders. The loss of dopaminergic neurons in the substantia nigra pars compacta and subsequent decrease of the dopamine level in the basal ganglia is recognized as the hallmark of PD. The classical view of the architecture of the dopamine depleted basal ganglia-thalamo-cortical circuit identifies changes in firing rates as the probable cause for the motor impairments in PD. Yet, more recent findings have shown that disturbances in other intrinsic dynamical properties of these networks may also contribute to motor deficits. Electrophysiological recordings in the basal ganglia of deep brain stimulation (DBS) patients (when OFF stimulation) have found pathological oscillations at beta frequency (13-30 Hz). This abnormal oscillatory activity has also been found in basal ganglia nuclei of animal models of PD. Additionally, the beta frequency oscillations were found to decrease when the patients are on dopamine replacement therapies and as they initiate movement. Beta frequency oscillations have been identified in the firing of single neurons and in the coupling of discharges between neurons. Within the framework of information theory, we proposed a time series model to analyse and relate the effects of changes in the dynamics of individual factors – such as alterations in firing rates, oscillations and synchrony (or auto and cross-correlations) caused by dopamine depletion – on the coding capacity (i.e., entropy) of a network. We estimated the entropy of a neural network based on the probabilities of current spiking conditioned on the observation of firing rate and spiking history of the current neuron and of neighbouring neurons. Moreover, we could estimate entropies for each of these factors separately, in healthy and dopamine depleted conditions, and assess their relative contribution to the decrease of coding capacity in disease. Furthermore, the causal characteristics of the model made it possible to compare the synaptic connectivity of neuronal populations in health with that in disease, by measuring the amount of directed information transferred between populations. We employed the model to study the external globus pallidus (GPe) network in control and 6-hydroxydopamine (6-OHDA) lesioned rats – a model for PD. We found a significant decrease in the coding capacity in lesioned animals, compared to controls, and that this decrease was predominantly on account of a reduction in the GPe firing rates. Although to a lesser extent, the amplification of the oscillatory activity (mainly in the beta frequency range) observed in the lesioned animals had also a significant impact on the reduction of their coding capacity. The higher synchrony found in the 6-OHDA rats had the least effect. We also found that the levels of coding capacity in the GPe were restored to levels close to control when the lesioned animals were treated with the dopamine agonist apomorphine. In addition, we detected a stronger coupling between the subthalamic nucleus (STN) and the GPe in the dopamine depleted rats, pointing to an abnormally exaggerated transfer of information within this network. We have shown that the GPe and the STN-GPe networks in the dopamine depleted rat exhibit information processing irregularities. We believe these deficits in processing and relaying information may also be present in other structures of the basal ganglia-thalamo-cortical circuit and that they may underlie the motor impairment in PD