Oscillatory Network Activity in Brain Functions and Dysfunctions

Recent experimental studies point to the notion that the brain is a complex dynamical system whose behaviors relating to brain functions and dysfunctions can be described by the physics of network phenomena. The brain consists of anatomical axonal connections among neurons and neuronal populations in various spatial scales. Neuronal interactions and synchrony of neuronal oscillations are central to normal brain functions. Breakdowns in interactions and modifications in synchronization behaviors are usual hallmarks of brain dysfunctions. Here, in this dissertation for PhD degree in physics, we report discoveries of brain oscillatory network activity from two separate studies. These studies investigated the large-scale brain activity during tactile perceptual decision-making and epileptic seizures. In the perceptual decision-making study, using scalp electroencephalography (EEG) recordings of brain potentials, we investigated how oscillatory activity functionally organizes different neocortical regions as a network during a tactile discrimination task. While undergoing EEG recordings, blindfolded healthy participants felt a linear three-dot array presented electromechanically, under computer control, and reported whether the central dot was offset to the left or right. Based on the current dipole modeling in the brain, we found that the source-level peak activity appeared in the left primary somatosensory cortex (SI), right lateral occipital complex (LOC), right posterior intraparietal sulcus (pIPS) and finally left dorsolateral prefrontal cortex (dlPFC) at 45, 130, 160 and 175 ms respectively. Spectral interdependency analysis showed that fine tactile discrimination is mediated by distinct but overlapping ~15 Hz beta and ~80 Hz gamma band large-scale oscillatory networks. The beta-network that included all four nodes was dominantly feedforward, similar to the propagation of peak cortical activity, implying its role in accumulating and maintaining relevant sensory information and mapping to action. The gamma-network activity, occurring in a recurrent loop linked SI, pIPS and dlPFC, likely carrying out attentional selection of task-relevant sensory signals. Behavioral measure of task performance was correlated with the network activity in both bands. In the study of epileptic seizures, we investigated high-frequency (\u3e 50 Hz) oscillatory network activity from intracranial EEG (IEEG) recordings of patients who were the candidates for epilepsy surgery. The traditional approach of identifying brain regions for epilepsy surgery usually referred as seizure onset zones (SOZs) has not always produced clarity on SOZs. Here, we investigated directed network activity in the frequency domain and found that the high frequency (\u3e80 Hz) network activities occur before the onset of any visible ictal activity, andcausal relationships involve the recording electrodes where clinically identifiable seizures later develop. These findings suggest that high-frequency network activities and their causal relationships can assist in precise delineation of SOZs for surgical resection

Estudo neurofisiológico da discriminação de distância em humanos

Tactile width discrimination processing has been extensively studied in rodents and has demonstrated multiple relevant basic mechanisms. Despite this relevance, the number of studies of width discrimination in humans has been scarce. During the present dissertation, neurophysiological correlates of width discrimination were analyzed through electroencephalography recordings in participants performing a width discrimination task in active or passive modes. Analysis of power in the delta, theta, alpha, beta, and gamma frequency bands revealed differences in the power for different frequency bands and electrodes recorded. Active width discrimination processing was characterized by an increase in the power of delta, theta and gamma frequency bands in electrodes F3 and F4, and an increase in power in the gamma frequency band in T4. Passive tactile width processing was characterized by an increase in the power of delta in electrodes Fp1 and T4, and an increase in gamma frequency band in Tp10. Altogether these results suggest that active and passive tactile width discrimination processing are characterized by an asymmetrical network involving prefrontal, frontal and temporal electrodes, in delta, theta, and gamma frequency bands.O estudo do processamento tátil de distâncias encontra-se bastante desenvolvido em roedores, tendo sido útil para a demonstração de múltiplos mecanismos básicos relevantes. Apesar desta relevância, o estudo da discriminação de distâncias em humanos é ainda bastante reduzido. Durante a presente dissertação foram analisados os correlatos neurofisiológicos, através do registo de eletroencefalografia, em participantes que realizavam uma tarefa de discriminação de distância em modo ativo ou passivo. A análise da potência das bandas de frequências delta, teta, alfa, beta e gama revelou diferenças na potência do sinal para diferentes bandas de frequências e elétrodos. O processamento ativo era caracterizado por um aumento da potência nas bandas de frequências delta, teta e gama nos elétrodos F3, F4; e um aumento da atividade na banda de frequência gama no elétrodo T4. O processamento passivo era caracterizado por um aumento da potência de delta nos elétrodos Fp1 e T4 e um aumento da potência de gama em Tp10. No seu conjunto, estes resultados sugerem que o processamento ativo e passivo da distância são caraterizados por uma rede assimétrica envolvendo elétrodos pré-frontais, frontais e temporais nas bandas de frequência delta, teta e gama.Mestrado em Biomedicina Molecula

Neurophysiological correlates of tactile width discrimination in humans

Introduction: Tactile information processing requires the integration of sensory, motor, and cognitive information. Width discrimination has been extensively studied in rodents, but not in humans. Methods: Here, we describe Electroencephalography (EEG) signals in humans performing a tactile width discrimination task. The first goal of this study was to describe changes in neural activity occurring during the discrimination and the response periods. The second goal was to relate specific changes in neural activity to the performance in the task. Results: Comparison of changes in power between two different periods of the task, corresponding to the discrimination of the tactile stimulus and the motor response, revealed the engagement of an asymmetrical network associated with fronto-temporo-parieto-occipital electrodes and across multiple frequency bands. Analysis of ratios of higher [Ratio 1: (0.5–20 Hz)/(0.5–45 Hz)] or lower frequencies [Ratio 2: (0.5–4.5 Hz)/(0.5–9 Hz)], during the discrimination period revealed that activity recorded from frontal-parietal electrodes was correlated to tactile width discrimination performance between-subjects, independently of task difficulty. Meanwhile, the dynamics in parieto-occipital electrodes were correlated to the changes in performance within-subjects (i.e., between the first and the second blocks) independently of task difficulty. In addition, analysis of information transfer, using Granger causality, further demonstrated that improvements in performance between blocks were characterized by an overall reduction in information transfer to the ipsilateral parietal electrode (P4) and an increase in information transfer to the contralateral parietal electrode (P3). Discussion: The main finding of this study is that fronto-parietal electrodes encoded between-subjects’ performances while parieto-occipital electrodes encoded within-subjects’ performances, supporting the notion that tactile width discrimination processing is associated with a complex asymmetrical network involving fronto-parieto-occipital electrodes.info:eu-repo/semantics/publishedVersio

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

Exact explosive synchronization transitions in Kuramoto oscillators with time-delayed coupling

Synchronization commonly occurs in many natural and man-made systems, from neurons in the brain to cardiac cells to power grids to Josephson junction arrays. Transitions to or out of synchrony for coupled oscillators depend on several factors, such as individual frequencies, coupling, interaction time delays and network structure-function relation. Here, using a generalized Kuramoto model of time-delay coupled phase oscillators with frequency-weighted coupling, we study the stability ofincoherent and coherent states and the transitions to or out of explosive (abrupt, first-order like) phase synchronization. We analytically derive the exact formulas for the critical coupling strengths at different time delays in both directions of increasing (forward) and decreasing (backward) coupling strengths. We find that time-delay does not affect the transition for the backward direction but can shift the transition for the forward direction of increasing coupling strength. These results provide valuable insights into our understanding of dynamical mechanisms for explosive synchronization in presence of often unavoidable time delays present in many physical and biological systems

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

Neurocognitive and Neuroplastic Mechanisms of Novel Clinical Signs in CRPS.

Complex regional pain syndrome (CRPS) is a chronic, debilitating pain condition that usually arises after trauma to a limb, but its precise etiology remains elusive. Novel clinical signs based on body perceptual disturbances have been reported, but their pathophysiological mechanisms remain poorly understood. Investigators have used functional neuroimaging techniques (including MEG, EEG, fMRI, and PET) to study changes mainly within the somatosensory and motor cortices. Here, we provide a focused review of the neuroimaging research findings that have generated insights into the potential neurocognitive and neuroplastic mechanisms underlying perceptual disturbances in CRPS. Neuroimaging findings, particularly with regard to somatosensory processing, have been promising but limited by a number of technique-specific factors (such as the complexity of neuroimaging investigations, poor spatial resolution of EEG/MEG, and use of modeling procedures that do not draw causal inferences) and more general factors including small samples sizes and poorly characterized patients. These factors have led to an underappreciation of the potential heterogeneity of pathophysiology that may underlie variable clinical presentation in CRPS. Also, until now, neurological deficits have been predominantly investigated separately from perceptual and cognitive disturbances. Here, we highlight the need to identify neurocognitive phenotypes of patients with CRPS that are underpinned by causal explanations for perceptual disturbances. We suggest that a combination of larger cohorts, patient phenotyping, the use of both high temporal, and spatial resolution neuroimaging methods, and the identification of simplified biomarkers is likely to be the most fruitful approach to identifying neurocognitive phenotypes in CRPS. Based on our review, we explain how such phenotypes could be characterized in terms of hierarchical models of perception and corresponding disturbances in recurrent processing involving the somatosensory, salience and executive brain networks. We also draw attention to complementary neurological factors that may explain some CRPS symptoms, including the possibility of central neuroinflammation and neuronal atrophy, and how these phenomena may overlap but be partially separable from neurocognitive deficits.This is the final version of the article. It first appeared from Frontiers via http://dx.doi.org/10.3389/fnhum.2016.0001