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

The neurophysiology of intersensory selective attention and task switching

Our ability to selectively attend to certain aspects of the world and ignore others is fundamental to our day-to-day lives. The need for selective attention stems from capacity limitations inherent in our perceptual and cognitive processing architecture. Because not every elemental piece of our environment can be fully processed in parallel, the nervous system must prioritize processing. This prioritization is generally referred to as selective attention. Meanwhile, we are faced with a world that is constantly in flux, such that we have to frequently shift our attention from one piece of the environment to another and from one task to another. This process is generally referred to as task-switching. Neural oscillations in the alpha band (~8-14 Hz) have been shown to index the distribution of selective attention, and there is increasing evidence that oscillations in this band are in fact utilized by the nervous system to suppress distracting, task-irrelevant information. In order to elaborate on what is known of the function of alpha oscillations as well as current models of both intersensory selective attention and task switching, I investigated the dynamics of alpha amplitude modulations within the context of intersenory selective attention and task switching in neurologically typical young adults. Participants were alternately cued to attend to either the visual or auditory aspect of a compound audio-visual stimulus while high-density electroencephalography was recorded. It is typically found that alpha power increases over parieto-occipital cortices when attention is directed away from the visual modality and to the auditory modality. I report evidence that alpha oscillations play a role in task-switching (e.g., when switching from attending the visual task versus repeating this task), specifically as biasing signals, that may operate to re-weight competition among two tasks-sets. I further investigated the development of these same processes in school-aged children and adolescents. While exhibiting typical patterns of alpha modulations relevant to selective attention, Young school-aged children (8-12 years), compared to older participants, did not demonstrate specific task switching modulation of alpha oscillations, suggesting that this process does not fully develop until late adolescence. Finally, children and adolescents on the autism spectrum failed altogether to exhibit differentiation of alpha power between attend-visual and attend-auditory conditions--an effect present in age and IQ matched controls--suggesting that ASD individuals may have a deficit in the overall top-down deployment of alpha oscillatory biasing signals. This could result in an inability to ignore distracting information in the environment, leading to an overwhelming, disordered experience of the world, resulting in profound effects on the both social interaction and cognitive development. Altogether, these findings add to growing evidence that alpha oscillations serve as domain general biasing signals and are integral to our flexible goal-oriented behavior. Furthermore, the flexible use of these biasing signals in selective attention and task switching develops over a protracted period, and appears to be aberrant in autism spectrum disorder

Neuronal Network Oscillations in the Control of Human Movement

The overarching aim of this thesis was to use neuroimaging and neuromodulation techniques to further understand the relationship between cortical oscillatory activity and the control of human movement. Modulations in motor cortical beta and alpha activity have been consistently implicated in the preparation, execution, and termination of movement. Here, I describe the outcome of four studies designed to further elucidate these motor-related changes in oscillatory activity. In Chapter 3, I report the findings of a study that used an established behavioural paradigm to vary the degree of uncertainty during the preparation of movement. I demonstrate that preparatory alpha and beta desynchronisation reflect a process of disengagement from the existing network to enable the creation of functional assemblies required for movement. Importantly, I also demonstrate a novel neural signature of transient alpha synchrony, that occurs after preparatory desynchronisation, that underlies the recruitment of functional assemblies required for directional control. The study described in Chapter 4 was designed to further investigate the functional role of preparatory alpha and beta desynchronisation by entraining oscillatory activity in the primary motor cortex (M1) using frequency-specific transcranial alternating current stimulation. No significant effects of stimulation were found on participant response times. However, no clear conclusion could be drawn due to limitations of the stimulation parameters that were used. In Chapter 5, I explored the inverse relationship between M1 beta power and cortical excitability using single-pulse transcranial magnetic stimulation to elicit motor-evoked potentials (MEPs). The amplitude of MEPs collected during a period of beta desynchronisation was significantly greater than during a resting baseline. Conversely, the amplitude of MEPs collected during the post-movement beta rebound that follows the termination of a movement was significantly reduced compared to baseline. This finding confirms the inverse relationship between M1 beta power and cortical excitability. The study in Chapter 6 explored the effect of experimental context on M1 beta power. When the participant was cued to expect an upcoming motor task, resting beta power was significantly increased, then when the likelihood of an upcoming motor requirement decreased, there was a significant concurrent decrease in resting beta power. This reflects increased coherence and functional connectivity within M1 and other motor areas, to ‘recalibrate’ the motor system in preparation for a synchronous input signal to more readily recruit the required functional assembly

Oscillatory activity in the basal ganglia - is it relevant to movement disorders therapy?

Chronic high frequency stimulation of the basal ganglia can be a highly effective intervention for movement disorders in patients. In the past decade, therapeutic benefits have been seen with stimulation of the subthalamic nucleus and globus pallidus interna for Parkinson's disease (PD) and dystonia, respectively. These procedures have allowed direct recording of basal ganglia activity and have suggested that abnormal synchronisation of neurons in these nuclei may contribute to motor impairment. This thesis explores the possible correlation between synchronised activity in the basal ganglia, as evidenced by oscillations in local field potentials, and movement disorders. In Chapter 3, we demonstrate the correlation between synchronization at frequencies under 10 Hz in the globus pallidus interna and dystonic EMG. This low frequency activity is shown to be locked to neuronal activity within GPi in patients with dystonia (Chapter 4). Deep brain stimulation is thought to suppress spontaneous pathological activity in the basal ganglia. Equally, however, it must also suppress any residual physiological activity in these nuclei. In Chapter 5, we demonstrate that the basal ganglia are involved in the processing of simple limb movements in the human, by separating the effects of deep brain stimulation on pathological and physiological activities based on baseline task performance. An impairment of motor performance was seen during high frequency stimulation in those patients with the best task performance at baseline. This deleterious effect, however, should be distinguished from the effect of direct stimulation at 20 Hz in Parkinson's disease. Oscillatory activity at around 20 Hz is thought to be a core feature in Parkinson's disease. In Chapter 6, we demonstrate that the excessive synchronization imposed by stimulation of the subthalamic nucleus at 20 Hz slows movement, in those patients with the best task performance at baseline. This supports the notion that synchronization around 20 Hz may be causally linked to bradykinesia. Last, the therapeutic effectiveness of DBS therapy for patients with PD partially relies on the accurate localisation of the motor region of the subthalamic nucleus. In Chapter 7, we propose an alternative method for the localization of this region using the spontaneous pathological 20 Hz activity to be found in this nucleus. The findings of these studies provide evidence that basal ganglia oscillatory activities of differing frequencies contribute to movement disorders

Translational pipelines for closed-loop neuromodulation

Closed-loop neuromodulation systems have shown significant potential for addressing unmet needs in the treatment of disorders of the central nervous system, yet progress towards clinical adoption has been slow. Advanced technological developments often stall in the preclinical stage by failing to account for the constraints of implantable medical devices, and due to the lack of research platforms with a translational focus. This thesis presents the development of three clinically relevant research systems focusing on refinements of deep brain stimulation therapies. First, we introduce a system for synchronising implanted and external stimulation devices, allowing for research into multi-site stimulation paradigms, cross-region neural plasticity, and questions of phase coupling. The proposed design aims to sidestep the limited communication capabilities of existing commercial implant systems in providing a stimulation state readout without reliance on telemetry, creating a cross-platform research tool. Next, we present work on the Picostim-DyNeuMo adaptive neuromodulation platform, focusing on expanding device capabilities from activity and circadian adaptation to bioelectric marker--based responsive stimulation. Here, we introduce a computationally optimised implementation of a popular band power--estimation algorithm suitable for deployment in the DyNeuMo system. The new algorithmic capability was externally validated to establish neural state classification performance in two widely-researched use cases: Parkinsonian beta bursts and seizures. For in vivo validation, a pilot experiment is presented demonstrating responsive neurostimulation to cortical alpha-band activity in a non-human primate model for the modulation of attention state. Finally, we turn our focus to the validation of a recently developed method to provide computationally efficient real-time phase estimation. Following theoretical analysis, the method is integrated into the commonly used Intan electrophysiological recording platform, creating a novel closed-loop optogenetics research platform. The performance of the research system is characterised through a pilot experiment, targeting the modulation of cortical theta-band activity in a transgenic mouse model

Neural mechanisms of attention and speech perception in complex, spatial acoustic environment

We can hold conversations with people in environments where typically there are additional simultaneous talkers in background acoustic space or noise like vehicles on the street or music playing at a café on the sidewalk. This seemingly trivial everyday task is difficult for people with hearing deficits and is extremely hard to model in machines. This dissertation focuses on exploring the neural mechanisms of how the human brain encodes such complex acoustic environments and how cognitive processes like attention shapes processing of the attended speech. My initial experiments explore the representation of acoustic features that help us localize single sound sources in the environment- features like direction and spectrotemporal content of the sounds, and the interaction of these representations with each other. I play natural American English sentences coming from five azimuthal directions in space. Using intracranial electrocorticography (ECoG) recordings from the human auditory cortex of the listener, I show that the direction of sound and the spectrotemporal content are encoded in two distinct aspects of neural response, the direction modulates the mean of the response and the spectrotemporal features contributes to the modulation of neural response around its mean. Furthermore, I show that these features are orthogonal to each other and do not interact. This representation enables successful decoding of both spatial and phonetic information. These findings contribute to defining the functional organization of responses in the human auditory cortex, with implications for more accurate neurophysiological models of spatial speech processing. I take a step further to investigate the role of attention in encoding the direction and phonetic features of speech. I play a mixture of male and female spatialized talkers eg. male at left side to the listener and female at right side (talker’s locations switch randomly after each sentence). I ask the listener to follow a given talker e.g. follow male talker as they switch their location after each uttered sentence. While the listener performs this experiment, I collect intracranial EEG data from their auditory cortex. I investigate the bottom-up stimulus dependent and attention independent encoding of such a cocktail party speech and the top-down attention driven role in the encoding of location and speech features. I find a bottom-up stimulus driven contralateral preference in encoding of the mixed speech i.e. Left brain hemisphere automatically and predominantly encodes speech coming from right direction and vice-versa. On top of this bottom-up representation, I find that attended talker’s direction modulates the baseline of the neural response and attended talker’s voice modulates the spectrotemporal tuning of the neural response. Moreover, the modulation to attended talker’s location is present throughout the auditory cortex but the modulation to attended talker’s voice is present only at higher order auditory cortex areas. My findings provide crucially needed evidence to determine how bottom-up and top-down signals interact in the auditory cortex in crowded and complex acoustic scenes to enable robust speech perception. Furthermore, they shed light on the hierarchical encoding of attended speech that have implications on bettering the auditory attention decoding models. Finally, I talk about a clinical case study where we show that electrical stimulation to specific sites in planum temporale (PT) of an epilepsy patient implanted with intracranial electrode leads to enhancement in speech in noise perception. When noisy speech is played with such an electrical stimulation, the patient perceives that the noise disappears, and that the speech is similar to clean speech that they hear without any noise. We performed series of analysis to determine functional organization of the three main sub regions of the human auditory cortex- planum temporale (PT), Heschl’s gyrus (HG) and superior temporal gyrus (STG). Using Cortico-Cortical Evoked Potentials (CCEPs), we modeled the PT sites to be located between the sites in HG and STG. Furthermore, we find that the discriminability of speech from nonspeech sounds increased in population neural responses from HG to the PT to the STG sites. These findings causally implicate the PT in background noise suppression and may point to a novel potential neuroprosthetic solution to assist in the challenging task of speech perception in noise. Together, this dissertation shows new evidence for the neural encoding of spatial speech; interaction of stimulus driven, and attention driven neural processes in spatial multi-talker speech perception and enhancement of speech in noise perception by electrical brain stimulation

EEG and TMS-EEG Studies on the Cortical Excitability and Plasticity associated with Human Motor Control and Learning

More than half of the activities of daily living rely on upper limb functions (Ingram et al., 2008). Humans perform upper limb movements with great ease and flexibility but even simple tasks require complex computations in the brain and can be affected following stroke leaving survivors with debilitating movement impairments. Hemispheric asymmetries related to motor dominance, imbalances between contralateral and ipsilateral primary motor cortices (M1) activity and the ability to adapt movements to novel environments play a key role in upper limb motor control and can affect recovery. Motor learning and control are critical in neurorehabilitation, however to effectively integrate these concepts into upper limb recovery treatments, a deeper understanding of the basic mechanisms of unimanual control is needed. This thesis aimed to investigate hemispheric asymmetries related to motor dominance, to evaluate the relative contribution of the contralateral and ipsilateral M1 during unilateral reaching preparation and finally to identify the neural correlates underlying the formation of a predictive internal model enabling to adapt movements to new environments. To this end electroencephalography (EEG), transcranial magnetic stimulation (TMS), simultaneous TMS-EEG were employed during a simple motor and a highly standardised robot-mediated task. The first study used TMS-EEG to examine differences in cortical excitability related to motor dominance by applying TMS over the dominant and non-dominant M1 at rest and during contraction. No hemispheric asymmetries related to hand dominance were found. The second study assessed the temporal dynamics of bi-hemispheric motor cortical excitability during right arm reaching preparation. TMS was applied either to the ipsilateral or contralateral M1 during different times of movement preparation. Significant bilateral M1 activation during unilateral reaching preparation was observed, with no significant differences between the contralateral and ipsilateral M1. Unimanual reaching preparation was associated with significant interactions of excitatory and inhibitory processes in both motor cortices. The third study investigated the neural correlates of motor adaptation. EEG was recorded during a robot-mediated adaptation task involving right arm reaching movements and cortical excitability was assessed by applying TMS over the contralateral M1 and simultaneously recording TMS responses with EEG before and after motor adaptation. It was found that an error-related negativity (ERN) over fronto-central regions correlated with performance improvements during adaptation, suggesting that this neural activity reflects the formation of a predictive internal model. Motor adaptation underlay significant modulations in cortical excitability (i.e. neuroplasticity) in sensorimotor regions. Finally, it was shown that native cortical excitability was linked to motor learning improvements during motor adaptation and explained the variability in motor learning across individuals. These experiments demonstrated that even unimanual motor control relies on interactions between excitatory and inhibitory mechanisms not only in the contralateral M1 but in a wider range of brain regions, shown by a bi-hemispheric activity during movement preparation, the formation of a predictive model in fronto-central regions during motor adaptation and neuroplastic changes in sensorimotor regions underlying motor adaptation during unimanual reaching