Analytical methods and experimental approaches for electrophysiological studies of brain oscillations

Brain oscillations are increasingly the subject of electrophysiological studies probing their role in the functioning and dysfunction of the human brain. In recent years this research area has seen rapid and significant changes in the experimental approaches and analysis methods. This article reviews these developments and provides a structured overview of experimental approaches, spectral analysis techniques and methods to establish relationships between brain oscillations and behaviour

Functional network correlates of language and semiology in epilepsy

Epilepsy surgery is appropriate for 2-3% of all epilepsy diagnoses. The goal of the presurgical workup is to delineate the seizure network and to identify the risks associated with surgery. While interpretation of functional MRI and results in EEG-fMRI studies have largely focused on anatomical parameters, the focus of this thesis was to investigate canonical intrinsic connectivity networks in language function and seizure semiology. Epilepsy surgery aims to remove brain areas that generate seizures. Language dysfunction is frequently observed after anterior temporal lobe resection (ATLR), and the presurgical workup seeks to identify the risks associated with surgical outcome. The principal aim of experimental studies was to elaborate understanding of language function as expressed in the recruitment of relevant connectivity networks and to evaluate whether it has value in the prediction of language decline after anterior temporal lobe resection. Using cognitive fMRI, we assessed brain areas defined by parameters of anatomy and canonical intrinsic connectivity networks (ICN) that are involved in language function, specifically word retrieval as expressed in naming and fluency. fMRI data was quantified by lateralisation indices and by ICN_atlas metrics in a priori defined ICN and anatomical regions of interest. Reliability of language ICN recruitment was studied in 59 patients and 30 healthy controls who were included in our language experiments. New and established language fMRI paradigms were employed on a three Tesla scanner, while intellectual ability, language performance and emotional status were established for all subjects with standard psychometric assessment. Patients who had surgery were reinvestigated at an early postoperative stage of four months after anterior temporal lobe resection. A major part of the work sought to elucidate the association between fMRI patterns and disease characteristics including features of anxiety and depression, and prediction of postoperative language outcome. We studied the efficiency of reorganisation of language function associated with disease features prior to and following surgery. A further aim of experimental work was to use EEG-fMRI data to investigate the relationship between canonical intrinsic connectivity networks and seizure semiology, potentially providing an avenue for characterising the seizure network in the presurgical workup. The association of clinical signs with the EEG-fMRI informed activation patterns were studied using the data from eighteen patients’ whose seizures and simultaneous EEG-fMRI activations were reported in a previous study. The accuracy of ICN_atlas was validated and the ICN construct upheld in the language maps of TLE patients. The ICN construct was not evident in ictal fMRI maps and simulated ICN_atlas data. Intrinsic connectivity network recruitment was stable between sessions in controls. Amodal linguistic processing and the relevance of temporal intrinsic connectivity networks for naming and that of frontal intrinsic connectivity networks for word retrieval in the context of fluency was evident in intrinsic connectivity networks regions. The relevance of intrinsic connectivity networks in the study of language was further reiterated by significant association between some disease features and language performance, and disease features and activation in intrinsic connectivity networks. However, the anterior temporal lobe (ATL) showed significantly greater activation compared to intrinsic connectivity networks – a result which indicated that ATL functional language networks are better studied in the context of the anatomically demarked ATL, rather than its functionally connected intrinsic connectivity networks. Activation in temporal lobe networks served as a predictor for naming and fluency impairment after ATLR and an increasing likelihood of significant decline with greater magnitude of left lateralisation. Impairment of awareness served as a significant classifying feature of clinical expression and was significantly associated with the inhibition of normal brain functions. Canonical intrinsic connectivity networks including the default mode network were recruited along an anterior-posterior anatomical axis and were not significantly associated with clinical signs

High-Density Diffuse Optical Tomography During Passive Movie Viewing: A Platform for Naturalistic Functional Brain Mapping

Human neuroimaging techniques enable researchers and clinicians to non-invasively study brain function across the lifespan in both healthy and clinical populations. However, functional brain imaging methods such as functional magnetic resonance imaging (fMRI) are expensive, resource-intensive, and require dedicated facilities, making these powerful imaging tools generally unavailable for assessing brain function in settings demanding open, unconstrained, and portable neuroimaging assessments. Tools such as functional near-infrared spectroscopy (fNIRS) afford greater portability and wearability, but at the expense of cortical field-of-view and spatial resolution. High-Density Diffuse Optical Tomography (HD-DOT) is an optical neuroimaging modality directly addresses the image quality limitations associated with traditional fNIRS techniques through densely overlapping optical measurements. This thesis aims to establish the feasibility of using HD-DOT in a novel application demanding exceptional portability and flexibility: mapping disrupted cortical activity in chronically malnourished children. I first motivate the need for dense optical measurements of brain tissue to achieve fMRI-comparable localization of brain function (Chapter 2). Then, I present imaging work completed in Cali, Colombia, where a cohort of chronically malnourished children were imaged using a custom HD-DOT instrument to establish feasibility of performing field-based neuroimaging in this population (Chapter 3). Finally, in order to meet the need for age appropriate imaging paradigms in this population, I develop passive movie viewing paradigms for use in optical neuroimaging, a flexible and rich stimulation paradigm that is suitable for both adults and children (Chapter 4)

Examining targeted brain stimulation to improve vigilant attention in right-hemispheric stroke

Neglect is a disabling neuropsychological syndrome frequently observed following right-hemispheric stroke. Affected individuals present with attentional deficits, ranging from a difficulty in orienting towards the contralesional space to a generalised difficulty with maintaining attention over time. Neglect may be persistent - particularly its non-lateralised component. This thesis focused on investigating the efficacy of a potential treatment involving non-invasive targeted brain stimulation to improve vigilant attention. In a randomised double-blind sham-controlled crossover study, healthy individuals across the lifespan and stroke patients with attentional impairments received real and sham transcranial direct current stimulation (tDCS) whilst performing a vigilance task. A high-definition montage was used to constrain current delivery over the right dorsolateral prefrontal cortex, a key region of the vigilance network. Results show that, at the group level, targeted tDCS improved target detection across all groups. By examining performance across temporal epochs, it was noted that tDCS did not impede worsening of performance with increasing time-on-task. The superiority of tDCS was however found throughout the task, outlasting stimulation delivery. A lesion anatomy study indicated that task performance was related to lesion location rather than volume. In addition, variability in patients' response to treatment was observed and linked to lesion profile, revealing that damage to specific brain regions caused lack of tDCS response. Finally, a concurrent tDCS-fMRI study was conducted to examine brain network response to tDCS. Brain stimulation did not affect local connectivity, but rather influenced functional connectivity within large-scale networks in the contralateral hemisphere. This finding emerged across groups using different analysis approaches, confirming its robustness. This systematic behavioural and imaging investigation supports a role of tDCS to improve non-lateralised deficits of neglect, which could be harnessed in future clinical trials. Furthermore, it sheds light on network response to precise cortical targeting, revealing its widespread effect.Open Acces

Investigating the neural basis of self-awareness deficits following traumatic brain injury

Self-awareness deficits are a common and disabling consequence of traumatic brain injury (TBI). ‘On-line’ awareness is one facet of self-awareness that can be studied by examining how people monitor their performance and respond to their errors. Performance monitoring, like many of the cognitive functions disrupted after TBI, is believed to depend on the coordinated activity of neural networks. The fronto-parietal control network (FPCN) is one such network that contains a sub-network called the salience network (SN). The SN consists of the dorsal anterior cingulate (dACC) and bilateral insulae cortex and is thought to monitor salient events (e.g. errors). I used advanced structure and function MRI techniques to investigate these networks and test two overarching hypotheses: first, performance monitoring is regulated by regions within the FPCN; and second, dysfunction of the FPCN leads to impaired self-awareness after TBI. My first study demonstrated two distinct frontal networks that respond to different error types. Predictable/internally signalled errors caused SN activation; whereas unpredictable/externally signalled errors caused activation of the ventral attentional network, a network thought to respond to unexpected events. This suggested the presence of parallel performance monitoring systems within the FPCN. My second study established that the ‘driving’ input into the SN originated in right anterior insula and subsequent behavioural adaptation was regulated by enhanced effective connectivity from the dACC to the left anterior insula. In my third study I identified a large group of TBI patients with impaired performance monitoring. These patients had additional metacognitive evidence of impaired self-awareness and demonstrated reduced functional connectivity between the dACC and the remainder of the FPCN at ‘rest’, and abnormally large insulae activation in response to errors. These studies clarified how the brain monitors and responds to salient events; and, provided evidence that self-awareness deficits after TBI are due to FPCN dysfunction, identifying this network as a potential target for future treatments.Open Acces

Neuroimaging the consciousness of self: Review, and conceptual-methodological framework

We review neuroimaging research investigating self-referential processing (SRP), that is, how we respond to stimuli that reference ourselves, prefaced by a lexical-thematic analysis of words indicative of “self-feelings”. We consider SRP as occurring verbally (V-SRP) and non-verbally (NV-SRP), both in the controlled, “top-down” form of introspective and interoceptive tasks, respectively, as well as in the “bottom-up” spontaneous or automatic form of “mind wandering” and “body wandering” that occurs during resting state. Our review leads us to outline a conceptual and methodological framework for future SRP research that we briefly apply toward understanding certain psychological and neurological disorders symptomatically associated with abnormal SRP. Our discussion is partly guided by William James’ original writings on the consciousness of self

Investigating the neural correlates of ongoing experience

Spontaneous thoughts are heterogeneous and inherently dynamic. Despite their time-variant properties, studies exploring spontaneous thoughts have identified thematic patterns that exhibit trait-like characteristics and are stable across time. Concurrently, structural and functional neuroimaging studies have shown unique and stable whole-brain network configurations linked to behaviour either through the static and dynamic intrinsic communication and activity of their core regions or through informational exchange with each other. This thesis aimed to explore how these within and between network interactions at different temporal scales might relate to variations in ongoing experience. We utilised different neuroimaging modalities (diffusion weighted and functional magnetic resonance imaging) and applied both static and dynamic analyses techniques. We found evidence of inter-individual variation in all cases associated with different patterns of spontaneous thoughts. Experiment 1 found that variation in white matter architecture projecting to the hippocampus, as well as the stable functional interaction of the hippocampus with the medial prefrontal cortex were linked to the tendency of experiencing thoughts related to the future or the past. Experiment 2 found that static functional connectivity of the precuneus and a lateral fronto-temporal network was related to visual imagery. Furthermore, we found that coupling of a lateral visual network with regions of the brainstem and cerebellum was associated with ruminative thinking, self-consciousness and attentional problems. Importantly, our results highlighted an interaction among these associations, where the brainstem visual network coupling moderated the relationship between parietal-frontal regions and reports of visual imagery. Finally, Experiment 3 used hidden Markov modelling to identify dynamic neural states linked to thoughts related to problem-solving and less intrusive thinking, as well as better physical and mental health. Collectively, these studies highlight the utility of using both static and dynamic measures of neural function to understand patterns of ongoing experience

The flexibly ordered brain

I investigate the human brain systems involved in the cognitive control of behaviour. Using novel cognitive paradigms and brain imaging, I identify brain systems that support the flexible structuring of behaviour. I then observe how these systems are implicated in patients with depression as they respond to psilocybin therapy. In the first of three experiments, I observe the changes in healthy adult brain activation that are associated with task-switching. This demonstrated that remapping rules introduces a switching-cost to response speed and activates the multiple-demand (MD) network. Critically, switching-costs and MD activation were greater when the rules being remapped were of an abstract and higher-order nature. Going deeper, in the second experiment, I investigate how healthy adult brains mitigate switching-costs by structuring behaviour into efficient routines. I observe that learning to optimise and structure behaviour covaries with changes in MD and default mode network (DMN) activation alongside increases in between-network connectivity. These concurrent behavioural and neural adaptations imply that cognitive demand is minimised when behavioural routines are structured. Indeed, these mechanisms are known to have broad roles in flexibly adapting behaviour and, subsequently, they have been implicated in disorders such as depression. Using these insights, in the third experiment, I examine the neural basis of the treatment response to psilocybin in patients with depression. In two clinical trials, I find that treatment response covaried with global increases in between-network connectivity. Converging functional cartography measures indicated that this global shift in network organisation related to increased dynamic flexibility and integration of the MD and DMN. Together, the findings in this thesis indicate that a ‘flexibly ordered brain’, the adaptive sequencing of neurocognitive states, is a necessary feature of well-being and for successfully navigating the demands of daily life.Open Acces

Task-based fMRI investigation of the newborn brain: sensorimotor development and learning

Human brain development relies upon the interaction between genetic and environmental factors, and the latter plays a critical role during the perinatal period. In this period, neuronal plasticity through experience-dependent activity is enhanced in the sensory systems, and drive the maturation of the brain. While plasticity is essential for maturation, it is also a source of vulnerability as altered early experiences may interact with the normal course of development. This is particularly evident in infants born preterm, who are prematurely exposed to a sensory-rich environment, and at risk or neurodevelopmental disorders. In keeping with the somatosensory system being at a critical period for development during late gestation, sensorimotor disorders, such as cerebral palsy, are more common in preterm compared with full-term born infants. It is therefore important to understand the normal trajectory of sensorimotor development and how this may be moulded by early sensory experiences. It is well acknowledged that the sensorimotor cortex is topographically organised so that different body parts map to a specific location within the cortex and this map is generally referred to as the ``homunculus". Although the somatotopy has been well characterised in the mature brain, it remains unknown when this organisation emerges during development. Animal studies hints that functional cortical maps might emerge across the equivalent period to the third trimester of human gestation, nevertheless there is currently no evidence. Therefore, I first investigated the topography of the preterm somatosensory cortex in a group of newborn infants. In this purpose I used fMRI and automated robotic tools and measured the functional responses to different sensory simulations (delivered to the mouth, wrists and ankles). The results provide evidence that it is possible to identify distinct areas in the somatosensory cortex devoted to different body parts even in the preterm brain supporting the presence of an immature \textit{homunculus}. Next, I wanted to investigate how activity and development in the sensorimotor system are influenced by experience. Experience-dependent plasticity is the basis of learning (e.g. adaptive behaviour), which is observed in newborn infants. Associative learning in particular has been widely investigated in infants, however, the underlining neuronal processes have previously been poorly understood. To study the neural correlates of associative learning in newborn infants, I developed and used a classical conditioning paradigm in combination with robot-assisted fMRI. The results confirm that associative learning can occur even at this early stage of life and with non-aversive stimuli. More importantly, I could observe learning-induced changes in brain activity within the primary sensory cortices, suggesting that such experience can shape cortical circuitry and is likely to influence early brain development.Open Acces