Deep brain stimulation for disorders of consciousness and diminished motivation:A search for awakenings

This thesis deals with patients who are amongst the most severely affected after severe brain injury: those with permanent disorders of consciousness or diminished motivation. The research in this thesis is an attempt to improve consciousness and the general behavioral performance of these patients with the use of experimental interventions, including medication (such as zolpidem), and more invasive procedures, such as deep brain stimulation (DBS). The thesis contains extensive descriptions of the role of the intralaminar thalamus in the arousal regulation system, the importance of recognizing and treating secondary complications after brain injury, such as hydrocephalus, as well as a pathophysiological elaboration on akinetic mutism: a severe disorder of diminished motivation. Moreover, it describes the neurophysiological changes that accompany the paradoxical effects of zolpidem, a sleeping pill that temporarily induces ‘awakenings’ in some patients with severe brain injury. Further, it describes the first clinical and neurophysiological results of an N=6 trial of DBS in patients with a minimally conscious state and shows the importance of recognizing pathological changes from the brain’s ‘physiological baseline’ that seem to disturb normal brain functions. The thesis concludes with a description of the use of moral case deliberation in dealing with research dilemmas in patients with loss of autonomy after severe brain injury

Cortical and subcortical contributions to human cognitive flexibility

Cognitive flexibility enables individuals to respond adaptively to an ever-changing world. Neurally, flexibility is underpinned by involvement from across the cerebrum, and there is evidence from animal and human neuroscience suggesting that integration of cortical and thalamic signals in the striatum is necessary for appropriate behavioural control. A commonly used assay of flexibility is reversal learning, an associative learning task with high inter-species translatability. Evidence from animal literature has clearly defined the importance of the striatal cholinergic system in regulating striatal activity and output from the basal ganglia, and there is nascent evidence suggesting this system operates in a similar way in humans. However, there is a need to further disentangle the role of cortical, striatal, and thalamic regions during reversal learning in humans to better understand how the system works, and whether it has heterogeneous functionality in different contexts. Furthermore, as studying these processes is not trivial, further methodological work is required to enable us to understand the system. In chapter two we systematically assess an automated parcellation technique for identifying specific thalamic nuclei. Despite generally being treated as a homologous structure in neuroimaging work, nuclei within the thalamus have dissociable roles, and have diverse contributions to cognitive functioning, including reversal learning. We found mixed efficacy for segmentations across the thalamus, with some regions being more accurately defined relative to a “gold standard” atlas than others. Crucially, we find that the centromedian and parafascicular nuclei, which have an important role in reversal learning, are clearly defined and have little overlap with contiguous regions. These results show we can use this automated parcellation technique to identify specific thalamic nuclei that are relevant for cognitive flexibility and use these parcellations to study functionally relevant processes. Recent work has demonstrated that the functional relevance of the striatal cholinergic system can be studied in vivo using magnetic resonance spectroscopy by separating the peaks of different metabolites. But this non-conventional approach has not yet been widely adopted, and work is needed to determine its reliability. Chapter three presents test-retest reliability data on the use of magnetic resonance spectroscopy to study cholinergic activity in the striatum and cortex. We find measures of choline containing compounds are highly correlated when peaks are separated and when they are not. Across time we find that choline concentrations are relatively inconsistent, and that this was due to changes in the functionally relevant metabolite choline. Conversely, metabolites that we think are not functionally relevant were stable over time. We believe these differences may underly differences in acetylcholine function over time and may explain some intra-individual behavioural variability. In chapter four we use functional magnetic resonance imaging and psychophysiological interaction analysis to study corticostriatal and thalamostriatal connectivity during serial reversal learning. Functional connectivity between the centromedian-parafascicular nuclei of the thalamus and the associative dorsal striatum, and between the lateral-orbitofrontal cortex and the associative dorsal striatum was related to processing feedback during reversal learning. Specifically, thalamostriatal connectivity was found across the task, and may reflect a general error signal used to identify potential changes in context. Conversely, corticostriatal connectivity was found to be specific to when behaviour changed and suggests this may be a mechanism for the implementing adaptive change. We also show findings from exploratory work that may explain further how the cortex supports flexibility during reversal learning. Lastly, we used magnetic resonance spectroscopy to investigate whether the state of the cholinergic system at rest is related to reversal learning performance and latent measures of behaviour using computational modelling. Choline concentrations at rest showed significant functional relevance to our measures of reversal learning. More specifically, we found that errors during reversal learning, and learning rates for positive and negative prediction errors, explained significant variance in choline. However, the relationship between choline levels and task performance presented here differ from previous work which instead used a multi-alternative reversal learning task, and suggests that the striatal cholinergic system may have dissociable roles in different contexts. Overall, we show that the striatum, its cholinergic interneuron system, and its afferent projections from the cortex and thalamus, are associated with performance during serial reversal learning. Moreover, these findings suggest that the system may operate in separable ways in different contexts which may be dependent on internal representations of task structure

The Neurofunctional Model of Consciousness: The Physiological Interconnectivity of Brain Networks

The present chapter integrates neural networks’ connectivity into a model that explores consciousness and volitional behavior from a neurofunctional perspective. The model poses a theoretical evidenced-based framework that organizes the brain journey of neural information flow from the ascending reticular activating system and non-specific thalamic nuclei, to cortical networks, such as the default mode network and the fronto-parietal network. These inter-connected brain networks can be divided within three hierarchical and inter-connected “functional neural loops”: (1) the “brainstem-thalamic neural loop” for arousal, (2) the “thalamo-cortical neural loop” for neural information distribution throughout the brain, and (3) the “cortico-cortical neural loop” for transforming neural information into the contents of consciousness that the individual can perceive and manipulate voluntarily. These three neural loops act as a global functional neural system, and its disruption due to brain damage can cause a person to experience catastrophic outcomes, such as a coma, a vegetative state, a minimal conscious state, or other cognitive and behavioral impairments

Exploring the electrophysiological responses to sudden sensory events

Living in rapidly changing and potentially dangerous environments has shaped animal nervous systems toward high sensitivity to sudden and intense sensory events - often signalling threats or affordances requiring swift motor reactions. Unsurprisingly, such events can elicit both rapid behavioural responses (e.g. the defensive eye-blink) and one of the largest electrocortical responses recordable from the scalp of several animals: the widespread Vertex Potential (VP). While generally assumed to reflect sensory-specific processing, growing evidence suggests that the VP instead largely reflects supramodal neural activity, sensitive to the behavioural-relevance of the eliciting stimulus. In this thesis, I investigate the relationship between sudden events and the brain responses and behaviours they elicit. In Chapters 1-3, I give a general introduction to the topic. In Chapter 4, I dissect the sensitivity of the VP to stimulus intensity - showing that its amplitude is sensitive only to the relative increase of intensity, and not the absolute intensity. In Chapter 5, I show that both increases and decreases of auditory and somatosensory stimulus intensity elicit the same supramodal VP, demonstrating that the VP is sensitive to any sufficiently abrupt sensory change, regardless of its direction or sensory modality. In Chapter 6, I observe strong correlations between the magnitudes of the VP and the eye-blink elicited by somatosensory stimuli (hand-blink reflex; HBR), demonstrating a tight relationship between cortical activity and behaviour elicited by sudden stimuli. In Chapter 7, I explore this relationship further, showing that the HBR is sensitive to high-level environmental dynamics. In Chapter 8, I propose an account of the underlying neural substrate of the VP, consistent with my results and the literature, which elucidates the relationship between the VP and behaviour. I also detail future experiments using fMRI and intracranial recordings to test this hypothesis, using the knowledge gained from this thesis

Recurrent inhibitory network among cholinergic inerneurons of the striatum

textThe striatum is the initial input nuclei of the basal ganglia, and it serves as an integral processing center for action selection and sensorimotor learning. Glutamatergic projections from the cortex and thalamus converge with dense dopaminergic axons from the midbrain to provide the primary inputs to the striatum. Striatal output is then relayed to downstream basal ganglia nuclei by GABAergic medium – sized spiny neurons, which comprise at least 95% of the population of neurons in the striatum. The remaining population of local circuit neurons is dedicated to regulating the activity of spiny projection neurons, and although spiny neurons form a weak lateral inhibitory network among themselves via local axon collaterals, feedforward modulation exerts more powerful control over spiny neuron excitability. Of the striatal interneurons, only one class is not GABAergic. These neurons are cholinergic and correspond to the tonically active neurons (TANs) recorded in vivo, which respond to specific environmental stimuli with a transient depression, or pause, of tonic firing. Striatal cholinergic interneurons account for less than 2 % of the striatal neuronal population, yet their axons form an extensive and complex network that permeates the entire striatum and significantly shapes striatal output by acting at numerous targets via varied receptor types. Indeed, the persistent level of ambient striatal acetylcholine as well as changes to that basal acetylcholine level underlie the major mechanisms of cholinergic signaling in the striatum, however regulation of this system by the local striatal microcircuitry is not well understood. This dissertation finds that activation of intrastriatal cholinergic fibers elicits polysynaptic GABAA inhibitory postsynaptic currents (IPSCs) in cholinergic interneurons recorded in brain slices. Excitation of striatal GABAergic neurons via nicotinic acetylcholine receptors (nAChRs) mediates this polysynaptic inhibition in a manner independent of dopamine. Moreover, activation of a single cholinergic interneuron is capable of eliciting polysynaptic GABAA IPSCs onto itself and nearby cholinergic interneurons. These findings provide an important insight into the striatal microcircuitry controlling cholinergic neuron excitability.Cellular and Molecular Biolog

Attention shapes our expectations and perceptions: The neural mechanisms of top-down attention during adulthood and development

Top-down attention is the focusing of attention at one\u27s will through knowledge regarding a current task. There is evidence that top-down attention involves the modulation of sensory cortices by higher order regions. However, the mechanisms of top-down attention across sensory modalities, its influence on early sensory inputs, as well as interactions with motivational systems remain unclear. We performed the following set of electrophysiological experiments in typically developed adults and adolescents to examine these areas. 1) The supramodal attentional theory holds that parietally-based attentional mechanisms are shared across sensory modalities. We tested the supramodal theory by examining if lateralized parieto-occipital alpha-band activity, an established metric of top-down spatial attention, was observed in an audiospatial and visuospatial task. In support of the supramodal theory, we observed similar anticipatory alpha-band processes across auditory and visual tasks, but we also found an interaction of supramodal and sensory-specific attentional control processes. 2) There is evidence that top-down attention influences information immediately upon its arrival to sensory cortices, although there is debate in this area. In the current work, volitionally-driven top-down attention was engaged toward one of several overlapping surfaces in an illusion, in which the perceived brightness of the attended surface was enhanced. We observed the attentional enhancement of early visual evoked potentials, indicating that top-down attention shapes the earliest activations in visual cortices. 3) It is well known that motivation impacts attention, but the neural bases of these interactions remain unclear. We examined how level of interest in stimuli influenced top-down spatial attention mechanisms in typically-developing adolescents. Motivation enhanced established attentional processes during the anticipation of high vs. low interest stimuli, but also independently influenced frontal and parieto-occipital activations. These findings provide potential implications to inform clinical measures to improve impaired attentional processes in clinical populations (e.g. individuals with autism spectrum disorders). In sum, these studies revealed the powerful influence of top-down attentional control and its interacting systems on neural activations through several stages of anticipatory and post-stimulus processing during development and adulthood