DEVELOPMENT OF NEUROPHYSIOLOGICAL APPROACHES FOR MONITORING AND INTERVENING MENTAL FATIGUE

Ph.DDOCTOR OF PHILOSOPH

Psychedelics, meditation, and self-consciousness

In recent years, the scientific study of meditation and psychedelic drugs has seen remarkable developments. The increased focus on meditation in cognitive neuroscience has led to a cross-cultural classification of standard meditation styles validated by functional and structural neuroanatomical data. Meanwhile, the renaissance of psychedelic research has shed light on the neurophysiology of altered states of consciousness induced by classical psychedelics, such as psilocybin and LSD, whose effects are mainly mediated by agonism of serotonin receptors. Few attempts have been made at bridging these two domains of inquiry, despite intriguing evidence of overlap between the phenomenology and neurophysiology of meditation practice and psychedelic states. In particular, many contemplative traditions explicitly aim at dissolving the sense of self by eliciting altered states of consciousness through meditation, while classical psychedelics are known to produce significant disruptions of self-consciousness, a phenomenon known as drug-induced ego dissolution. In this article, we discuss available evidence regarding convergences and differences between phenomenological and neurophysiological data on meditation practice and psychedelic drug-induced states, with a particular emphasis on alterations of self-experience. While both meditation and psychedelics may disrupt self-consciousness and underlying neural processes, we emphasize that neither meditation nor psychedelic states can be conceived as simple, uniform categories. Moreover, we suggest that there are important phenomenological differences even between conscious states described as experiences of self-loss. As a result, we propose that self-consciousness may be best construed as a multidimensional construct, and that “self-loss,” far from being an unequivocal phenomenon, can take several forms. Indeed, various aspects of self-consciousness, including narrative aspects linked to autobiographical memory, self-related thoughts and mental time travel, and embodied aspects rooted in multisensory processes, may be differently affected by psychedelics and meditation practices. Finally, we consider long-term outcomes of experiences of self-loss induced by meditation and psychedelics on individual traits and prosocial behavior. We call for caution regarding the problematic conflation of temporary states of self-loss with “selflessness” as a behavioral or social trait, although there is preliminary evidence that correlations between short-term experiences of self-loss and long-term trait alterations may exist

The neurophysiologic landscape of the sleep onset: a systematic review

Background: The sleep onset process is an ill-defined complex process of transition from wakefulness to sleep, characterized by progressive modifications at the subjective, behavioural, cognitive, and physiological levels. To this date, there is no international consensus which could aid a principled characterisation of this process for clinical research purposes. The current review aims to systemise the current knowledge about the underlying mechanisms of the natural heterogeneity of this process. Methods: In this systematic review, studies investigating the process of the sleep onset from 1970 to 2022 were identified using electronic database searches of PsychINFO, MEDLINE, and Embase. Results: A total of 139 studies were included; 110 studies in healthy participants and 29 studies in participants with sleep disorders. Overall, there is a limited consensus across a body of research about what distinct biomarkers of the sleep onset constitute. Only sparse data exists on the physiology, neurophysiology and behavioural mechanisms of the sleep onset, with majority of studies concentrating on the non-rapid eye movement stage 2 (NREM 2) as a potentially better defined and a more reliable time point that separates sleep from the wake, on the sleep wake continuum. Conclusions: The neurophysiologic landscape of sleep onset bears a complex pattern associated with a multitude of behavioural and physiological markers and remains poorly understood. The methodological variation and a heterogenous definition of the wake-sleep transition in various studies to date is understandable, given that sleep onset is a process that has fluctuating and ill-defined boundaries. Nonetheless, the principled characterisation of the sleep onset process is needed which will allow for a greater conceptualisation of the mechanisms underlying this process, further influencing the efficacy of current treatments for sleep disorders.This paper represents independent research in part funded by the NIHR Maudsley Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London

THE IMPACT OF ACUTE EXERCISE AND SLEEP QUALITY ON EXECUTIVE FUNCTION: THE POTENTIAL MEDIATING EFFECTS OF FUNCTIONAL CONNECTIVITY IN OLDER ADULTS

Background: Although, improved longevity is a major public health accomplishment, the prevalence of chronic disease, including cognitive impairment, increases with age. Insufficient sleep and physical inactivity exacerbate chronic disease and may accelerate the onset of dementia. While a cure remains elusive, a growing body of evidence demonstrates that exercise training facilitates better sleep and enhanced cognition. Exercise-altered patterns of neural activity, including resting state functional connectivity (rsFC) and task-based functional activation, likely coincide with and may facilitate cognitive improvements in the aging brain. Purpose: This study sought to examine the joint impact of acute exercise and sleep quality on executive function in older adults. We also aimed to determine the degree to which exercise-induced changes in prefrontal rsFC influence the relationship between sleep and executive function performance/functional activation. Methods: Using a within subjects counter-balanced design, 21 participants (aged 55-85) underwent at least three days of objective sleep monitoring (actigraphy), followed by two experimental visits on separate days. During each visit, participants engaged in 30-minutes of rest or exercise followed immediately by resting state and task-based functional MRI. After the MRI scanning session, participants completed several executive function assessments. Neuroimaging and behavioral data were processed using AFNI (version 17.1.06) and SPSS (version 23), respectively. Results: Repeated measures ANOVA and multivariate linear regression revealed two significant voxel-wise interactions in the (L) precuneus. Our findings demonstrated that acute exercise increased prefrontal rsFC and functional activation in long sleepers (> 7.5 hours/night), while decreasing these parameters for individuals with less total sleep time. Moreover, these results correspond to behavioral data demonstrating that acute exercise and adequate sleep improved select aspects of executive function performance, while decreasing inhibitory control in short sleepers alone (< 7.5 hours). Conclusion: These findings suggest that the effects of acute exercise on prefrontal rsFC are similar, or even related, to the effects of acute exercise on conflict-dependent functional activation, and that this relationship may depend on sleep duration. Moreover, our results imply that although acute exercise elicited improved executive function for those with adequate sleep, it may weaken already vulnerable, and perhaps fatigued, executive function networks among short sleepers

Neurodevelopment & risk factors in schizophrenia

Schizophrenia is a complex psychiatric disorder with positive, negative, and cognitive symptoms. The causes are not yet fully understood, but it is believed that together with a strong genetic foundation, a ‘second environmental hit’ may be responsible to triggering a psychotic episode. Early-onset schizophrenia (EOS) a rare and more severe form of the disorder compared to its adult-onset counterpart and it is regarded to be more genetically loaded. This being as children and adolescents are less likely to have accumulated environmental triggers that are often considered risks to develop schizophrenia. Neurotic personality and anxiety symptoms are considered candidate schizophrenia risk factors. Working memory (WM) performance, the ability to hold information “online” in the matter of a few seconds, as well as its neural correlates are severely impaired in EOS, and such impairment is considered endophenotypic to the disorder. In addition, the expression of neurophysiological indices of cognition such as the mismatch negativity (MMN) and P300 event-related potentials (ERPs) are consistently demonstrated to be reliable biomarkers for the disorder, as shown by electroencephalography. This thesis on one hand, explores the influence of neuroticism and anxiety levels in healthy participants in ERPs during the auditory roving oddball and the hollow mask illusion experiments that are continually shown to be affected in schizophrenia literature. On the other hand, it explores meta-analytically convergent structural and functional brain abnormalities in EOS literature and follows a longitudinal fMRI cohort of EOS and healthy adolescents who were scanned twice in a 4-year span, while they performed the n-back task (WM task). These experiments are aimed to reveal brain areas that may qualify as endophenotypic markers of impaired WM neurodevelopment in schizophrenia. Our results showed that anxiety and neuroticism do not fully explain their status as schizophrenia risk factors by their relationship with the schizophrenia biomarker ERPs (P50 sensory gating, MMN, P300 and P600). The meta- analysis strongly indicates that a dysfunction in the functional network that underlies salience and other executive functions related to incentive and goal-oriented processes may be central across cognitive paradigms in EOS. Longitudinally, functional connectivity and maturation impairments are prevalent in the WM functional substrate of adolescents with EOS as they undergo neurodevelopmental processes by transitioning into early adulthood

EEG-fMRI in epilepsy and sleep

This thesis used simultaneous electroencephalogram (EEG) and functional magnetic resonance imaging (fMRI) to investigate both epilepsy and sleep. Initially, EEG-fMRI was used in a cohort of patients with complex epilepsy referred from a tertiary epilepsy clinic for both pre-surgical evaluation and diagnostic reasons. The results suggest a limited utility of EEG-fMRI in the epilepsy clinic with a very complex patient group. Following on, investigation of early blood oxygen level dependent (BOLD) signal changes in a group of patients with focal epilepsy demonstrated potentially meaningful BOLD changes occurring six seconds prior to interictal epileptiform discharges, and modelling less than this six seconds can result in overlap of the haemodynamic response function used to model BOLD changes. The same analysis was used to model endogenously occurring sleep paroxysms; K-complexes (KCs), vertex sharp waves (VSWs) and sleep spindles (SSs), finding early BOLD signal changes with SSs in group data. Finally, KCs and VSWs were investigated in more detail in a group of participants under both sleep deprived and non-deprived conditions, demonstrating an increase in overall activation for both KCs and VSWs following sleep deprivation. Overall, we find early BOLD changes are not restricted to pathological events and sleep deprivation can enhance BOLD responses

How sleep deprivation degrades task performance: combining experimental analysis with simulations of adenosinergic effects of basal ganglia and cortical circuits

Thesis (Ph.D.)--Boston UniversityHumans configure themselves into "neural machines" to perform optimally on distinct tasks, and they excel at maintaining such configurations for brief episodes. The neural configuration needed for peak performance, however, is subject to perturbations on multiple time scales. This thesis reports new empirical analyses and computational modeling to advance understanding of the variations in reaction time (RT) on simple RT tasks that are associated with the duration of the preceding inter-stimulus interval (order of seconds); the time-on-task duration (order of minutes); and sleep deprivation duration (order of hours to days). Responses from the psychomotor vigilance task (PVT), including anticipations (false alarms), normal RTs, and very long RTs (lapses in attention), were analyzed to discover the effects of: the 1 - 9 second inter-stimulus interval (ISI); the 10-minute task session; up to 50 hours of sleep deprivation (SD); and wake-promoting agents, caffeine and modafinil. Normal RTs and lapses in attention were negatively correlated with ISI length, whereas anticipations were positively correlated. Anticipations, normal RTs, and lapses increased as time-on-task increased, and during SD. Both caffeine and modafinil reduced lapses and anticipations during SD and decreased RT variability. A simple neural network model incorporating both a time-dependent inhibitory process and a time-dependent excitatory process was developed. The model robustly simulated the ISI effect on behavior. The SD effects were reproducible with two parameter adjustments. Informed modeling of drug effects required greater neurobiological detail. In the basal ganglia (BG), adenosine accumulation during SD has two notable effects: it antagonizes dopamine to reduce BG responsiveness to incoming cortical signals, and it reduces cholinergic transmission to parietal and prefrontal cortices, thus reducing attention to visual signals. A detailed computational model of interactions between BG and cortex during PVT was developed to simulate effects of adenosine and their amelioration by caffeine. The model simulates drug, ISI and SD effects on anticipations, RTs, and lapses. This model can be used to describe the effects of SD over a wide range of tasks requiring planned and reactive movements, and can predict and model effects of pharmacological agents acting on the adenosinergic, cholinergic and dopaminergic systems

Electrostimulation Contingencies and Attention, Electrocortical Activity and Neurofeedback

There is a growing body of evidence for diverse ways of modulating neuronal processing to improve cognitive performance. These include brain-based feedback, self-regulation techniques such as EEG-neurofeedback, and stimulation strategies, alone or in combination. The thesis goal was to determine whether a combined strategy would have advantages for normal cognitive function; specifically operant control of EEG activity in combination with transcutaneous electro-acustimulation. In experiment one the association between transcutaneous electroacustimulation (EA) and improved perceptual sensitivity was demonstrated with a visual GO/NOGO attention task (Chen et al, 2011). Furthermore reduced commission errors were related to an electrocortical motor inhibition component during and after alternating high and low frequency EA, whereas habituation in the control group with sham stimulation was related to different independent components. Experiment two applied frequency-domain ICA to detect changes in EEG power spectra from the eyes-closed to the eyes-open state (Chen et al, 2012). A multiple step approach was provided for analysing the spatiotemporal dynamics of default mode and resting state networks of cerebral EEG sources, preferable to conventional scalp EEG data analysis. Five regions were defined, compatible with fMRI studies. In experiment three the EA approach of Exp I was combined with sensorimotor rhythm (SMR) neurofeedback. SMR training improved perceptual sensitivity, an effect not found in a noncontingent feedback group. However, non-significant benefits resulted from EA. With ICA spectral power analysis changes in frontal beta power were associated with contingent SMR training. Possible long-term effects on an attention network in the resting EEG were also found after SMR training, compared with mock SMR training. In conclusion, this thesis has supplied novel evidence for significant cognitive and electrocortical effects of neurofeedback training and transcutaneous electro-acustimulation in healthy humans. Possible implications of these findings and suggestions for future research are considered

Development of Low-Frequency Repetitive Transcranial Magnetic Stimulation as a Tool to Modulate Visual Disorders: Insights from Neuroimaging

Repetitive transcranial magnetic stimulation (rTMS) has become a popular neuromodulation technique, increasingly employed to manage several neurological and psychological conditions. Despite its popular use, the underlying mechanisms of rTMS remain largely unknown, particularly at the visual cortex. Moreover, the application of rTMS to modulate visual-related disorders is under-investigated. The goal of the present research was to address these issues. I employ a multitude of neuroimaging techniques to gain further insight into neural mechanisms underlying low-frequency (1 Hz) rTMS to the visual cortex. In addition, I begin to develop and refine clinical low-frequency rTMS protocols applicable to visual disorders as an alternative therapy where other treatment options are unsuccessful or where there are simply no existing therapies. One such visual disorder that can benefit from rTMS treatment is the perception of visual hallucinations that can occur following visual pathway damage in otherwise cognitively healthy individuals. In Chapters 23, I investigate the potential of multiday low-frequency rTMS to the visual cortex to alleviate continuous and disruptive visual hallucinations consequent to occipital injury. Combining rTMS with magnetic resonance imaging techniques reveals functional and structural cortical changes that lead to the perception of visual hallucinations; and rTMS successfully attenuates these anomalous visual perceptions. In Chapters 45, I compare the effects of alternative doses of low-frequency rTMS to the visual cortex on neurotransmitter levels and intrinsic functional connectivity to gain insight into rTMS mechanisms and establish the most effective protocol. Differential dose-dependent effects are observed on neurotransmitter levels and functional connectivity that suggest the choice of protocol critically depends on the neurophysiological target. Collectively, this work provides a basic framework for the use of low-frequency rTMS and neuroimaging in clinical application for visual disorders