Neuroimaging of endogenous lapses of responsiveness,

Attention lapses (ALs) and microsleeps (MSs) are complete lapses of responsiveness in which performance is completely disrupted for a short period of time, but consciousness is retained in the case of ALs. ALs are behaviourally different from MSs, as in an AL the eyes remain open whereas in a MS eyes are partially or completely closed. Both ALs and MSs can result in catastrophic consequences, especially in the transportation sector. Research over the past two decades has investigated the AL and MS phenomena using behavioural and physiological means. However, both ALs and MSs need further investigation to separate the different types of ALs physiologically, and to explore the neural signature of MSs in relation to normal sleep and drowsiness. Hence, the objective of this project was to understand the underlying physiological substrates of endogenous (internal) ALs and MSs which could potentially result in differentiating types of ALs and provide more understanding of MSs. Data from two previous Christchurch Neurotechnology Research Programme (NeuroTech™) studies (C and D) were combined resulting in a total of 40 subjects. During each session, subjects performed a 2-D continuous visuomotor tracking (CVT) task for 50 min (Study C) and 20 min (Study D). For each participant, tracking performance, eye-video, EEG, and fMRI were simultaneously collected. A human expert visually inspected the tracking performance and eye-video recordings to identify and categorize lapses of responsiveness for each participant. Participants performed the 2-D CVT task without interruptions. The repetitive nature of the task and the lack of a motivational factor made the task monotonous and fatiguing. As a result, it was more likely to introduce boredom leading to task-unrelated thoughts (TUTs), which divides attention between the task and the internal thoughts unrelated to the task, also fatigue which will introduce a trend of vigilance decrement over time. The project had hypotheses focusing on the changes in the brain’s activity compared to the baseline of good responsiveness tracking. We expected a decrease in dorsal attention network (DAN) activity during ALs due to a decoupling of attention from the external environment. Furthermore, we hypothesized that the ALs were due to involuntary mind-blanks. As such, we expected no change in default mode network (DMN) activity, as would have otherwise been expected if the ALs were due to mind-wandering. Functional connectivity (FC) of the brain was also investigated between the networks of interest which were the DMN, DAN, frontoparietal network (FPN), sensorimotor network (SMN), visual network (VSN), salience network (SN), eye-movement network (EMN), and working memory network (WMN), by analysing data from fMRI. EEG data were also used to perform analysis on ALs and MSs, by analysing changes in power in the delta, theta, alpha, beta, and gamma bands. Voxel-wise fMRI throughout the whole brain, group-ICA, haemodynamic response (HR) over the regions of interest (ROIs), and FC analyses were performed to reveal the neural signature during ALs. In voxel-wise analysis, a significant increase in activity was found in two regions: the dorsal anterior cingulate cortex (dACC) and the supplementary motor area (SMA). The group-ICA analysis did not show any significant results but did show a trend of increased activity in an independent component (IC) that was spatially correlated with SMN. Dynamic HR analysis was performed to further investigate findings from the voxel-wise analysis. Our results were not significant but there were strong trends of change. There was a trend of increased HR 7.5 s after the onset of the AL in the left intraparietal sulcus (IPS) of the DAN. There was also a decrease of 2.5 s before the onset of the AL in the right posterior parietal cortex (PPC) of the FPN. There was also an increase in the HR 5 s after the onset of the AL in the dACC of the SN. Finally, an increase in the HR 15 s before the onset of ALs in the left inferior parietal lobule (IPL) of the DMN is a major finding, as it is an indication that a lapse is about to happen. The HR analysis provided consistent findings with the voxel-wise analysis. FC analysis showed increases in FC within all networks of interest during the ALs. On looking at FC between networks, there was an increase in FC between the DMN and the FPN, no change between the DAN and the FPN, a decrease in FC between the SMN and the FPN, and an increase in FC between the FPN and the VSN. The EMN had an increased FC with the DMN, while it had both increases and decreases in FC with the DAN. There was also an increase in FC between the SN and the DAN, and no change between the SN and the DMN. Finally, a decrease in FC was found between the WMN and the DMN. These findings indicate an overlap between decoupling due to ALs and the process of recovery from ALs. The EEG analysis showed no significant change in the relative difference between average spectral power during ALs and their average baselines for any band of interest for ALs. During MSs, there was a significant increase in power relative to responsive baselines in the delta, theta, alpha, beta, and gamma bands. However, we could not be completely sure that all motion-related artefacts had been removed. Hence, we investigated this further by removing the effect of the global signal, which left only an increase in gamma activity, in addition to a trend of decreased activity in the alpha band. The significant increase in BOLD seen in the voxel-wise analysis is considered to represent the recovery of responsiveness following ALs. This was also seen in trends in group ICA and HR analyses. Overall, findings from the FC analysis show that, in addition to decoupling during ALs, and recovery from ALs, it is highly likely that the ALs during the 2-D CVT task were due to involuntary mind-blanks. This is supported by three major findings: (1) no significant increase in DMN activity in both voxel-wise and HR analyses, (2) the decrease in the HR in the FPN prior to the onset of the AL, and (3) the decrease in FC between the DMN and the WMN. This is further supported behaviourally by the short average duration of ALs (~ 1.7 s), in contrast to what would be likely during mind-wandering. Finally, the significant results from the EEG analysis of MSs, agreed with the literature in delta, theta, and alpha bands. However, increased power in beta and gamma bands was an important finding. We consider this increased high-frequency activity reflects unconscious ‘cognitive’ activity during a MS aimed at restoring consciousness after having fallen asleep during an active task. This highlights a key behavioural and physiological difference between MSs and sleep. Even after removing the effect of the global signal, we still believe that MSs and sleep are physiologically different in the recovery process. To summarize our key findings: (1) this is the first study to demonstrate that ALs during a continuous task are likely to be due to involuntary mind-blanks, (2) the increase in the HR in the DMN 15 s before the onset of AL could be a predictive signature of these lapses, and finally (3) MSs are physiologically different from sleep in terms of the recovery process. This project has improved our understanding of endogenous ALs and MSs and taken us a step closer to accurate detection/prediction systems which can increase prevention of fatal accidents

SLEEPING WHILE AWAKE: A NEUROPHYSIOLOGICAL INVESTIGATION ON SLEEP DURING WAKEFULNESS.

Il sonno e la veglia vengono comunemente considerati come due stati distinti. L\u2019alternanza tra essi, la cui presenza \ue8 stata dimostrata in ogni specie animale studiata fino ad oggi, sembra essere una delle caratteristiche che definisce la nostra vita. Allo stesso tempo, per\uf2, le scoperte portate alla luce negli ultimi decenni hanno offuscato i confini tra questi due stati. I meccanismi del sonno hanno sempre affascinato i neurofisiologi, che infatti, nell\u2019ultimo secolo, li hanno caratterizzati in dettaglio: ora sappiamo che all\u2019attivit\ue0 del sonno sottost\ue0 una specifica attivit\ue0 neuronale chiamata slow oscillation. La slow oscillation, che \ue8 costituita da (ancora una volta) un\u2019alternanza tra periodi di attivit\ue0 e periodi di iperpolarizzazione e silenzio neuronale (OFF-periods), \ue8 la modalit\ue0 base di attivazione del cervello dormiente. Questa alternanza \ue8 dovuta alla tendenza dei neuroni surante lo stato di sonno, di passare ad un periodo silente dopo un\u2019attivazione iniziale, una tendenza a cui viene dato il nome di bistabilit\ue0 neuronale. Molti studi hanno dimostrato come la bistabilit\ue0 neuronale tipica del sonno ed i relativi OFF-periods, possano accadere anche durante la veglia in particolari condizioni patologiche, nelle transizioni del sonno e durante le deprivazioni di sonno. Per questo motivo, se accettassimo che la bistabilit\ue0 neuronale e gli OFF-periods rappresentino una caratteristica fondamentale del sonno, allora dovremmo ammettere che stiamo assistendo ad un cambio di paradigma: da una prospettiva neurofisiologica il sonno pu\uf2 intrudere nella veglia. In questa tesi ho analizzato i nuovi -fluidi- confini tra sonno e veglia e le possibili implicazioni di questi nel problema della persistenza personale attraverso il tempo. Inoltre, ho studiato le implicazioni cliniche dell\u2019intrusione di sonno nella veglia in pazienti con lesioni cerebrali focali di natura ischemica. In particolare, i miei obiettivi sono stati: 1) Dimostrare come la bistabilit\ue0 neuronale possa essere responsabile della perdita di funzione nei pazienti affetti da ischemia cerebrale e come questo potrebbe avere implicazioni nello studio della patofisiologia dell\u2019ischemia cerebrale e nella sua terapia; 2) Stabilire le basi per un modello di sonno locale presente nella vita di tutti i giorni: la sensazione di sonnolenza. Infatti, essa potrebbe riflettere la presenza di porzioni di corteccia in stato di sonno, ma durante lo stato di veglia; 3) Difendere il criterio biologico di identit\ue0, che troverebbe nell\u2019attivit\ue0 cerebrale la continuit\ue0 necessaria al mantenimento della nostra identit\ue0 nel tempo.Sleep and wakefulness are considered two mutually exclusive states. The alternation between those two states seems to be a defining characteristic of our life, a ubiquitous phenomenon demonstrated in every animal species investigated so far. However, during the last decade, advances in neurophysiology have blurred the boundaries between those states. The mechanisms of sleep have always intrigued neurophysiologists and great advances have been made over the last century in understanding them: we now know that the defining characteristic underlying sleep activity is a specific pattern of neuronal activity, namely the slow oscillation. The slow oscillation, which is characterized by the periodic alternation between periods of activity (ON-periods) and periods of hyperpolarization and neuronal silence (OFF-periods) is the default mode of activity of the sleeping cortex. This alternation is due to the tendency of neurons to fall into a silent period after an initial activation; such tendency is known as \u201cbistability\u201d. There is accumulating evidence that sleep-like bistability, and the ensuing OFF-periods, may occur locally in the awake human brain in some pathological conditions, in sleep transition, as well as after sleep deprivation. Therefore, to the extent that bistability and OFF periods represents the basic neuronal features of sleep, a paradigm shift is in place: from a neurophysiological perspective sleep can intrude into wakefulness. In this thesis, I explore the fluid boundaries between sleep and wakefulness and investigate their possible implications on the problem of personal persistence over time. Moreover, I study the clinical implications of the intrusion of sleep into wakefulness in patients with focal brain injury due to stroke. Specifically, I aim to: 1) show how the sleep-like bistability can be responsible for the loss of function in stroke patients. This may have implications for understanding the pathophysiology of stroke and helping to foster recovery; 2) establish the basis for a model of local sleep that might be present in the everyday life, id est the sensation of sleepiness. Indeed, sleepiness could reflect islands of sleep during wakefulness; 3) advocate the biological criterion of identity, in which the continuity necessary for maintaining ourselves over time could be represented by never resting activity in the brain

Simultaneous pupillometry and functional Magnetic Resonance Imaging (fMRI) for the detection of stress-related endophenotypes

Mental diseases constitute a core health challenge of the 21st century. To date, diagnostics in psychiatry have been primarily based on subjective self-reports, largely bypassing the biological underpinnings and phenotypic heterogeneity of psychiatric disorders. As an effort to implement a more biologically valid classification of mental disorders, recent initiatives like the Research Domain Criteria (RDoC) project aim to identify endophenotypes that reflect transdiagnostic core mechanisms of psychiatric disorders. Stress is known to play a fundamental role in the development of mood and anxiety disorders. One key system involved in the physiological response to stress is the brainstem?s noradrenergic (NA) arousal center located in the locus coeruleus (LC), and previous studies indicate that pupil size provides an indirect index for activity of the LC-NA system. In order to investigate the relationship between spontaneous drifts in autonomic arousal and global brain activity in healthy human subjects, we first determined the fMRI correlates of spontaneous pupil fluctuations during the resting state. We found that pupil dilations are strongly coupled to activation of the dorsal anterior cingulate cortex (dACC) and bilateral insula (salience network [SN]). To assess whether this link between the pupil and the SN would also extend to emotional arousal, we next investigated the neural correlates of reward anticipation-induced pupil dilations in healthy subjects. Here, we could show that a cue signaling the possibility to receive a monetary reward evoked strong pupil dilations, the magnitude of which predicted response time to a target cue. Again, pupil dilations were strongly linked to SN activation. Furthermore, our results suggest that pupillometry is helpful to dissect different phases of reward anticipation and associated brain activity, disentangling reward prediction, arousal modulation and attentionrelated processes. These observations led us to the conclusion that the SN modulates arousal levels to optimize task performance, that is, to counteract drowsiness/ transitions to sleep during the resting state and to facilitate reward-directed behaviors in the reward anticipation task. Taken together, pupillometry appears to provide a reliable index for activity of the SN, a core network related to psychiatric disorders, making it a promising tool for the detection of stress-related endophenotypes

Simultaneous pupillometry and functional Magnetic Resonance Imaging (fMRI) for the detection of stress-related endophenotypes

Mental diseases constitute a core health challenge of the 21st century. To date, diagnostics in psychiatry have been primarily based on subjective self-reports, largely bypassing the biological underpinnings and phenotypic heterogeneity of psychiatric disorders. As an effort to implement a more biologically valid classification of mental disorders, recent initiatives like the Research Domain Criteria (RDoC) project aim to identify endophenotypes that reflect transdiagnostic core mechanisms of psychiatric disorders. Stress is known to play a fundamental role in the development of mood and anxiety disorders. One key system involved in the physiological response to stress is the brainstem’s noradrenergic (NA) arousal center located in the locus coeruleus (LC), and previous studies indicate that pupil size provides an indirect index for activity of the LC-NA system. In order to investigate the relationship between spontaneous drifts in autonomic arousal and global brain activity in healthy human subjects, we first determined the fMRI correlates of spontaneous pupil fluctuations during the resting state. We found that pupil dilations are strongly coupled to activation of the dorsal anterior cingulate cortex (dACC) and bilateral insula (salience network [SN]). To assess whether this link between the pupil and the SN would also extend to emotional arousal, we next investigated the neural correlates of reward anticipation-induced pupil dilations in healthy subjects. Here, we could show that a cue signaling the possibility to receive a monetary reward evoked strong pupil dilations, the magnitude of which predicted response time to a target cue. Again, pupil dilations were strongly linked to SN activation. Furthermore, our results suggest that pupillometry is helpful to dissect different phases of reward anticipation and associated brain activity, disentangling reward prediction, arousal modulation and attentionrelated processes. These observations led us to the conclusion that the SN modulates arousal levels to optimize task performance, that is, to counteract drowsiness/ transitions to sleep during the resting state and to facilitate reward-directed behaviors in the reward anticipation task. Taken together, pupillometry appears to provide a reliable index for activity of the SN, a core network related to psychiatric disorders, making it a promising tool for the detection of stress-related endophenotypes

DEVELOPMENT OF NEUROPHYSIOLOGICAL APPROACHES FOR MONITORING AND INTERVENING MENTAL FATIGUE

Ph.DDOCTOR OF PHILOSOPH

Analysis and detection of driver fatigue caused by sleep deprivation

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Aeronautics and Astronautics, 2007.Includes bibliographical references (leaves 167-181).Human errors in attention and vigilance are among the most common causes of transportation accidents. Thus, effective countermeasures are crucial for enhancing road safety. By pursuing a practical and reliable design of an Active Safety system which aims to predict and avoid road accidents, we identify the characteristics of drowsy driving and devise a systematic way to infer the state of driver alertness based on driver-vehicle data. Although sleep and fatigue are major causes of impaired driving, neither effective regulations nor acceptable countermeasures are available yet. The first part of this thesis analyzes driver-vehicle systems with discrete sleep-deprivation levels, and reveals differences in the performance characteristics of drivers. Inspired by the human sleep-wake cycle mechanism and attributes of driver-vehicle systems, we design and perform human-in-the-loop experiments in a test bed built with STISIM Drive, an interactive fixed-based driving simulator. In the simulated driving, participants were given various driving tasks and secondary tasks for both non and partially sleep-deprived conditions. This experiment demonstrates that sleep deprivation has a greater effect on rule-based tasks than on skill-based tasks; when drivers are sleep-deprived, their performance of responding to unexpected disturbances degrades while they are robust enough to continue such routine driving tasks as straight lane tracking, following a lead vehicle, lane changes, etc. In the second part of the thesis we present both qualitative and quantitative guidelines for designing drowsy driver detection systems in a probabilistic framework based on the Bayesian network paradigm and experimental data.(cont.) We consider two major causes of sleep, i.e., sleep debt and circadian rhythm, in the framework with various driver-vehicle parameters, and also address temporal aspects of drowsiness and individual differences of subjects. The thesis concludes that detection of drowsy driving based on driver-vehicle data is a feasible but difficult problem which has diverse issues to be addressed; the ultimate challenge lies in the human operator.by Ji Hyun Yang.Ph.D

The effects of a gradual shift rotation and a split shift nap intervention on cognitive, physiological and subjective responses under simulated night shift settings

Introduction: Shift work, particularly work that occurs at night has been associated with numerous challenges to occupational safety and productivity. This stems from the associated extended wakefulness, circadian disruptions and sleep loss from the inversion of the sleep wake cycle, which predisposes shift workers to reduced alertness, increased fatigue and decrements in performance capacity. These effects may be exacerbated over consecutive night shifts as a result of reductions in sleep length associated with attempting to sleep against the alerting signals of the circadian rhythm during the day. Although a variety of shift work countermeasures exist, new and innovative fatigue management strategies are needed to mitigate the effects of night work. This study proposed two night shift interventions; the Rolling rotation and a split shift nap combination. Aims: The aim of this study was to explore the effects of these interventions to a conventional Fixed night shift arrangement. Selected performance, physiological and subjective measures were applied to track any effects during a five-day shift work study. Methods: The study was laboratory-based and performance was quantified through the application of computer-based perceptual, cognitive and motor tests. Student participants (24 females and 21 males) partook in the study, which adopted a nonrepeated measures design and spanned five consecutive days. During this time, participants were required to perform a simple beading task over five 8-hour shifts. Participants were split according to sex and chronotype between four independent conditions; 1. Fixed night condition required participants to complete one afternoon shift (14h00 – 22h00) and four consecutive night shifts (22h00 - 06h00) 2. Rolling rotation condition gradually “rolled” participants into the night shift by delaying the start and end of an afternoon shift by two hours each day (16h00 – 00h00, 18h00 – 02h00, 20h00 – 04h00, 22h00 – 06h00) until the times matched that of the Fixed night condition. 3. The split shift nap system was made up of two independent groups, both of which completed one afternoon (14h00 to 22h00) and four night shifts. The Nap early condition worked from 20h00 to 08h00, napping between 00h00 and 04h00, while the Nap late condition worked from 00h00 to 12h00 and napped between 04h00 and 08h00 during the night shifts. Napping, the opportunity for which was 200 minutes occurred in the laboratory, but post shift recovery sleep, for all conditions, happened outside the laboratory. During each shift, six test batteries were completed, in which the following measures were taken: 1. Performance: beading output, eye accommodation time, choice reaction time, visual vigilance, simple reaction time, processing speed and object recognition, working memory, motor response time and tracking performance. 2. Physiological: heart rate, heart rate variability (r-MSSD, normalised Low frequency power: LFnu). 3. Self-reported measures: subjective sleepiness and reported sleep length and quality while outside the laboratory. Results: Analyses revealed that: 1. Measures of beading performance, simple reaction time, vigilance and object recognition, working memory, motor response time and control, all physiological measures, except LFnu and subjective sleepiness demonstrated the effects of time of day / fatigue, irrespective of condition. 2. There was no evidence of cumulative fatigue over the four night shifts in the performance and subjective measures and most of the physiological indicators. Beading output decreased significantly over the course of the night shifts, while reported post shift sleep length was significantly reduced with the start of the night shifts, irrespective of condition. 3. The majority of the physiological and performance measures did not differ significantly between conditions. However, there were some effects: the Rolling rotation condition produced the highest beading output compared to the Nap late condition; working memory was significantly lower in the Nap late condition compared to the other conditions. Furthermore, the nap opportunity in both the Nap early and Nap late conditions reduced subjective sleepiness, while napping during the night shift reduced post shift sleep length compared to the Rolling rotation and Fixed night conditions. There was also evidence of sleep inertia following pre-post nap test comparisons, which mainly affected visual perception tasks in both nap conditions. Sleep inertia possibly also accounted for an apparent dissociation between subjective and performance measures. Conclusions: Quantifying and interpreting the effects of night shift work in a laboratory setting has limitations. These stem mainly from the limited ecological validity of the performance outcome measures adopted and the characteristics of the sample that is tested. However, in order to fully understand the efficacy of any shift work countermeasure, the laboratory setting offers a safe, controlled environment in which to do so. The conclusions should thus be considered in light of these limitations. Night shift work negatively affected all elements of human information processing. The combination of reduced physiological arousal, extended wakefulness, increased perceptions of sleepiness and reduced total sleep obtained explained these decrements in performance. While cumulative fatigue has been reported as a challenge associated with night shift work, there was no conclusive evidence of this in the current study. In the case of the Rolling rotation, the gradual introduction to the night shift delayed the inevitable reduction in alertness and performance, which limits the viability of this intervention. The inclusion of the nap interventions was associated with reduced perceptions of sleepiness, which did not translate into improved performance, relative to the Rolling rotation and Fixed night conditions. Apart from considerations of how to manage sleep inertia post nap, the split shift nap intervention can provide an alternative to conventional night shift work arrangements

An fMRI study of abrupt-awake episodes during behavioral microsleeps.

This paper reports the brain activation patterns of five subjects who were abruptly awakened from microsleeps in a simulated automotive driving experiment. By comparing the BOLD signals between behavioral microsleep (BM), abrupt awakening (AA) and post-abrupt awakening (post-AA) stages, we observed that visual area, frontal cortex, limbic lobe manifested more intense activation during the AA stage while frontal cortex, temporal cortex, primary motor area and insula were more activated during the post-AA stage. These results suggested that the subjects were likely in mental states differ from those associated with decision making processes as they went through and emerged from the abrupt awakening episodes