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

비침습적 뇌파 신호를 이용한 응급환자의 생체반응 모니터링 기법

학위논문 (박사) -- 서울대학교 대학원 : 공과대학 협동과정 바이오엔지니어링전공, 2021. 2. 김희찬.뇌파는 대뇌피질이나 두피의 전극을 통해서 뇌의 전기적 신호를 기록한 것을 의미한다. 뇌 기능 관찰을 위한 진단도구로써 뇌파는 뇌전증이나 치매 진단 등의 목적으로 활용되고 있다. 본 논문에서는 비침습적 뇌파를 이용하여 응급환자의 주요 생리학적 지표를 모니터링하는 기술을 개발하였다. 처음 두 연구에서 심폐소생술의 효과를 평가하기 위한 심정지 돼지실험모델을 고안하였다. 현재의 심폐소생술 지침은 체순환 평가를 위해 기도삽관을 통한 호기말 이산화탄소 분압의 측정을 권고한다. 하지만, 정확한 기도삽관이 특히 병원 밖 상황에서 어려울 수 있다. 따라서, 간편히 측정할 수 있고 소생 환자의 신경학적 예후를 진단하는데 사용되는 뇌파를 이용한 예측 기술이 심폐소생술 품질평가지표의 대안으로 제안되었다. 첫 번째 실험에서는 고품질과 저품질 기본심폐소생술을 10회 반복하면서 측정된 뇌파를 분석하였다. 심폐소생술의 품질에 따른 뇌파의 변화를 이용하여 체순환 평가를 위한 EEG-based Brain Resuscitation Index (EBRI) 모델을 도출하였다. EBRI 모델에서 획득한 호기말 이산화탄소 분압 예측치는 실제 값과 양의 상관관계를 보이며, 병원 밖 상황에서의 활용 가능성을 보였다. 두 번째 실험에서는 두 가지 심폐소생술(기본심폐소생술, 전문심폐소생술)이 수행되었다. 제세동 직전에 수집된 뇌파는 심폐소생술 도중 경동맥혈류의 회복률과 함께 분석되었다. 심폐소생술 도중 경동맥혈류의 회복률을 반영하는 뇌파 변수를 규명한 후, 이를 이용하여 높은 회복률(30% 이상)과 낮은 회복률(30% 미만)을 구분하는 기계학습 기반 이진분류모델을 도출하였다. 서포트 벡터 머신 기반의 예측모델이 0.853의 정확도와 0.909의 곡선하면적을 보이며 가장 우수한 성능을 보였다. 이러한 예측모델은 심정지 환자의 뇌 소생을 향상시켜 빠른 뇌 기능 회복을 가능하게 할 것으로 기대된다. 세 번째 연구에서 비침습적 뇌파를 이용하여 두개내압을 예측하는 모델을 개발하기 위한 외상성 뇌손상 돼지실험모델이 고안되었다. 외상성 뇌손상은 물리적 충격에 의해 정상적인 뇌 기능이 중단된 상태를 의미하며, 이 때의 두개내압 상승과 관류저하가 뇌파에 영향을 끼칠 수 있다. 따라서, 우리는 뇌파 기반 두개내압 예측모델을 개발하였다. 폴리카테터로 실험동물의 두개내압을 변경하면서 뇌파를 획득하였다. 두개내압의 정상구간(25 mmHg 미만)과 위험구간(25 mmHg 이상)을 유의미하게 구분하는 뇌파 변수를 규명한 후 기계학습 기반 이진분류모델을 도출하였다. 다층 퍼셉트론 기반의 예측모델이 0.686의 정확도와 0.754의 곡선하면적을 보이며 가장 우수한 성능을 보였다. 또다른 비침습 데이터인 심박수 정보와 함께 사용하였을 때 정확도와 곡선하면적은 각각 0.760과 0.834로 향상되었다. 제안된 예측모델은 응급상황에서 비침습적으로 두개내압을 관찰하여 정상 수준의 두개내압을 유지하는데 도움을 줄 것으로 기대된다. 본 논문은 응급환자의 주요 생리학적 지표를 비침습적 뇌파를 이용하여 관찰하는 예측모델을 제안하고 성능을 검증하였다. 본 연구에서는 뇌파를 이용하여 즉각적인 호기말 이산화탄소 분압, 경동맥혈류, 두개내압을 추정하기 위한 예측모델을 수립하였다. 하지만, 뇌파 데이터는 장기간의 신경학적, 기능적 회복과 함께 평가되어야 한다. 본 논문에서 개발한 예측모델의 성능과 적용 가능성은 향후 다양한 임상연구를 통해 cerebral performance category와 modified Rankin scale 등의 신경학적 평가지표와 함께 분석, 개선되어야 할 것이다.Electroencephalogram (EEG) is a recording of the electrical activity of the brain, measured using electrodes attached to the cerebrum cortex or the scalp. As a diagnostic tool for brain disorders, EEG has been widely used for clinical purposes such as epilepsy- and dementia diagnosis. This study develops an EEG-based noninvasive critical care monitoring method for emergency patients. In the first two studies, ventricular fibrillation swine models were designed to develop EEG-based monitoring methods for evaluating the effectiveness of cardiopulmonary resuscitation (CPR). The CPR guidelines recommend measuring end-tidal carbon dioxide (ETCO2) via endotracheal intubation to assess systemic circulation. However, accurate insertion of the endotracheal tube might be difficult in an out-of-hospital setting (OOHS). Therefore, an easily measurable EEG, which has been used to predict resuscitated patients neurologic prognosis, was suggested as a surrogate indicator for CPR feedback. In the first experimental setup, the high- and low quality CPRs were altered 10 times repeatedly, and the EEG parameters were analyzed. Linear regression of an EEG-based brain resuscitation index (EBRI) was used to estimate ETCO2 levels as a novel feedback indicator of systemic circulation during CPR. A positive correlation was found between the EBRI and the real ETCO2, which indicates the feasibility of EBRI in OOHSs. In the second experimental setup, two types of CPR mode were performed: basic life support and advanced cardiovascular life support. EEG signals that were measured between chest compressions and defibrillation shocks were analyzed to monitor the cerebral circulation with respect to the recovery of carotid blood flow (CaBF) during CPR. Significant EEG parameters were identified to represent the CaBF recovery, and machine learning (ML)-based classification models were established to differentiate between the higher (≥ 30%) and lower (< 30%) CaBF recovery. The prediction model based on the support vector machine (SVM) showed the best performance, with an accuracy of 0.853 and an area under the curve (AUC) of 0.909. The proposed models are expected to guide better cerebral resuscitation and enable early recovery of brain function. In the third study, a swine model of traumatic brain injury (TBI) was designed to develop an EEG-based prediction model of an elevated intracranial pressure (ICP). TBI is defined as the disruption of normal brain function due to physical impact. This can increase ICP, and the resulting hypoperfusion can affect the cerebral electrical activity. Thus, we developed EEG-based prediction models to monitor ICP levels. During the experiments, EEG was measured while the ICP was adjusted with the Foley balloon catheter. Significant EEG parameters were determined to differentiate between the normal (< 25 mmHg) and dangerous (≥ 25 mmHg) ICP levels and ML-based binary classifiers were established to distinguish between these two groups. The multilayer perceptron model showed the best performance with an accuracy of 0.686 and an AUC of 0.754, which were improved to 0.760 and 0.834, respectively, when a noninvasive heart rate was also used as an input. The proposed prediction models are expected to instantly treat an elevated ICP (≥ 25 mmHg) in emergency settings. This study presents a new EEG-based noninvasive monitoring method of the physiologic parameters of emergency patients, especially in an OOHS, and evaluates the performance of the proposed models. In this study, EEG was analyzed to predict immediate ETCO2, CaBF, and ICP. The prediction models demonstrate that a noninvasive EEG can yield clinically important predictive outcomes. Eventually, the EEG parameters should be investigated with regard to the long-term neurological and functional outcomes. Further clinical trials are warranted to improve and evaluate the feasibility of the proposed method with respect to the neurological evaluation scores, such as the cerebral performance category and modified Rankin scale.Abstract i Contents iv List of Tables viii List of Figures x List of Abbreviations xii Chapter 1 General Introduction 1 1.1 Electroencephalogram 1 1.2 Clinical use of spontaneous EEG 5 1.3 EEG and cerebral hemodynamics 7 1.4 EEG use in emergency settings 9 1.5 Noninvasive CPR assessment 10 1.6 Noninvasive traumatic brain injury assessment 16 1.7 Thesis objectives 21 Chapter 2 EEG-based Brain Resuscitation Index for Monitoring Systemic Circulation During CPR 23 2.1 Introduction 23 2.2 Methods 25 2.2.1 Ethical statement 25 2.2.2 Study design and setting 25 2.2.3 Experimental animals and housing 27 2.2.4 Surgical preparation and hemodynamic measurements 27 2.2.5 EEG measurement 29 2.2.6 Data analysis 32 2.2.7 EBRI calculation 33 2.2.8 Delta-EBRI calculation 34 2.3 Results 36 2.3.1 Hemodynamic parameters 36 2.3.2 Changes in EEG parameters 37 2.3.3 EBRI calculation 39 2.3.4 Delta-EBRI calculation 41 2.4 Discussion 42 2.4.1 Accomplishment 42 2.4.2 Limitations 45 2.5 Conclusion 46 Chapter 3 EEG-based Prediction Model of the Recovery of Carotid Blood Flow for Monitoring Cerebral Circulation During CPR 47 3.1 Introduction 47 3.2 Methods 50 3.2.1 Ethical statement 50 3.2.2 Study design and setting 50 3.2.3 Experimental animals and housing 52 3.2.4 Surgical preparation and hemodynamic measurements 54 3.2.5 EEG measurement 55 3.2.6 Data processing 57 3.2.7 Data analysis 58 3.2.8 Development of machine-learning based prediction model 59 3.3 Results 63 3.3.1 Results of CPR process 63 3.3.2 EEG changes with the recovery of CaBF 66 3.3.3 Changes in EEG parameters depending on four CaBF groups 68 3.3.4 Changes in EEG parameters depending on two CaBF groups 69 3.3.5 EEG parameters for prediction models 70 3.3.6 Performances of prediction models 73 3.4 Discussion 76 3.4.1 Accomplishment 76 3.4.2 Limitations 78 3.5 Conclusion 80 Chapter 4 EEG-based Prediction Model of an Increased Intra-Cranial Pressure for TBI patients 81 4.1 Introduction 81 4.2 Methods 83 4.2.1 Ethical statement 83 4.2.2 Study design and setting 83 4.2.3 Experimental animals and housing 85 4.2.4 Surgical preparation and hemodynamic measurements 86 4.2.5 EEG measurement 88 4.2.6 Data processing 90 4.2.7 Data analysis 90 4.2.8 Development of machine-learning based prediction model 91 4.3 Results 92 4.3.1 Hemodynamic changes during brain injury phase 92 4.3.2 EEG changes with an increase of ICP 93 4.3.3 EEG parameters for prediction models 94 4.3.4 Performances for prediction models 95 4.4 Discussion 100 4.4.1 Accomplishment 100 4.4.2 Limitations 104 4.5 Conclusion 104 Chapter 5 Summary and Future works 105 5.1 Thesis summary and contributions 105 5.2 Future direction 108 Bibilography 113 Abstract in Korean 135Docto

Cerebral Autoregulation-Based Blood Pressure Management In The Neuroscience Intensive Care Unit: Towards Individualizing Care In Ischemic Stroke And Subarachnoid Hemorrhage

The purpose of this thesis is to review the concept of cerebral autoregulation, to establish the feasibility of continuous bedside monitoring of autoregulation, and to examine the impact of impaired autoregulation on functional and clinical outcomes following subarachnoid hemorrhage and ischemic stroke. Autoregulation plays a key role in the regulation of brain blood flow and has been shown to fail in acute brain injury. Disturbed autoregulation may lead to secondary brain injury as well as worse outcomes. Furthermore, there exist several methodologies, both invasive and non-invasive, for the continuous assessment of autoregulation in individual patients. Resultant autoregulatory parameters of brain blood flow can be harnessed to derive optimal cerebral perfusion pressures, which may be targeted to achieve better outcomes. Multiple studies in adults and several in children have highlighted the feasibility of individualizing mean arterial pressure in this fashion. The thesis herein argues for the high degree of translatability of this personalized approach within the neuroscience intensive care unit, while underscoring the clinical import of autoregulation monitoring in critical care patients. In particular, this document recapitulates findings from two separate, prospectively enrolled patient groups with subarachnoid hemorrhage and ischemic stroke, elucidating how deviation from dynamic and personalized blood pressure targets associates with worse outcome in each cohort. While definitive clinical benefits remain elusive (pending randomized controlled trials), autoregulation-guided blood pressure parameters wield great potential for constructing an ideal physiologic environment for the injured brain. The first portion of this thesis discusses basic autoregulatory physiology as well as various tools to interrogate the brain’s pressure reactivity at the bedside. It then reviews the development of the optimal cerebral perfusion pressure as a biological hemodynamic construct. The second chapter pertains to the clinical applications of bedside neuromonitoring in patients with aneurysmal subarachnoid hemorrhage. In this section, the personalized approach to blood pressure monitoring is discussed in greater detail. Finally, in the third chapter, a similar autoregulation-oriented blood pressure algorithm is applied to a larger cohort of patients with ischemic stroke. This section contends that our novel, individualized strategy to hemodynamic management in stroke patients represents a better alternative to the currently endorsed practice of maintaining systolic blood pressures below fixed and static thresholds

Accuracy of EEG Biomarkers in the Detection of Clinical Outcome in Disorders of Consciousness after Severe Acquired Brain Injury: Preliminary Results of a Pilot Study Using a Machine Learning Approach

Accurate outcome detection in neuro-rehabilitative settings is crucial for appropriate long-term rehabilitative decisions in patients with disorders of consciousness (DoC). EEG measures derived from high-density EEG can provide helpful information regarding diagnosis and recovery in DoC patients. However, the accuracy rate of EEG biomarkers to predict the clinical outcome in DoC patients is largely unknown. This study investigated the accuracy of psychophysiological biomarkers based on clinical EEG in predicting clinical outcomes in DoC patients. To this aim, we extracted a set of EEG biomarkers in 33 DoC patients with traumatic and nontraumatic etiologies and estimated their accuracy to discriminate patients' etiologies and predict clinical outcomes 6 months after the injury. Machine learning reached an accuracy of 83.3% (sensitivity = 92.3%, specificity = 60%) with EEG-based functional connectivity predicting clinical outcome in nontraumatic patients. Furthermore, the combination of functional connectivity and dominant frequency in EEG activity best predicted clinical outcomes in traumatic patients with an accuracy of 80% (sensitivity = 85.7%, specificity = 71.4%). These results highlight the importance of functional connectivity in predicting recovery in DoC patients. Moreover, this study shows the high translational value of EEG biomarkers both in terms of feasibility and accuracy for the assessment of DoC

Selected topics on the neuroscience of altered perceptions and illusory beliefs

Six neuropsychological topics illustrating altered perceptions and illusory beliefs are explored with particular emphasis on the neurobiological underpinnings of such phenomena. The first five topics are phantom limb, out-of-body experiences including depersonalization and near-death experiences, delusions with an emphasis on the effects of psychedelic drugs, autonomic reflex actions including respiration and heartbeat, and virtual reality. The last topic focuses on three disorders impairing perception and cognition, namely, Anton-Babinski, Charles Bonnet, and Diogenes Syndromes. Many of the related neurobiological mechanisms reflect disturbances of both lower-level and multisensory processing along with specific cortical impairments such as at the temporoparietal junction. The latter has been linked, for example, to out-of-body experiences. Similarly, aberrant neural learning and signaling such as that based on synaptic receptor disturbances show how the interplay between lower-level brain activity and that in the prefrontal cortex contributes to delusions. Specific hypotheses set forth to explain these alterations in perception and cognition are reviewed, such as a remapping theory which depicts cortical reorganization in response to synaptic changes mediated by receptors. The effects of these perceptual/cognitive distortions on experiential pleasure/pain and on adaptability are also explored

Efficacy of Rhythmic Auditory Stimulation on Ataxia and Functional Dependence Post-Cerebellar Stroke

Ataxia, from Greek meaning, “lack of order,” is described as irregular movement and discoordination of body, gait, eyes, and speech. Ataxia is associated with cerebellar damage due to stroke and other cerebellar pathologies. Ataxia frequently results in functional impairment. Standard physical and occupational therapies in stroke rehabilitation facilitate motor recovery, especially within 90 days. However, many patients experience movement derangements beyond this time frame. Rhythmic auditory stimulation has been shown to be an effective intervention in chronic motor deficits like those observed after cerebellar stroke. Efficacy among patients with chronic stroke-induced ataxia is unexplored. This randomized control trial seeks to determine the benefit of rhythmic auditory stimulation over standard of care for rehabilitation of cerebellar stroke-induced ataxia. Patient progress will be assessed using validated disability and ataxia scales. It is projected that rhythmic auditory stimulation will improve ataxia and independence among patients with chronic disability post-cerebellar stroke, versus standard rehabilitation

Effectiveness of intensive physiotherapy for gait improvement in stroke: systematic review

Introduction: Stroke is one of the leading causes of functional disability worldwide. Approximately 80% of post-stroke subjects have motor changes. Improvement of gait pattern is one of the main objectives of physiotherapists intervention in these cases. The real challenge in the recovery of gait after stroke is to understand how the remaining neural networks can be modified, to be able to provide response strategies that compensate for the function of the affected structures. There is evidence that intensive training, including physiotherapy, positively influences neuroplasticity, improving mobility, pattern and gait velocity in post-stroke recovery. Objectives: Review and analyze in a systematic way the experimental studies (RCT) that evaluate the effects of Intensive Physiotherapy on gait improvement in poststroke subjects. Methodology: Were only included all RCT performed in humans, without any specific age, that had a clinical diagnosis of stroke at any stage of evolution, with sensorimotor deficits and functional gait changes. The databases used were: Pubmed, PEDro (Physiotherapy Evidence Database) and CENTRAL (Cochrane Center Register of Controlled Trials). Results: After the application of the criteria, there were 4 final studies that were included in the systematic review. 3 of the studies obtained a score of 8 on the PEDro scale and 1 obtained a score of 4. The fact that there is clinical and methodological heterogeneity in the studies evaluated, supports the realization of the current systematic narrative review, without meta-analysis. Discussion: Although the results obtained in the 4 studies are promising, it is important to note that the significant improvements that have been found, should be carefully considered since pilot studies with small samples, such as these, are not designed to test differences between groups, in terms of the effectiveness of the intervention applied. Conclusion: Intensive Physiotherapy seems to be safe and applicable in post-stroke subjects and there are indications that it is effective in improving gait, namely speed, travelled distance and spatiotemporal parameters. However, there is a need to develop more RCTs with larger samples and that evaluate the longterm resultsN/

Strategies of Neuroprotection after Successful Resuscitation

Post-cardiac arrest syndrome (PCAS) incorporates post-cardiac arrest brain injury, post-cardiac arrest myocardial dysfunction, systemic ischemia/reperfusion syndrome and the precipitating pathology. Brain injury remains the leading cause of death in the post-cardiac arrest period. One of our main goals during post-resuscitation care is to guide a proper neuroprotective strategy. We are going to summarize the tools of neuroprotection in post-cardiac arrest therapy. The role of normoxia/normocapnia, normoglycemia, seizure control, sedation and pharmacologic strategies will be discussed in brief. The handling of temperature management and the management of hemodynamic variables to secure satisfactory cerebral perfusion will be worked out in details. Targeted temperature management is the main tool of neuroprotection in post-cardiac arrest therapy. We are going to conclude the principles of temperature control after successful resuscitation pointing out its beneficial effects. This method has also several complications that are going to be discussed highlighting its hemodynamic impacts. There is no evidence about target hemodynamic parameters during post-cardiac arrest syndrome to maintain cerebral perfusion neither about the most effective hemodynamic monitoring system. We are presenting preliminary data of our study where we investigate the effect of PiCCO™ (Pulse index Continous Cardiac Output) monitoring on the outcome in this patient group