Electrophysiological Brain Monitoring after Cardiac Arrest with Temperature Management

Cardiac arrest (CA) is the leading cause of disability and death annually in the United States. Therapeutic hypothermia (TH) has been recommended as one of the standard practices for improving neurological outcome and survival to treat out-of-hospital CA patients after resuscitation. However, many clinical prognostic markers after resuscitation for predicting outcome have been less reliable under hypothermia. Therefore, there is a strong need to evaluate the prognostic value of current prognostic markers for hypoxic-ischemic brain injury after CA. The first part of this work was to review current literature and assess the prognostic value of current significant breakthroughs in neurophysiologic and electrophysiological methods for CA patients treated with TH in order to provide a comprehensive frame for future work. Due to the restrictions of standard clinical examinations and neuroimaging techniques in detecting brain injury, electroencephalography (EEG) has emerged as one of the commonly used bed-side real-time monitoring tools for prognostication. Instead of the subjective and impractical analysis of waveform-based raw EEG signals, we applied two quantitative methods – information quantity (IQ) and sub-band IQ (SIQ) – to quantify and examine the accuracy of prognostic value of EEG markers on predicting recovery under TH in the second part of this work. Our study discovered that both IQ and SIQ accurately predict neurologic outcome at the early stage of cerebral recovery. Moreover, high-frequency oscillations (HFO) were particularly noticeable during the recovery from severe brain injury indicated by IQ, and SIQ was able to provide additional standard clinical EEG bands of interests. The ischemic brain after CA is sensitive to trivial fluctuations of temperature. Previously, we only observed temperature management strongly affects the recovery of global EEG. However, EEG signals can be decomposed into different frequency sub-bands in clinical practices, which are related to different brain functions, and the association has not been elucidated between the recovery of each sub-band EEG and temperature management. In the third part of this work, we employed SIQ, of which indicative ability has been proven in the last part, to determine the most relevant sub-bands of EEG during brain recovery with temperature manipulation. It was found for the first time that gamma-band EEG activity, linked with high cognitive processes, was primarily affected by temperature and strongly associated with neurologic outcome, while delta-band played a role as constant component of EEG without stable relationship with temperature or outcome. Somatosensory evoked potentials (SSEPs), especially N20 responses in human, are able to evaluate the somatosensory system functioning, which are also regarded as a reliable early prognostic marker for post-CA neurologic outcome. Transcranial direct current stimulation (tDCS) is a non-invasive technique to modulate the cerebral excitability and activity which has been confirmed by motor evoked potentials (MEPs), but it is still unclear whether it can affect the somatosensory cortex. The final part of this work preliminarily studied the alternations of excitability of somatosensory cortex by tDCS and investigated the potential of SSEPs on measuring the after-effect of tDCS

Ciliary parathyroid hormone signaling activates transforming growth factor-β to maintain intervertebral disc homeostasis during aging

© 2018 The Author(s). Degenerative disc disease (DDD) is associated with intervertebral disc degeneration of spinal instability. Here, we report that the cilia of nucleus pulposus (NP) cells mediate mechanotransduction to maintain anabolic activity in the discs. We found that mechanical stress promotes transport of parathyroid hormone 1 receptor (PTH1R) to the cilia and enhances parathyroid hormone (PTH) signaling in NP cells. PTH induces transcription of integrin αvβ6 to activate the transforming growth factor (TGF)-β-connective tissue growth factor (CCN2)-matrix proteins signaling cascade. Intermittent injection of PTH (iPTH) effectively attenuates disc degeneration of aged mice by direct signaling through NP cells, specifically improving intervertebral disc height and volume by increasing levels of TGF-β activity, CCN2, and aggrecan. PTH1R is expressed in both mouse and human NP cells. Importantly, knockout PTH1R or cilia in the NP cells results in significant disc degeneration and blunts the effect of PTH on attenuation of aged discs. Thus, mechanical stress-induced transport of PTH1R to the cilia enhances PTH signaling, which helps maintain intervertebral disc homeostasis, particularly during aging, indicating therapeutic potential of iPTH for DDD

Electrophysiological Brain Monitoring after Cardiac Arrest with Temperature Management

Cardiac arrest (CA) is the leading cause of disability and death annually in the United States. Therapeutic hypothermia (TH) has been recommended as one of the standard practices for improving neurological outcome and survival to treat out-of-hospital CA patients after resuscitation. However, many clinical prognostic markers after resuscitation for predicting outcome have been less reliable under hypothermia. Therefore, there is a strong need to evaluate the prognostic value of current prognostic markers for hypoxic-ischemic brain injury after CA. The first part of this work was to review current literature and assess the prognostic value of current significant breakthroughs in neurophysiologic and electrophysiological methods for CA patients treated with TH in order to provide a comprehensive frame for future work. Due to the restrictions of standard clinical examinations and neuroimaging techniques in detecting brain injury, electroencephalography (EEG) has emerged as one of the commonly used bed-side real-time monitoring tools for prognostication. Instead of the subjective and impractical analysis of waveform-based raw EEG signals, we applied two quantitative methods – information quantity (IQ) and sub-band IQ (SIQ) – to quantify and examine the accuracy of prognostic value of EEG markers on predicting recovery under TH in the second part of this work. Our study discovered that both IQ and SIQ accurately predict neurologic outcome at the early stage of cerebral recovery. Moreover, high-frequency oscillations (HFO) were particularly noticeable during the recovery from severe brain injury indicated by IQ, and SIQ was able to provide additional standard clinical EEG bands of interests. The ischemic brain after CA is sensitive to trivial fluctuations of temperature. Previously, we only observed temperature management strongly affects the recovery of global EEG. However, EEG signals can be decomposed into different frequency sub-bands in clinical practices, which are related to different brain functions, and the association has not been elucidated between the recovery of each sub-band EEG and temperature management. In the third part of this work, we employed SIQ, of which indicative ability has been proven in the last part, to determine the most relevant sub-bands of EEG during brain recovery with temperature manipulation. It was found for the first time that gamma-band EEG activity, linked with high cognitive processes, was primarily affected by temperature and strongly associated with neurologic outcome, while delta-band played a role as constant component of EEG without stable relationship with temperature or outcome. Somatosensory evoked potentials (SSEPs), especially N20 responses in human, are able to evaluate the somatosensory system functioning, which are also regarded as a reliable early prognostic marker for post-CA neurologic outcome. Transcranial direct current stimulation (tDCS) is a non-invasive technique to modulate the cerebral excitability and activity which has been confirmed by motor evoked potentials (MEPs), but it is still unclear whether it can affect the somatosensory cortex. The final part of this work preliminarily studied the alternations of excitability of somatosensory cortex by tDCS and investigated the potential of SSEPs on measuring the after-effect of tDCS

Regulation of Periosteal Myeloid-Lineage Cells for Cortical Bone Formation

Cortical bone mass determines bone strength and fracture resistance, which is mediated by the periosteum. Periosteal bone formation decreases with age but can be stimulated and revived by mechanical loading. Yet the mechanism that regulates cortical bone homeostasis and loading-induced periosteal bone formation has not been fully understood. This dissertation uncovered the underlying cellular and molecular mechanisms of cortical bone formation. Chapter 1 provides a broad introduction of periosteal bone formation to the field of what has been known. In Chapter 2 and Chapter 3, two distinct subpopulations of myeloid-lineage cells, tartrate-resistant acid phosphatase–positive (TRAP+) and CD68+F4/80+, have been identified in the periosteum. We have found that periosteal TRAP+ mononuclear cells secrete platelet-derived growth factor-BB (PDGF-BB), which sequentially recruits periosteum-derived cells (PDCs) to the periosteal bone surface. The recruited PDCs differentiate into osteoblasts coupled with angiogenesis to maintain the cortical bone homeostasis. We specifically deleted Pdgfb in TRAP+ cells using a Trap-cre;Pdgfbf/f mouse model. Significant declines in periosteal bone formation with impaired PDC recruitment and periostin expression were noted in the knockout mice. Consistent with these findings, the knockout of PDGF receptor β also showed a remarkable decrease of PDCs on the periosteal bone surface. Based on these observations, we explored the regulation of myeloid-lineage cells in mechanical loading-induced periosteal bone formation. Surprisingly, mechanical loading did not induce significant changes in the number of periosteal TRAP+ cells as expected. Another subpopulation of periosteal myeloid-lineage cells, CD68+F4/80+ but TRAP-, was found to be increased after mechanical loading. Mechanistically, mechanical loading induced the differentiation of CD68+F4/80- into CD68+F4/80+ macrophages through piezo-type mechanosensitive ion channel component 1 (PIEZO1) signaling. CD68+F4/80+ macrophages secrete and further activate TGF-β1 via thrombospondin-1 (Thbs1) to recruit osteoprogenitors to the periosteal bone surface for cortical bone formation. Knockout of Tgfb1 in myeloid-lineage cells attenuated mechanical loading-induced periosteal bone formation in mice. Administration of Thbs1 inhibitor significantly impaired loading-induced TGF-β activation and recruitment of osteoprogenitors in the periosteum. In conclusion, this dissertation has distilled the essential role of periosteal myeloid-lineage cells in regulating PDCs or osteoprogenitors for cortical bone homeostasis and loading-induced cortical bone formation

Electrophysiological Monitoring of Brain Injury and Recovery after Cardiac Arrest

Reliable prognostic methods for cerebral functional outcome of post cardiac-arrest (CA) patients are necessary, especially since therapeutic hypothermia (TH) as a standard treatment. Traditional neurophysiological prognostic indicators, such as clinical examination and chemical biomarkers, may result in indecisive outcome predictions and do not directly reflect neuronal activity, though they have remained the mainstay of clinical prognosis. The most recent advances in electrophysiological methods—electroencephalography (EEG) pattern, evoked potential (EP) and cellular electrophysiological measurement—were developed to complement these deficiencies, and will be examined in this review article. EEG pattern (reactivity and continuity) provides real-time and accurate information for early-stage (particularly in the first 24 h) hypoxic-ischemic (HI) brain injury patients with high sensitivity. However, the signal is easily affected by external stimuli, thus the measurements of EP should be combined with EEG background to validate the predicted neurologic functional result. Cellular electrophysiology, such as multi-unit activity (MUA) and local field potentials (LFP), has strong potential for improving prognostication and therapy by offering additional neurophysiologic information to understand the underlying mechanisms of therapeutic methods. Electrophysiology provides reliable and precise prognostication on both global and cellular levels secondary to cerebral injury in cardiac arrest patients treated with TH

Fabrication Method for the High-Accuracy Optical Fiber Delay Line with Specified Length

We propose a novel scheme for fabricating high-accuracy optical fiber delay lines (OFDLs). The fabrication system integrates a self-designed optical fiber cutting device and a high-accuracy fiber length measurement module based on optical frequency domain reflectometry. The optical fiber cutting device can cleave optical fibers to a specific length with the help of the motorized stage. The accuracy of fiber-cutting was determined by the positional accuracy of the motorized stage, which can reach several microns or even lower. This integrated design significantly reduces the errors and uncertainties introduced by fiber-cutting. To test, a set of OFDLs of a certain length was fabricated by this system. The deviation from the desired fiber length was kept below 50 μm, thus proving high fabrication accuracy and repeatability

A Tunable Dual-Passband Microwave Photonic Filter Based on Optically Injected Distributed Feedback Semiconductor Lasers and Dual-Output Mach-Zehnder Modulator

In this paper, a novel approach to achieving a wideband tunable dual-passband microwave photonic filter (MPF) is proposed based on optical-injected distributed feedback (DFB) semiconductor lasers and a dual-output Mach–Zehnder modulator (DOMZM). The fundamental concepts for realizing the MPF are the wavelength-selective amplification effect and the period-one oscillation state under optically injected DFB lasers. These effects provide a widely tunable range of center frequency, along with high flexibility and low insertion loss. The proposed MPF is experimentally demonstrated, showing that the dual-passband center frequency in the MPF can be tuned independently from 19 to 37 GHz by adjusting the detuning frequency and injection ratio. Meanwhile, the insertion loss of the system is about 15 dB when there is no optical or electrical amplifier in the MPF link. The out-of-band suppression ratio of the MPF is more than 20 dB, which can be improved by adjusting the power of the two optical signals