Fu Zen Shaw

Roles of Oxidative Stress, Apoptosis, PGC-1α and Mitochondrial Biogenesis in Cerebral Ischemia

The primary physiological function of mitochondria is to generate adenosine triphosphate through oxidative phosphorylation via the electron transport chain. Overproduction of reactive oxygen species (ROS) as byproducts generated from mitochondria have been implicated in acute brain injuries such as stroke from cerebral ischemia. It was well-documented that mitochondria-dependent apoptotic pathway involves pro- and anti-apoptotic protein binding, release of cytochrome c, leading ultimately to neuronal death. On the other hand, mitochondria also play a role to counteract the detrimental effects elicited by excessive oxidative stress. Recent studies have revealed that oxidative stress and the redox state of ischemic neurons are also implicated in the signaling pathway that involves peroxisome proliferative activated receptor-γ (PPARγ) co-activator 1α (PGC1-α). PGC1-α is a master regulator of ROS scavenging enzymes including manganese superoxide dismutase 2 and the uncoupling protein 2, both are mitochondrial proteins, and may contribute to neuronal survival. PGC1-α is also involved in mitochondrial biogenesis that is vital for cell survival. Experimental evidence supports the roles of mitochondrial dysfunction and oxidative stress as determinants of neuronal death as well as endogenous protective mechanisms after stroke. This review aims to summarize the current knowledge focusing on the molecular mechanisms underlying cerebral ischemia involving ROS, mitochondrial dysfunction, apoptosis, mitochondrial proteins capable of ROS scavenging, and mitochondrial biogenesis.

A Fully Integrated 8-Channel Closed-Loop Neural-Prosthetic CMOS SoC for Real-Time Epileptic Seizure Control

An 8-channel closed-loop neural-prosthetic SoC is presented for real-time intracranial EEG (iEEG) acquisition, seizure detection, and electrical stimulation in order to suppress epileptic seizures. The SoC is composed of eight energy-efficient analog front-end amplifiers (AFEAs), a 10-b delta-modulated SAR ADC (DMSAR ADC), a configurable bio-signal processor (BSP), and an adaptive high-voltage-tolerant stimulator. A wireless power-and-data transmission system is also embedded. By leveraging T-connected pseudo-resistors, the high-pass (low-pass) cutoff frequency of the AFEAs can be adjusted from 0.1 to 10 Hz (0.8 to 7 kHz). The noise-efficiency factor (NEF) of the AFEA is 1.77, and the DMSAR ADC achieves an ENOB of 9.57 bits. The BSP extracts the epileptic features from time-domain entropy and frequency spectrum for seizure detection. A constant 30- μA stimulus current is delivered by closed-loop control. The acquired signals are transmitted with on-off keying (OOK) modulation at 4 Mbps over the MedRadio band for monitoring. A multi-LDO topology is adopted to mitigate the interferences across different power domains. The proposed SoC is fabricated in 0.18- μm CMOS and occupies 13.47 mm2. Verified on Long Evans rats, the proposed SoC dissipates 2.8 mW and achieves high detection accuracy (> 92%) within 0.8 s.

Relationship between electroencephalogram slow-wave magnitude and heart rate variability during sleep in humans

To explore whether depth of sleep is related to changes in autonomic control, continuous power-spectral analysis of the electroencephalogram (EEG) and heart rate variability (HRV) was performed in ten normal subjects during nocturnal sleep. Quiet sleep (QS) was associated with an increase in high-frequency power (HF) of HRV (0.15-0.4 Hz) but a decrease in low-frequency power (LF) (0.04-0.15 Hz) to HF ratio (LF/HF) compared with awakening. During QS, LF/HF was significantly and negatively correlated with delta power of EEG (0.5-4.0 Hz), whereas mean R-R interval and HF were not. We conclude that during QS, cardiac sympathetic regulation is negatively related to the depth of sleep, although vagal regulation is not. Our methodology offers a quantitative analysis to study the interaction between cerebral cortical and autonomic functions.

Facilitation of Sensory and Motor Recovery by Thermal Intervention for the Hemiplegic Upper Limb in Acute Stroke Patients A Single-Blind Randomized Clinical Trial

Background and Purpose— Thermal stimulation (TS) is commonly used in orthopedic rehabilitation, but the role of TS in the facilitation of sensorimotor recovery in hemiplegic patients remains unknown. This study addressed the issue of TS intervention in the facilitation of functional outcomes. Methods— Forty-six stroke survivors were randomly assigned to standard rehabilitation treatment and standard treatment plus TS (30 minutes daily for 6 weeks). Twenty-nine patients completed the experiment. Six measures, including Brunnstrom stage, modified motor assessment scale, grasping strength, angles of wrist extension and flexion, sensation by monofilament, and muscle tone by modified Ashworth scale, were performed weekly to evaluate sensory and motor functional outcomes. Results— The performance of Brunnstrom stage and wrist extension and sensation were improved significantly after TS intervention. Recovery rates of 6 measures after TS were significantly higher than those of the control, except for grasping. Similar muscle tones were found in both groups. Conclusion— TS on the paretic hand significantly enhances the recovery of several aspects of sensory and motor functions in hemiplegic stroke patients.

Protective effects of peroxisome proliferator‐activated receptors γ coactivator‐1α against neuronal cell death in the hippocampal CA1 subfield after transient global ischemia

Peroxisome proliferator‐activated receptors γ coactivator‐1α (PGC‐1α) may regulate the mitochondrial antioxidant defense system under many neuropathological settings. However, the exact role of PGC‐1α in ischemic brain damage is still under debate. Based on an experimental model of transient global ischemia (TGI), this study evaluated the hypothesis that the activation of PGC‐1α signaling pathway protects hippocampal CA1 neurons against delayed neuronal death after TGI. In Sprague‐Dawley rats, significantly increased content of oxidized proteins in the hippocampal CA1 tissue was observed as early as 30 min after TGI, followed by augmentation of PGC‐1α expression at 1 hr. Expression of uncoupling protein 2 (UCP2) and superoxide dismutases 2 (SOD2) in the hippocampal CA1 neurons was upregulated 4–48 hr after TGI. In addition, knock‐down of PGC‐1α expression by pretreatment with a specific antisense oligodeoxynucleotide in the hippocampal CA1 subfield downregulated the expression of UCP2 and SOD2 with resultant exacerbation of oxidative stress and augmentation of delayed neuronal cell death in the hippocampus after TGI. Overall, our results indicate that PGC‐1α is induced by cerebral ischemia leading to upregulation of UCP2 and SOD2, thereby providing a neuroprotective effect against ischemic brain injury in the hippocampus by ameliorating oxidative stress.

Dynamic changes of touch- and laser heat-evoked field potentials of primary somatosensory cortex in awake and pentobarbital-anesthetized rats

In this investigation, changes of mechanical- (MEP) and laser-evoked potentials (LEP) in rat primary somatosensory cortex during the course of pentobarbital (PB) anesthesia were examined. Temporal analysis of changes in the magnitude and latency of MEP and LEP, EEG activity, gross motor behaviors, and the tail flick response following laser stimulation before, during, and after PB administration (50 mg/kg, i.p.) was performed and correlated in chronically implanted rats. During the wakeful condition, there were two major cortical components each following mechanical stimulation (MEP1 and MEP2, n=17) and laser stimulation (LEP1 and LEP2, n=10), respectively. After PB administration, the positive peak in MEP1 was enhanced, and all other components disappeared. These components returned with different time courses. Two hours after PB administration, when the rat had spontaneous movements and flexor reflexes, LEP2 showed reversed polarity. MEP2 returned gradually 3 h after PB administration when the rat regained its ability to execute coordinated movements. After 4 h, LEP1 began to reappear and LEP2 returned to its negative polarity. We found that PB facilitated Abeta fiber-related cortical evoked potential (MEP1), while differentially inhibited Adelta and C fiber-related components (MEP2, LEP1 and LEP2). Characterization of these anesthesia-induced changes in cortical output may be useful in studying the neural basis of tactile and pain sensations.

Comparison of touch- and laser heat-evoked cortical field potentials in conscious rats

Field potentials and multiunit activities from chronically implanted cortical electrodes were used to study tactile and nociceptive information processing from the tail of the rat. Fourteen stainless steel screws implanted in the skull were used as electrodes to record field potentials in different cortical areas. Electrical, mechanical, and laser pulses were applied to the tail to induce evoked cortical field potentials. Evoked responses were compared before and after sodium pentobarbital anesthesia (50 mg/kg, i.p.). In both electrical- and mechanical-evoked potential (EEP and MEP) studies, two major peaks were found in the conscious animal. The polarity of the late component was modified after pentobarbital anesthesia. In the laser-evoked potential (LEP) study, two distinct negative peaks were found. Both peaks were very sensitive to anesthesia. Following quantitative analysis, our data suggest that the first positive peak of EEP and MEP corresponded to the activation of the Abeta fiber, the second negative peak of MEP and the first peak of LEP corresponded to Adelta fiber activation, while the second peak of LEP corresponded to C fiber activation. The absolute magnitudes of all cortical components were positively related to the intensity of the stimulation. From spatial mapping analysis, a localized concentric source of field potential was observed in the primary somatosensory cortex (SI) only after activation of the Abeta fiber. Larger responsive cortical areas were found in response to Adelta and C fiber activation. In an intracortical recording experiment, both tactile and nociceptive stimulation evoked heightened unit activity changes at latencies corresponding to respective field potentials. We conclude that different cortical areas are involved in the processing of A and C fiber afferent inputs, and barbiturate anesthesia modifies their processing.

A Portable Wireless Online Closed-Loop Seizure Controller in Freely Moving Rats

A considerable portion of epilepsy cannot be well treated by available therapies nowadays. Brain stimulation with closed-loop seizure control has recently been proposed as an innovative and effective alternative. A portable wireless online closed-loop seizure controller in freely moving rats was developed and shown with several aspects of advantages, including the following: 1) high accuracy of real-time seizure detection (92-99% during wake-sleep states); 2) low cost; and 3) low power consumption. The seizure detection latency was not greater than 0.6 s after seizure onset. A wireless communication feature also provided flexibility for subjects freeing from the hassle of wires. The observation showed that the stimulation elicited no abnormal behavior and had no sleep interruption to the subjects. The experiment data supported the functional possibility of a real-time closed-loop seizure controller.

A low-noise flexible integrated system for recording and analysis of multiple electrical signals during sleep-wake states in rats.

A low-noise flexible system for the simultaneous recording and analysis of several electrical signals (EEG, ECG, EMG, and diaphragm EMG) from the same rat was constructed for studying changes in physiological functions during the sleep-wake cycle. The hardware in the system includes a multichannel amplifier, a video camera, a timer code generator, and a PC. A miniature buffer headstage with high-input impedance connected to a 6-channel amplifier was developed. All electrical activities devoid of 60 Hz interference could be consistently recorded by our low-cost amplifier with no shielding treatment. The analytical software was established in the LabVIEW environment and consisted of three major frames: temporal, spectral, and nonlinear analyses. These analytical tools demonstrated several distinct utilities. For example, the sleep-wake states could be successfully distinguished by combining temporal and spectral analyses. An obvious theta rhythm during rapid-eye-movement sleep (REMS) was recorded from parietal to occipital cortical areas but not from the frontal area. In addition, two types of sleep apnea with/without cardiac arrhythmias were observed under REMS condition. Moreover, the evoked potentials of the primary somatosensory cortex elicited by innocuous electrical pulses were modulated by vigilant states, especially under a slow-wave sleep state. These results show that our system delivers high-quality signals and is suitable for sleep investigations. The system can be easily expanded by combining other recording devices, like a plethysmograph. This compact system can also be easily modified and applied to other related physiological or pharmacological studies.

Activation of calcium/calmodulin-dependent protein kinase IV and peroxisome proliferator-activated receptor γ coactivator-1α signaling pathway protects against neuronal injury and promotes mitochondrial biogenesis in the hippocampal CA1 subfield after transient global ischemia

Delayed neuronal cell death occurs in the vulnerable CA1 subfield of the hippocampus after transient global ischemia (TGI). We demonstrated previously, based on an experimental model of TGI, that the significantly increased content of oxidized proteins in hippocampal CA1 neuron was observed as early as 30 min after TGI, followed by augmentation of PGC‐1α expression at 1 hr, as well as up‐regulation of mitochondrial uncoupling protein 2 (UCP2) and superoxide dismutases 2 (SOD2). Using the same animal model, the present study investigated the role of calcium/calmodulin‐dependent protein kinase IV (CaMKIV) and PGC‐1α in delayed neuronal cell death and mitochondrial biogenesis in the hippocampus. In Sprague‐Dawley rats, significantly increased expression of nuclear CaMKIV was noted in the hippocampal CA1 subfield as early as 15 min after TGI. In addition, the index of mitochondrial biogenesis, including a mitochondrial DNA‐encoded polypeptide, cytochrome c oxidase subunit 1 (COX1), and mitochondrial number significantly increased in the hippocampal CA1 subfield 4 hr after TGI. Application bilaterally into the hippocampal CA1 subfield of an inhibitor of CaMKIV, KN‐93, 30 min before TGI attenuated both CaMKIV and PGC‐1α expression, followed by down‐regulation of UCP2 and SOD2, decrease of COX1 expression and mitochondrial number, heightened protein oxidation, and enhanced hippocampal CA1 neuronal damage. This study provides correlative evidence for the neuroprotective cascade of CaMKIV/PGC‐1α which implicates at least in part the mitochondrial antioxidants UCP2 and SOD2 as well as mitochondrial biogenesis in ischemic brain injury.