EEG/ECoG/EMG publications

Introduction The abrupt cessation of chronic benzodiazepine administration is associated with the development of withdrawal symptoms like increased susceptibility to seizures or seizure development in both animals and humans. Although withdrawal phenomena have been studied in detail in adult animals, information about their development and nature in the immature brain is lacking. Substantial experimental evidence suggests that exposure to BZDs early in life permanently alters brain circuitry and functions. However, the possible long-term modification of seizure propensity has not yet been studied. Methods Clonazepam (CZP) was injected into rat pups daily at a dose of 1 mg/kg for five consecutive days, starting on postnatal day 7 (P7) and continuing until P11. Seizure susceptibility was assessed using a pentylenetetrazol (PTZ)-induced seizure model. PTZ induces three types of seizures in rodents that differ by developmental profile and manifestations: convulsive myoclonic seizures (mS) and generalized tonic-clonic seizures (GTCS), and absence-like rhythmic spike-and-wave EEG activity (RMA). Seizures were induced with a single threshold dose of 50–60 mg/kg on days 2, 4, 7, 10, or 14, or with three additive doses of 20 mg/kg on days 7 and 14, or 3 months after the end of treatment. Convulsions accompanying mS and GTCS were detected behaviorally, and RMA was detected in EEG recordings. Results The effects of early-life CZP exposure on susceptibility to PTZ-induced seizures were highly dependent on the interval after treatment cessation and the seizure type. Cessation of CZP after a single PTZ threshold dose resulted in an increase in seizure severity compared to controls that was driven by an increased incidence of GTCS lasting 1 week (up to P18). Early-life CZP exposure led to decreased latency to the first RMA and increased RMA frequency after the first PTZ dose of 20 mg/kg in adult (P90) animals, but it did not change RMA parameters in juvenile rats. Conclusion Abruptly ceasing clonazepam administration in infant rats results in the development of withdrawal phenomena, represented by a striking increase in seizure propensity. Interestingly, transient augmentation of GABAergic inhibition during critical periods of synaptogenesis and neural network formation and maturation permanently modifies susceptibility to PTZ-induced epileptiform activity.

Objectives The study of autonomic responses to cardiac arrest (CA) resuscitation deserves attention due to the impact of autonomic function on survival and arousal. Orexins are known to modulate autonomic function, but the role of endogenous orexin in hyperacute recovery of autonomic function post-resuscitation is not well understood. We hypothesized that endogenous orexin facilitates hyperacute cardiovascular sympathetic activity post-resuscitation, and this response could be attenuated by suvorexant, a dual orexin receptor antagonist. Methods A well-established 7-min asphyxial CA rat model was studied. Heart rate (HR) and blood pressure were monitored from baseline to 90-min post-resuscitation. Autonomic function was evaluated by spectral analysis of HR variability, whereby the ratio of low- and high-frequency components (LF/HF ratio) represents the balance between sympathetic/parasympathetic activities. Plasma orexin-A levels and orexin receptors immunoreactivity in the rostral ventrolateral medulla (RVLM), the key central region for regulating sympathetic output, were measured post-resuscitation. Neurological outcome was assessed via neurologic-deficit score at 4-h post-resuscitation. Key results A significant increase in HR was found over 25–40 min post-resuscitation ( p < 0.01 vs. baseline), which was attenuated by suvorexant significantly ( p < 0.05). Increased HR (from 15-to 25-min post-resuscitation) was correlated with better neurological outcomes ( rs = 0.827, p = 0.005). There was no evident increase in mean arterial pressure over 25–40 min post-resuscitation, while systolic pressure was reduced greatly by suvorexant ( p < 0.05). The LF/HF ratio was higher in animals with favorable outcomes than in animals injected with suvorexant over 30–40 min post-resuscitation ( p < 0.05). Plasma orexin-A levels elevated at 15-min and peaked at 30-min post-resuscitation ( p < 0.01 vs. baseline). Activated orexin receptors-immunoreactive neurons were found co-stained with tyrosine hydroxylase-immunopositive cells in the RVLM at 2-h post-resuscitation. Conclusion Together, increased HR and elevated LF/HF ratio indicative of sympathetic arousal during a critical window (25–40 min) post-resuscitation are observed in animals with favorable outcomes. The orexin system appears to facilitate this hyperacute autonomic response post- CA.

Sudden and surprising sensory events trigger neural processes that swiftly adjust behavior. To study the phylogenesis and the mechanism of this phenomenon, we trained two male rhesus monkeys to keep a cursor inside a visual target by exerting force on an isometric joystick. We examined the effect of surprising auditory stimuli on exerted force, scalp electroencephalographic (EEG) activity, and local field potentials (LFPs) recorded from the dorsolateral prefrontal cortex. Auditory stimuli elicited (1) a biphasic modulation of isometric force, a transient decrease followed by a corrective tonic increase, and (2) EEG and LFP deflections dominated by two large negativepositive waves (N70 and P130). The EEG potential was symmetrical and maximal at the scalp vertex, highly reminiscent of the human vertex potential. Electrocortical potentials and force were tightly coupled: the P130 amplitude predicted the magnitude of the corrective force increase, particularly in the LFPs recorded from deep rather than superficial cortical layers. These results disclose a phylogenetically preserved corticomotor mechanism supporting adaptive behavior in response to salient sensory events. Significance Statement Survival in the natural world depends on an animals capacity to adapt ongoing behavior to abrupt unexpected events. To study the neural mechanisms underlying this capacity, we trained monkeys to apply constant force on a joystick while we recorded their brain activity from the scalp and the prefrontal cortex contralateral to the hand holding the joystick. Unexpected auditory stimuli elicited a biphasic force modulation: a transient reduction followed by a corrective adjustment. The same stimuli also elicited EEG and LFP responses, dominated by a biphasic wave that predicted the magnitude of the behavioral adjustment. These results disclose a phylogenetically preserved corticomotor mechanism supporting adaptive behavior in response to unexpected events.

Objective There is a complex interaction between nervous and cardiovascular systems, but sparse data exist on brain–heart electrophysiological responses to cardiac arrest resuscitation. Our aim was to investigate dynamic changes in autonomic and cortical function during hyperacute stage post‐resuscitation. Methods Ten rats were resuscitated from 7‐min cardiac arrest, as indicators of autonomic response, heart rate (HR), and its variability (HRV) were measured. HR was monitored through continuous electrocardiography, while HRV was assessed via spectral analysis, whereby the ratio of low−/high‐frequency (LF/HF) power indicates the balance between sympathetic/parasympathetic activities. Cortical response was evaluated by continuous electroencephalography and quantitative analysis. Parameters were quantified at 5‐min intervals over the first‐hour post‐resuscitation. Neurological outcome was assessed by Neurological Deficit Score (NDS, range 0–80, higher = better outcomes) at 4‐h post‐resuscitation. Results A significant increase in HR was noted over 15–30 min post‐resuscitation ( p < 0.01 vs.15‐min, respectively) and correlated with higher NDS ( r s = 0.56, p < 0.01). LF/HF ratio over 15–20 min was positively correlated with NDS ( r s = 0.75, p < 0.05). Gamma band power surged over 15–30 min post‐resuscitation ( p < 0.05 vs. 0–15 min, respectively), and gamma band fraction during this period was associated with NDS ( r s ≥0.70, p < 0.05, respectively). Significant correlations were identified between increased HR and gamma band power during 15–30 min ( r s ≥0.83, p < 0.01, respectively) and between gamma band fraction and LF/HF ratio over 15–20 min post‐resuscitation ( r s = 0.85, p < 0.01). Interpretations Hyperacute recovery of autonomic and cortical function is associated with favorable functional outcomes. While this observation needs further validation, it presents a translational opportunity for better autonomic and neurologic monitoring during early periods post‐resuscitation to develop novel interventions.

Cardiac arrest (CA) entails significant risks of coma resulting in poor neurological and behavioral outcomes after resuscitation. Significant subsequent morbidity and mortality in post-CA patients are largely due to the cerebral and cardiac dysfunction that accompanies prolonged whole-body ischemia post-CA syndrome (PCAS). PCAS results in strong inflammatory responses including neuroinflammation response leading to poor outcome. Currently, there are no proven neuroprotective therapies to improve post-CA outcomes apart from therapeutic hypothermia. Furthermore, there are no acceptable approaches to promote cortical or cognitive arousal following successful return of spontaneous circulation (ROSC). Hypothalamic orexinergic pathway is responsible for arousal and it is negatively affected by neuroinflammation. However, whether activation of the orexinergic pathway can curtail neuroinflammation is unknown. We hypothesize that targeting the orexinergic pathway via intranasal orexin-A (ORXA) treatment will enhance arousal from coma and decrease the production of proinflammatory cytokines resulting in improved functional outcome after resuscitation. We used a highly validated CA rat model to determine the effects of intranasal ORXA treatment 30-minute post resuscitation. At 4hrs post-CA, the mRNA levels of proinflammatory markers (IL1β, iNOS, TNF-α, GFAP, CD11b) and orexin receptors (ORX1R and ORX2R) were examined in different brain regions. CA dramatically increased proinflammatory markers in all brain regions particularly in the prefrontal cortex, hippocampus and hypothalamus. Post-CA intranasal ORXA treatment significantly ameliorated the CA-induced neuroinflammatory markers in the hypothalamus. ORXA administration increased production of orexin receptors (ORX1R and ORX2R) particularly in hypothalamus. In addition, ORXA also resulted in early arousal as measured by quantitative electroencephalogram (EEG) markers, and recovery of the associated behavioral neurologic deficit scale score (NDS). Our results indicate that intranasal delivery of ORXA post-CA has an anti-inflammatory effect and accelerates cortical EEG and behavioral recovery. Beneficial outcomes from intranasal ORXA treatment lay the groundwork for therapeutic clinical approach to treating post-CA coma.

We develop a framework to uncover and analyse dynamical anomalies from massive, nonlinear and non-stationary time series data. The framework consists of three steps: preprocessing of massive datasets to eliminate erroneous data segments, application of the empirical mode decomposition and Hilbert transform paradigm to obtain the fundamental components embedded in the time series at distinct time scales, and statistical/scaling analysis of the components. As a case study, we apply our framework to detecting and characterizing high-frequency oscillations (HFOs) from a big database of rat electroencephalogram recordings. We find a striking phenomenon: HFOs exhibit on–off intermittency that can be quantified by algebraic scaling laws. Our framework can be generalized to big data-related problems in other fields such as large-scale sensor data and seismic data analysis.

There has been continued interest in clinical objective measures of binaural processing. One commonly proposed measure is the binaural interaction component (BIC), which is obtained typically by recording auditory brainstem responses (ABRs)—the BIC reflects the difference between the binaural ABR and the sum of the monaural ABRs (i.e., binaural − (left + right)). We have recently developed an alternative, direct measure of sensitivity to interaural time differences, namely, a following response to modulations in interaural phase difference (the interaural phase modulation following response; IPM-FR). To obtain this measure, an ongoing diotically amplitude-modulated signal is presented, and the interaural phase difference of the carrier is switched periodically at minima in the modulation cycle. Such periodic modulations to interaural phase difference can evoke a steady state following response. BIC and IPM-FR measurements were compared from 10 normal-hearing subjects using a 16-channel electroencephalographic system. Both ABRs and IPM-FRs were observed most clearly from similar electrode locations—differential recordings taken from electrodes near the ear (e.g., mastoid) in reference to a vertex electrode (Cz). Although all subjects displayed clear ABRs, the BIC was not reliably observed. In contrast, the IPM-FR typically elicited a robust and significant response. In addition, the IPM-FR measure required a considerably shorter recording session. As the IPM-FR magnitude varied with interaural phase difference modulation depth, it could potentially serve as a correlate of perceptual salience. Overall, the IPM-FR appears a more suitable clinical measure than the BIC.

Spectro-Temporal Receptive Fields (STRFs) were estimated from both multi-unit sorted clusters and high-gamma power responses in human auditory cortex. Intracranial electrophysiological recordings were used to measure responses to a random chord sequence of Gammatone stimuli. Traditional methods for estimating STRFs from single-unit recordings, such as spike-triggered-averages, tend to be noisy and are less robust to other response signals such as local field potentials. We present an extension to recently advanced methods for estimating STRFs from generalized linear models (GLM). A new variant of regression using regularization that penalizes non-zero coefficients is described, which results in a sparse solution. The frequency-time structure of the STRF tends toward grouping in different areas of frequency-time and we demonstrate that group sparsity-inducing penalties applied to GLM estimates of STRFs reduces the background noise while preserving the complex internal structure. The contribution of local spiking activity to the high-gamma power signal was factored out of the STRF using the GLM method, and this contribution was significant in 85 percent of the cases. Although the GLM methods have been used to estimate STRFs in animals, this study examines the detailed structure directly from auditory cortex in the awake human brain. We used this approach to identify an abrupt change in the best frequency of estimated STRFs along posteromedial-to-anterolateral recording locations along the long axis of Heschl's gyrus. This change correlates well with a proposed transition from core to non-core auditory fields previously identified using the temporal response properties of Heschl's gyrus recordings elicited by click-train stimuli.

An extensive photosensitive-polyimide (PSPI)-based method for designing and fabricating various neural electrode architectures was developed. The method aims to broaden the design flexibility and expand the fabrication capability for neural electrodes to improve the quality of recorded signals and integrate other functions. After characterizing PSPI's properties for micromachining processes, we successfully designed and fabricated various neural electrodes even on a non-flat substrate using only one PSPI as an insulation material and without the time-consuming dry etching processes. The fabricated neural electrodes were an electrocorticogram (ECoG) electrode, a mesh intracortical electrode with a unique lattice-like mesh structure to fixate neural tissue, and a guide cannula electrode with recording microelectrodes placed on the curved surface of a guide cannula as a microdialysis probe. In vivo neural recordings using anesthetized rats demonstrated that these electrodes can be used to record neural activities repeatedly without any breakage and mechanical failures, which potentially promises stable recordings for long periods of time. These successes make us believe that this PSPI-based fabrication is a powerful method, permitting flexible design, and easy optimization of electrode architectures for a variety of electrophysiological experimental research with improved neural recording performance.

This study examines the feasibility of using electroencephalograms (EEGs) to rapidly detect the intent to open one's hand in individuals with complete hand paralysis following a subcortical ischemic stroke. If detectable, this motor-planning activity could be used in real time to trigger a motorized hand exoskeleton or an electrical stimulation device that opens/closes the hand. While EEG-triggered movement-assist devices could restore function, they may also promote recovery by reinforcing the use of remaining cortical circuits. EEGs were recorded while participants were cued to either relax or attempt to extend their fingers. Linear-discriminant analysis was used to detect onset of finger-extension from the EEGs in a leave-one-trial-out cross-validation process. In each testing trial, the classifier was applied in pseudo-real-time starting from an initial hand-relaxed phase, through movement planning, and into the initial attempted-finger-extension phase (finger-extension phase estimated from typical time-to-movement-onset measured in the unaffected hand). The classifiers detected attempted-finger-extension at a significantly higher rate during both motor-planning and early attempted execution compared to rest. To reduce inappropriate triggering of a movement-assist device during rest, the classification threshold could be adjusted to require more certainty about one's intent to move before triggering a device. Additionally, a device could be set to activate only after multiple time samples in a row were classified as finger-extension events. These options resulted in some sessions with no false triggers while the person was resting, but moderate-to-high true trigger rates during attempted-movements.