John M. Zempel

Intrinsic functional architecture in the anaesthetized monkey brain.

The traditional approach to studying brain function is to measure physiological responses to controlled sensory, motor and cognitive paradigms. However, most of the brain’s energy consumption is devoted to ongoing metabolic activity not clearly associated with any particular stimulus or behaviour. Functional magnetic resonance imaging studies in humans aimed at understanding this ongoing activity have shown that spontaneous fluctuations of the blood-oxygen-level-dependent signal occur continuously in the resting state. In humans, these fluctuations are temporally coherent within widely distributed cortical systems that recapitulate the functional architecture of responses evoked by experimentally administered tasks. Here, we show that the same phenomenon is present in anaesthetized monkeys even at anaesthetic levels known to induce profound loss of consciousness. We specifically demonstrate coherent spontaneous fluctuations within three well known systems (oculomotor, somatomotor and visual) and the ‘default’ system, a set of brain regions thought by some to support uniquely human capabilities. Our results indicate that coherent system fluctuations probably reflect an evolutionarily conserved aspect of brain functional organization that transcends levels of consciousness.

Electrophysiological correlates of the brain's intrinsic large-scale functional architecture

Spontaneous fluctuations in the blood-oxygen-level-dependent (BOLD) signals demonstrate consistent temporal correlations within large-scale brain networks associated with different functions. The neurophysiological correlates of this phenomenon remain elusive. Here, we show in humans that the slow cortical potentials recorded by electrocorticography demonstrate a correlation structure similar to that of spontaneous BOLD fluctuations across wakefulness, slow-wave sleep, and rapid-eye-movement sleep. Gamma frequency power also showed a similar correlation structure but only during wakefulness and rapid-eye-movement sleep. Our results provide an important bridge between the large-scale brain networks readily revealed by spontaneous BOLD signals and their underlying neurophysiology.

The Temporal Structures and Functional Significance of Scale-free Brain Activity

Scale-free dynamics, with a power spectrum following P proportional to f(-beta), are an intrinsic feature of many complex processes in nature. In neural systems, scale-free activity is often neglected in electrophysiological research. Here, we investigate scale-free dynamics in human brain and show that it contains extensive nested frequencies, with the phase of lower frequencies modulating the amplitude of higher frequencies in an upward progression across the frequency spectrum. The functional significance of scale-free brain activity is indicated by task performance modulation and regional variation, with beta being larger in default network and visual cortex and smaller in hippocampus and cerebellum. The precise patterns of nested frequencies in the brain differ from other scale-free dynamics in nature, such as earth seismic waves and stock market fluctuations, suggesting system-specific generative mechanisms. Our findings reveal robust temporal structures and behavioral significance of scale-free brain activity and should motivate future study on its physiological mechanisms and cognitive implications.

Cortical network functional connectivity in the descent to sleep

Descent into sleep is accompanied by disengagement of the conscious brain from the external world. It follows that this process should be associated with reduced neural activity in regions of the brain known to mediate interaction with the environment. We examined blood oxygen dependent (BOLD) signal functional connectivity using conventional seed-based analyses in 3 primary sensory and 3 association networks as normal young adults transitioned from wakefulness to light sleep while lying immobile in the bore of a magnetic resonance imaging scanner. Functional connectivity was maintained in each network throughout all examined states of arousal. Indeed, correlations within the dorsal attention network modestly but significantly increased during light sleep compared to wakefulness. Moreover, our data suggest that neuronally mediated BOLD signal variance generally increases in light sleep. These results do not support the view that ongoing BOLD fluctuations primarily reflect unconstrained cognition. Rather, accumulating evidence supports the hypothesis that spontaneous BOLD fluctuations reflect processes that maintain the integrity of functional systems in the brain.

Loss of Resting Interhemispheric Functional Connectivity after Complete Section of the Corpus Callosum

Slow (<0.1 Hz), spontaneous fluctuations in the functional magnetic resonance imaging blood oxygen level-dependent (BOLD) signal have been shown to exhibit phase coherence within functionally related areas of the brain. Surprisingly, this phenomenon appears to transcend levels of consciousness. The genesis of coherent BOLD fluctuations remains to be fully explained. We present a resting state functional connectivity study of a 6-year-old child with a radiologically normal brain imaged both before and after complete section of the corpus callosum for the treatment of intractable epilepsy. Postoperatively, there was a striking loss of interhemispheric BOLD correlations with preserved intrahemispheric correlations. These unique data provide important insights into the relationship between connectional anatomy and functional organization of the human brain. Such observations have the potential to increase our understanding of large-scale brain systems in health and disease as well as improve the treatment of neurologic disorders.

How quickly can GABAA receptors open

We have examined GABAA receptor activation by making rapid applications of GABA to outside-out patches excised from cultured postnatal rat cerebellar neurons. The rate of development of current increases with increasing GABA concentration from a low to a high concentration asymptote. The low concentration asymptote is about 10 s-1 for patches taken from granule cells and 4 s-1 for patches from Purkinje cells. The high concentration asymptote is about 6000 s-1 for patches taken from either granule cells or Purkinje cells. The high concentration asymptote gives an estimate of the fastest rate at which these channels can open and indicates that agonist binding steps are not rate limiting. The concentration dependence of the development of current indicates that more than one GABA molecule is bound to most receptors with open channels and that the final binding step is of low affinity (about 500 microM). A comparison with GABA-mediated postsynaptic currents suggests that the properties of the GABAA receptor play a major role in determining the shape of inhibitory synaptic responses and that the cleft concentration of GABA reaches at least 500 microM.

Accuracy of Bedside Electroencephalographic Monitoring in Comparison With Simultaneous Continuous Conventional Electroencephalography for Seizure Detection in Term Infants

OBJECTIVE. Our goals were to compare (1) single-channel amplitude-integrated electroencephalography alone, (2) 2-channel amplitude-integrated electroencephalography alone, and (3) amplitude-integrated electroencephalography plus 2-channel electroencephalography with simultaneous continuous conventional electroencephalography for seizure detection in term infants to check the accuracy of limited channels and compare the different modalities of bedside electroencephalography monitoring. METHODS. Infants referred to a tertiary center with clinical seizures underwent simultaneous continuous conventional electroencephalography and 2-channel (C3-P3 and C4-P4) bedside monitoring. Off-line analysis of the continuous conventional electroencephalographic results was performed independently by 2 neurologists. Two experienced neonatal readers reviewed results obtained with amplitude-integrated electroencephalography and 2-channel electroencephalography combined and single-channel and 2-channel amplitude-integrated electroencephalography. All readings were performed independently and then compared. RESULTS. Twenty-one term newborns were monitored. Seizures were detected in 7 patients who had up to 12 electrical seizures, with 1 infant in status epilepticus. Seizures were identified correctly in 6 of 7 patients with amplitude-integrated electroencephalography plus 2-channel electroencephalography. The missed infant had an isolated 12-second seizure. With amplitude-integrated electroencephalography plus 2-channel electroencephalography, 31 of 41 non–status epilepticus seizures were correctly identified (sensitivity, 76%; specificity, 78%; positive predictive value, 78%; negative predictive value, 78%), with a substantial level of interrater agreement. The seizures missed were predominantly slow sharp waves of occipital origin from a single patient (7 of 10 seizures). Nine false-positive results were obtained in 351 hours of recording (1 false-positive result per 39 hours). These were thought to be related to muscle, electrode, and patting artifacts. Use of amplitude-integrated electroencephalography alone (1 or 2 channel) provided low sensitivity (27%–56%) and low interobserver agreement. CONCLUSIONS. Limited-channel bedside electroencephalography combining amplitude-integrated electroencephalography with 2-channel electroencephalography, interpreted by experienced neonatal readers, detected the majority of electrical seizures in at-risk newborn infants.

Modulation of the brain’s functional network architecture in the transition from wake to sleep

The transition from quiet wakeful rest to sleep represents a period over which attention to the external environment fades. Neuroimaging methodologies have provided much information on the shift in neural activity patterns in sleep, but the dynamic restructuring of human brain networks in the transitional period from wake to sleep remains poorly understood. Analysis of electrophysiological measures and functional network connectivity of these early transitional states shows subtle shifts in network architecture that are consistent with reduced external attentiveness and increased internal and self-referential processing. Further, descent to sleep is accompanied by the loss of connectivity in anterior and posterior portions of the default-mode network and more locally organized global network architecture. These data clarify the complex and dynamic nature of the transitional period between wake and sleep and suggest the need for more studies investigating the dynamics of these processes.

Therapeutic hypothermia in neonatal hypoxic ischemic encephalopathy: electrographic seizures and magnetic resonance imaging evidence of injury.

OBJECTIVE To evaluate the electrographic seizure burden in neonates with hypoxic ischemic encephalopathy (HIE) treated with or without therapeutic hypothermia and stratified results by severity of HIE and severity of injury as assessed by magnetic resonance imaging (MRI). STUDY DESIGN Between 2007 and 2011, video-electroencephalography (EEG) monitoring was initiated in neonates with moderate to severe HIE. Seizure burden (in seconds) was calculated, and brain MRI scans were quantitatively scored. Data were analyzed by ANOVA, the Student t test, and the χ(2) test. RESULTS Sixty-nine neonates with moderate or severe HIE were prospectively enrolled, including 51 who received therapeutic hypothermia and 18 who did not. The mean duration of video-EEG monitoring was longer in the therapeutic hypothermia group (72 ± 34 hours vs 48 ± 34 hours; P = .01). The therapeutic hypothermia group had a lower electrographic seizure burden (log units) after controlling for injury, as assessed by MRI (2.9 ± 0.6 vs 6.2 ± 0.9; P = .003). A reduction in seizure burden was seen in neonates with moderate HIE (P = .0001), but not in those with severe HIE (P = .80). Among neonates with injury assessed by MRI, seizure burden was lower in those with mild (P = .0004) and moderate (P = .02) injury, but not in those with severe injury (P = .90). CONCLUSION Therapeutic hypothermia was associated with reduced electrographic seizure burden in neonatal HIE. This effect was detected on video-EEG in infants with moderate HIE, but not in those with severe HIE. When stratified by injury as assessed by MRI, therapeutic hypothermia was associated with a reduced seizure burden in infants with mild and moderate injury, but not in those with severe injury.

A pilot study of continuous limited-channel aEEG in term infants with encephalopathy.

OBJECTIVE To evaluate the accuracy, feasibility, and impact of limited-channel amplitude integrated electroencephalogram (aEEG) monitoring in encephalopathic infants. STUDY DESIGN Encephalopathic infants were placed on limited-channel aEEG with a software-based seizure event detector for 72 hours. A 12-hour epoch of conventional EEG-video (cEEG) was simultaneously collected. Infants were randomly assigned to monitoring that was blinded or visible to the clinical team. If a seizure detection event occurred in the visible group, the clinical team interpreted whether the event was a seizure, based on review of the limited-channel aEEG. EEG data were reviewed independently offline. RESULTS In more than 68 hours per infant of limited-channel aEEG monitoring, 1116 seizures occurred (>90% clinically silent), with 615 detected by the seizure event detector (55%). Detection improved with increasing duration of seizures (73% >30 seconds, 87% >60 seconds). Bedside physicians were able to accurately use this algorithm to differentiate true seizures from false-positives. The visible group had a 52% reduction in seizure burden (P = .114) compared with the blinded group. CONCLUSIONS Monitoring for seizures with limited-channel aEEG can be accurately interpreted, compares favorably with cEEG, and is associated with a trend toward reduced seizure burden.