Veronica S. Weiner

Rapid fragmentation of neuronal networks at the onset of propofol-induced unconsciousness

The neurophysiological mechanisms by which anesthetic drugs cause loss of consciousness are poorly understood. Anesthetic actions at the molecular, cellular, and systems levels have been studied in detail at steady states of deep general anesthesia. However, little is known about how anesthetics alter neural activity during the transition into unconsciousness. We recorded simultaneous multiscale neural activity from human cortex, including ensembles of single neurons, local field potentials, and intracranial electrocorticograms, during induction of general anesthesia. We analyzed local and global neuronal network changes that occurred simultaneously with loss of consciousness. We show that propofol-induced unconsciousness occurs within seconds of the abrupt onset of a slow (<1 Hz) oscillation in the local field potential. This oscillation marks a state in which cortical neurons maintain local patterns of network activity, but this activity is fragmented across both time and space. Local (<4 mm) neuronal populations maintain the millisecond-scale connectivity patterns observed in the awake state, and spike rates fluctuate and can reach baseline levels. However, neuronal spiking occurs only within a limited slow oscillation-phase window and is silent otherwise, fragmenting the time course of neural activity. Unexpectedly, we found that these slow oscillations occur asynchronously across cortex, disrupting functional connectivity between cortical areas. We conclude that the onset of slow oscillations is a neural correlate of propofol-induced loss of consciousness, marking a shift to cortical dynamics in which local neuronal networks remain intact but become functionally isolated in time and space.

A Transition in Brain State during Propofol-Induced Unconsciousness

Rhythmic oscillations shape cortical dynamics during active behavior, sleep, and general anesthesia. Cross-frequency phase-amplitude coupling is a prominent feature of cortical oscillations, but its role in organizing conscious and unconscious brain states is poorly understood. Using high-density EEG and intracranial electrocorticography during gradual induction of propofol general anesthesia in humans, we discovered a rapid drug-induced transition between distinct states with opposite phase-amplitude coupling and different cortical source distributions. One state occurs during unconsciousness and may be similar to sleep slow oscillations. A second state occurs at the loss or recovery of consciousness and resembles an enhanced slow cortical potential. These results provide objective electrophysiological landmarks of distinct unconscious brain states, and could be used to help improve EEG-based monitoring for general anesthesia.

Central Ghrelin Resistance Permits the Overconsolidation of Fear Memory

BACKGROUND There are many contradictory findings about the role of the hormone ghrelin in aversive processing, with studies suggesting that ghrelin signaling can both inhibit and enhance aversion. Here, we characterize and reconcile the paradoxical role of ghrelin in the acquisition of fearful memories. METHODS We used enzyme-linked immunosorbent assay to measure endogenous acyl-ghrelin and corticosterone at time points surrounding auditory fear learning. We used pharmacological (systemic and intra-amygdala) manipulations of ghrelin signaling and examined several aversive and appetitive behaviors. We also used biotin-labeled ghrelin to visualize ghrelin binding sites in coronal brain sections of amygdala. All work was performed in rats. RESULTS In unstressed rodents, endogenous peripheral acyl-ghrelin robustly inhibits fear memory consolidation through actions in the amygdala and accounts for virtually all interindividual variability in long-term fear memory strength. Higher levels of endogenous ghrelin after fear learning were associated with weaker long-term fear memories, and pharmacological agonism of the ghrelin receptor during the memory consolidation period reduced fear memory strength. These fear-inhibitory effects cannot be explained by changes in appetitive behavior. In contrast, we show that chronic stress, which increases both circulating endogenous acyl-ghrelin and fear memory formation, promotes profound loss of ghrelin binding sites in the amygdala and behavioral insensitivity to ghrelin receptor agonism. CONCLUSIONS These studies provide a new link between stress, a novel type of metabolic resistance, and vulnerability to excessive fear memory formation and reveal that ghrelin can regulate negative emotionality in unstressed animals without altering appetite.

Depth from shading and disparity in humans and monkeys

A stimulus display was devised that enabled us to examine how effectively monkeys and humans can process shading and disparity cues for depth perception. The display allowed us to present these cues separately, in concert and in conflict with each other. An oddities discrimination task was used. Humans as well as monkeys were able to utilize both shading and disparity cues but shading cues were more effectively processed by humans. Humans and monkeys performed better and faster when the two cues were presented conjointly rather than singly. Performance was significantly degraded when the two cues were presented in conflict with each other suggesting that these cues are processed interactively at higher levels in the visual system. The fact that monkeys can effectively utilize depth information derived from shading and disparity indicates that they are a good animal model for the study of the neural mechanisms that underlie the processing of these two depth cues.

The integration of disparity, shading and motion parallax cues for depth perception in humans and monkeys

A visual stimulus display was created that enabled us to examine how effectively the three depth cues of disparity, motion parallax and shading can be integrated in humans and monkeys. The display was designed to allow us to present these three depth cues separately and in various combinations. Depth was processed most effectively and most rapidly when all three cues were presented together indicating that these separate cues are integrated at yet unknown sites in the brain. Testing in humans and monkeys yielded similar results suggesting that monkeys are a good animal model for the study of the underlying neural mechanisms of depth perception.

How the parallel channels of the retina contribute to depth processing.

Reconstructing the third dimension in the visual scene from the two dimensional images that impinge on the retinal surface is one of the major tasks of the visual system. We have devised a visual display that makes it possible to study stereoscopic depth cues and motion parallax cues separately or in concert using rhesus macaques. By varying the spatial frequency of the display and its luminance and chrominance, it is possible to selectively activate channels that originate in the primate retina. Our results show that (i) the parasol system plays a central role in processing motion parallax cues; (ii) the midget system plays a central role in stereoscopic depth perception at high spatial frequencies, and (iii) red/green colour selective neurons can effectively process both cues but blue/yellow neurons cannot do so.