Local cortical dynamics of burst suppression in the anaesthetized brain

Burst suppression is an electroencephalogram pattern that consists of a quasi-periodic alternation between isoelectric ‘suppressions’ lasting seconds or minutes, and high-voltage ‘bursts’. It is characteristic of a profoundly inactivated brain, occurring in conditions including hypothermia, deep general anaesthesia, infant encephalopathy and coma. It is also used in neurology as an electrophysiological endpoint in pharmacologically induced coma for brain protection after traumatic injury and during status epilepticus. Classically, burst suppression has been regarded as a ‘global’ state with synchronous activity throughout cortex. This assumption has influenced the clinical use of burst suppression as a way to broadly reduce neural activity. However, the extent of spatial homogeneity has not been fully explored due to the challenges in recording from multiple cortical sites simultaneously. The neurophysiological dynamics of large-scale cortical circuits during burst suppression are therefore not well understood. To address this question, we recorded intracranial electrocorticograms from patients who entered burst suppression while receiving propofol general anaesthesia. The electrodes were broadly distributed across cortex, enabling us to examine both the dynamics of burst suppression within local cortical regions and larger-scale network interactions. We found that in contrast to previous characterizations, bursts could be substantially asynchronous across the cortex. Furthermore, the state of burst suppression itself could occur in a limited cortical region while other areas exhibited ongoing continuous activity. In addition, we found a complex temporal structure within bursts, which recapitulated the spectral dynamics of the state preceding burst suppression, and evolved throughout the course of a single burst. Our observations imply that local cortical dynamics are not homogeneous, even during significant brain inactivation. Instead, cortical and, implicitly, subcortical circuits express seemingly different sensitivities to high doses of anaesthetics that suggest a hierarchy governing how the brain enters burst suppression, and emphasize the role of local dynamics in what has previously been regarded as a global state. These findings suggest a conceptual shift in how neurologists could assess the brain function of patients undergoing burst suppression. First, analysing spatial variation in burst suppression could provide insight into the circuit dysfunction underlying a given pathology, and could improve monitoring of medically-induced coma. Second, analysing the temporal dynamics within a burst could help assess the underlying brain state. This approach could be explored as a prognostic tool for recovery from coma, and for guiding treatment of status epilepticus. Overall, these results suggest new research directions and methods that could improve patient monitoring in clinical practice.Burroughs Wellcome Fund (Career Award at the Scientific Interface)National Institutes of Health (U.S.) (Director's Pioneer Award DP10D003646)National Institutes of Health (U.S.) (Transformative 1R01GM104948

A transient cortical state with sleep-like sensory responses precedes emergence from general anesthesia in humans

During awake consciousness, the brain intrinsically maintains a dynamical state in which it can coordinate complex responses to sensory input. How the brain reaches this state spontaneously is not known. General anesthesia provides a unique opportunity to examine how the human brain recovers its functional capabilities after profound unconsciousness. We used intracranial electrocorticography and scalp EEG in humans to track neural dynamics during emergence from propofol general anesthesia. We identify a distinct transient brain state that occurs immediately prior to recovery of behavioral responsiveness. This state is characterized by large, spatially distributed, slow sensory-evoked potentials that resemble the K-complexes that are hallmarks of stage two sleep. However, the ongoing spontaneous dynamics in this transitional state differ from sleep. These results identify an asymmetry in the neurophysiology of induction and emergence, as the emerging brain can enter a state with a sleep-like sensory blockade before regaining responsivity to arousing stimuli.National Institutes of Health (U.S.) (Grant K99-MH111748)National Institutes of Health (U.S.) (Grant R00-NS080911)National Institutes of Health (U.S.) (Grant DP2-OD006454)National Institutes of Health (U.S.) (Grant S10-RR023401)National Institutes of Health (U.S.) (Grant R01- NS062092)National Institutes of Health (U.S.) (Grant R01AG056015)National Institutes of Health (U.S.) (Grant P01GM118269)National Institutes of Health (U.S.) (Grant R01-EB009282

Activation of adenosine A1 and A2A receptors modulates dopamine D2 receptor-induced responses in stably transfected human neuroblastoma cells.

Adenosine can influence dopaminergic neurotransmission in the basal ganglia via postsynaptic interaction between adenosine A2A and dopamine D2 receptors. We have used a human neuroblastoma cell line (SH-SY5Y) that was found to express constitutively moderate levels of adenosine A1 and A2A receptors (approximately 100 fmol/mg of protein) to investigate the interactions of A2A/D2 receptors, at a cellular level. After transfection with human D2L receptor cDNA, SH-SY5Y cells expressed between 500 and 1,100 fmol of D2 receptors/mg of protein. In membrane preparations, stimulation of adenosine A2A receptors decreased the affinity of dopamine D2 receptors for dopamine. In intact cells, the calcium concentration elevation induced by KCI treatment was moderate, and dopamine had no effect on either resting intracellular free Ca2+ concentration ([Ca2+]i) or KCI-induced responses. In contrast, pretreatment with adenosine deaminase for 2 days dramatically increased the elevation of [Ca2+]i evoked by KCI, which then was totally reversed by dopamine. The effects induced by 48-h adenosine inactivation were mimicked by application of adenosine A1 antagonists and could not be further reversed by acute activation of either A1 or A2A receptors. Acute application of the selective A2 receptor agonist CGS-21680 counteracted the D2 receptor-induced [Ca2+]i responses. The present study shows that SH-SY5Y cells are endowed with functional adenosine A2A and A1 receptors and that A2A receptors exert an antagonistic acute effect on dopamine D2 receptor-mediated functions. In contrast, A1 receptors induce a tonic modulatory role on these dopamine functions

Supplemental Instruction in Introductory Biology I: Enhancing the Performance and Retention of Underrepresented Minority Students

Supplemental instruction classes have been shown in many studies to enhance performance in the supported courses and even to improve graduation rates. Generally, there has been little evidence of a differential impact on students from different ethnic/racial backgrounds. At San Francisco State University, however, supplemental instruction in the Introductory Biology I class is associated with even more dramatic gains among students from underrepresented minority populations than the gains found among their peers. These gains do not seem to be the product of better students availing themselves of supplemental instruction or other outside factors. The Introductory Biology I class consists of a team-taught lecture component, taught in a large lecture classroom, and a laboratory component where students participate in smaller lab sections. Students are expected to master an understanding of basic concepts, content, and vocabulary in biology as well as gain laboratory investigation skills and experience applying scientific methodology. In this context, supplemental instruction classes are cooperative learning environments where students participate in learning activities that complement the course material, focusing on student misconceptions and difficulties, construction of a scaffolded knowledge base, applications involving problem solving, and articulation of constructs with peers