Altered Activity in the Central Medial Thalamus Precedes Changes in the Neocortex during Transitions into Both Sleep and Propofol Anesthesia

How general anesthetics cause loss of consciousness is unknown. Some evidence points toward effects on the neocortex causing “top-down” inhibition, whereas other findings suggest that these drugs act via subcortical mechanisms, possibly selectively stimulating networks promoting natural sleep. To determine whether some neuronal circuits are affected before others, we used Morlet wavelet analysis to obtain high temporal resolution in the time-varying power spectra of local field potentials recorded simultaneously in discrete brain regions at natural sleep onset and during anesthetic-induced loss of righting reflex in rats. Although we observed changes in the local field potentials that were anesthetic-specific, there were some common changes in high-frequency (20–40 Hz) oscillations (reductions in frequency and increases in power) that could be detected at, or before, sleep onset and anesthetic-induced loss of righting reflex. For propofol and natural sleep, these changes occur first in the thalamus before changes could be detected in the neocortex. With dexmedetomidine, the changes occurred simultaneously in the thalamus and neocortex. In addition, the phase relationships between the low-frequency (1–4 Hz) oscillations in thalamic nuclei and neocortical areas are essentially the same for natural sleep and following dexmedetomidine administration, but a sudden change in phase, attributable to an effect in the central medial thalamus, occurs at the point of dexmedetomidine loss of righting reflex. Our data are consistent with the central medial thalamus acting as a key hub through which general anesthesia and natural sleep are initiated.

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Study Suggests Disruptive Effects of Anesthesia on Brain Cell Connections Are Temporary

A study of juvenile rat brain cells suggests that the effects of a commonly used anesthetic drug on the connections between brain cells are temporary.

The study, published in this week’s issue of the journal PLOS ONE, was conducted by biologists at the University of California, San Diego and Weill Cornell Medical College in New York in response to concerns, arising from multiple studies on humans over the past decade, that exposing children to general anesthetics may increase their susceptibility to long-term cognitive and behavioral deficits, such as learning disabilities.

An estimated six million children, including 1.5 million infants, undergo surgery in the United States requiring general anesthesia each year and a least two large-scale clinical studies are now underway to determine the potential risks to children and adults.

“Since these procedures are unavoidable in most cases, it’s important to understand the mechanisms associated with the potentially toxic effects of anesthetics on the developing brain, and on the adult brain as well,” said Shelley Halpain, a professor of biology at UC San Diego and the Sanford Consortium for Regenerative Medicine, who co-headed the investigation. “Because the clinical studies haven’t been completed, preclinical studies, such as ours, are needed to define the effects of various anesthetics on brain structure and function.”

“There is concern now about cognitive dysfunction from surgery and anesthesia—how much these effects are either permanent or slowly reversible is very controversial,” said Hugh Hemmings, Jr., chair of anesthesiology at Weill Cornell and the study’s other senior author. “It has been suggested recently that some of the effects of anesthesia may be more lasting than previously thought. It is not clear whether the residual effects after an operation are due to the surgery itself, or the hospitalization and attendant trauma, medications and stress—or a combination of these issues.”

However, he added, “There is evidence that some of the delayed or persistent cognitive effects after surgery are not primarily due to anesthesia itself, but more importantly to brain inflammation resulting from the surgery. But this is not yet clear.”

The team of biologists examined one of the most commonly used general anesthetics, a derivative of ether called “isoflurane” used to maintain anesthesia during surgery.

“Previous studies in cultured neurons and in the intact brains of rodents provided evidence suggesting that exposure to anesthetics might render neurons more susceptible to cell death through a process called ‘apoptosis’,” said Halpain. “While overt cell death could certainly be one way to explain any long-lasting neurocognitive consequences of general anesthesia, we hypothesized that there could be other cellular mechanisms that disrupt neural circuits without inducing cell death per se.”

One such mechanism, she added, is known as “synaptotoxicity.” In this mechanism of neural-circuit disruption, the “synapses,” or junctions between neurons, become weakened or shrink away due to some factor that injures the neurons locally along their axons (the long processes of neurons that transmit signals) and dendrites (the threadlike extensions of neurons that receive nerve signals) without inducing the neurons themselves to die.

In the experiments at UC San Diego headed by Jimcy Platholi, a postdoctoral researcher in Halpain’s lab who is now at Weill Cornell, the scientists used neurons from embryonic rats taken from the hippocampus, a part of the mammalian forebrain essential for encoding newly acquired memories and ensuring that short-term memories are converted into long-term memories. The researchers cultured these brain cells in a laboratory dish for three weeks, allowing the neurons time to mature and to develop a dense network of synaptic connections and “dendritic spines”—specialized structures that protrude from the dendrites and are essential mediators of activity throughout neural networks.

“Evidence from animal studies indicates that new dendritic spines emerge and existing spines expand in size during learning and memory,” explained Halpain. “Therefore, the overall numbers and size of dendritic spines can profoundly impact the strength of neural networks. Since neural network activity underlies all brain function, changes in dendritic spine number and shape can influence cognition and behavior.”

Using neurons in culture, rather than intact animal brains, allowed the biologists to take images of the synapses at high spatial resolution using techniques called fluorescence light microscopy and confocal imaging. They also used time-lapse microscopy to observe structural changes in individual dendritic spines during exposure to isoflurane. Karl Herold, a research associate in the Hemmings laboratory and a co-author of the study, performed some of the image analysis.

“Imaging of human brain synapses at this level of detail is impossible with today’s technology and it remains very challenging even in laboratory rodents,” said Halpain. “It was important that we performed our study using rodent neurons in a culture dish, so that we could really drill down into the subcellular and molecular details of how anesthetics work.”

The researchers wondered whether brief exposure to isoflurane would alter the numbers and size of dendritic spines, so they applied the anesthetic to the cultured rat cells at concentrations and durations (up to 60 minutes) that are frequently used during surgery.

“We observed detectable decreases in dendritic spine numbers and shape within as little as 10 minutes,” said Halpain. “However this spine loss and shrinkage was reversible after the anesthetic was washed out of the culture.”

“Our study was reassuring in the sense that the effects are not irreversible and this fits in with known clinical effects,” said Hemmings. “For the most part, we find that the effects are reversible.”

“We clearly see an effect—a very marked effect on the dendritic spines—from use of this drug that was reversible, suggesting that it is not a toxic effect, but something more relevant to the pharmacological actions of the drug,” he added. “Connecting what we found to the cognitive effects of isoflurane will require much more detailed analysis.”

The team plans to follow up its study with future experiments to probe the molecular mechanisms and long-lasting consequences of isoflurane’s effects on neuron synapses and examine other commonly-used anesthetics for surgery.

Major dopamine system helps restore consciousness after general anesthesia

Researchers may be one step closer to better understanding how anesthesia works. A study in the August issue of Anesthesiology, the official medical journal of the American Society of Anesthesiologists® (ASA®), found stimulating a major dopamine-producing region in the brain, the ventral tegmental area (VTA), caused rats to wake from general anesthesia, suggesting that this region plays a key role in restoring consciousness after general anesthesia. Activating this region at the end of surgery could provide a novel approach to proactively induce consciousness from anesthesia in surgical patients, researchers say.

"While generally safe, it is well known that patients should not be under general anesthesia longer than necessary," said Ken Solt, M.D., lead author, Massachusetts General Hospital Department of Anesthesia, Critical Care and Pain Medicine and assistant professor of anesthesia, Harvard Medical School, Boston. "Currently, there are no treatments to reverse the effects of general anesthesia. We must wait for the anesthetics to wear off. Having the ability to control the process of arousal from general anesthesia would be advantageous as it might speed recovery to normal cognition after surgery and enhance operating room (O.R.) efficiencies."

Although the brain circuits that drive the process of emerging from general anesthesia are not well understood, recent studies suggest that certain arousal pathways in the brain may be activated by certain drugs to promote consciousness. The authors previously reported that methylphenidate (Ritalin), a drug used to treat attention deficit hyperactivity disorder, awakened rats from general anesthesia by activating dopamine-releasing pathways.

In the current study, rats were given the general anesthetics isoflurane or propofol. Once unconscious, researchers performed targeted electrical stimulation, through implanted steel electrodes, on the two major regions of the rats’ brains that contain dopamine-releasing cells – the VTA (the area of the brain that controls cognition, motivation and reward in humans) and the substantia nigra, which controls movement.

Researchers found that electrical stimulation of the VTA caused the rats to regain consciousness, suggesting that dopamine released from cells in this area of the brain is likely involved in arousal. Interestingly, electrical stimulation of the VTA had an effect similar to that of the drug methylphenidate in restoring consciousness after anesthesia.

"We now have evidence that dopamine released by cells in the VTA is mainly responsible for the awakening effect seen with methylphenidate," said Dr. Solt. "Because dopamine-releasing cells in the VTA are important for cognition, we may be able to use drugs that act on this region not only to induce consciousness in anesthetized patients, but to potentially treat common postoperative emergence-related problems such as delirium and restore cognitive function."

Study examines how brain ‘reboots’ itself to consciousness after anesthesia

One of the great mysteries of anesthesia is how patients can be temporarily rendered completely unresponsive during surgery and then wake up again, with all their memories and skills intact.

A new study by Dr. Andrew Hudson, an assistant professor of anesthesiology at the David Geffen School of Medicine at UCLA, and colleagues provides important clues about the processes used by structurally normal brains to navigate from unconsciousness back to consciousness. Their findings are currently available in the early online edition of Proceedings of the National Academy of Sciences.

Previous research has shown that the anesthetized brain is not “silent” under surgical levels of anesthesia but experiences certain patterns of activity, and it spontaneously changes its activity patterns over time, Hudson said.

For the current study, the research team recorded the brain’s electrical activity in a rodent model that had been administered the inhaled anesthesia isoflurane by placing electrodes in several brain areas associated with arousal and consciousness. They then slowly decreased the amount of anesthesia, as is done with patients in the operating room, monitoring how the electrical activity in the brain changed and looking for common activity patterns across all the study subjects.

The researchers found that the brain activity occurred in discrete clumps, or clusters, and that the brain did not jump between all of the clusters uniformly.

A small number of activity patterns consistently occurred in the anesthetized rodents, Hudson noted. The patterns depended on how much anesthesia the subject was receiving, and the brain would jump spontaneously from one activity pattern to another. A few activity patterns served as “hubs” on the way back to consciousness, connecting activity patterns consistent with deeper anesthesia to those observed under lighter anesthesia.

"Recovery from anesthesia, is not simply the result of the anesthetic ‘wearing off’ but also of the brain finding its way back through a maze of possible activity states to those that allow conscious experience," Hudson said. "Put simply, the brain reboots itself."

The study suggests a new way to think about the human brain under anesthesia and could encourage physicians to reexamine how they approach monitoring anesthesia in the operating room. Additionally, if the results are applicable to other disorders of consciousness — such as coma or minimally conscious states — doctors may be better able to predict functional recovery from brain injuries by looking at the spontaneously occurring jumps in brain activity.

In addition, this work provides some constraints for theories about how the brain leads to consciousness itself, Hudson said.

Going forward, the UCLA researchers will test other anesthetic agents to determine if they produce similar characteristic brain activity patterns with “hub” states. They also hope to better characterize how the brain jumps between patterns.

Rats’ brains may “remember” odor experienced while under general anesthesia

Rats’ brains may remember odors they were exposed to while deeply anesthetized, suggests research in rats published in the April issue of Anesthesiology.

Previous research has led to the belief that sensory information is received by the brain under general anesthesia but not perceived by it. These new findings suggest the brain not only receives sensory information, but also registers the information at the cellular level while anesthetized without behavioral reporting of the same information after recovering from anesthesia.

In the study, rats were exposed to a specific odor while under general anesthesia. Examination of the brain tissue after they had recovered from anesthesia revealed evidence of cellular imprinting, even though the rats behaved as if they had never encountered the odor before.

“It raises the question of whether our brains are being imprinted during anesthesia in ways we don’t recognize because we simply don’t remember,” said Yan Xu, Ph.D., lead author and vice chairman for basic sciences in the Department of Anesthesiology at the University of Pittsburgh School of Medicine. “The fact that an anesthetized brain can receive sensory information – and distinguish whether that information is novel or familiar during and after anesthesia, even if one does not remember receiving it – suggests a need to re-evaluate how the depth of anesthesia should be measured clinically.”

Researchers randomly assigned 107 rats to 12 different anesthesia and odor exposure paradigms: some were exposed to the same odor during and after anesthesia, some to air before and an odor after, some to familiar odors, others to novel odors, and still others were not exposed to odors at all. After the rats had recovered from the anesthesia, researchers observed their behavior of looking for hidden odors or interacting with scented beads to determine their memory of the smell. Researchers then analyzed the rats’ brains at a cellular level. While the rats had no memory of being exposed to the odor under anesthesia, changes in the brain tissue on a cellular level suggested the rats “remembered” the exposure to the odor under anesthesia and no longer registered the odor as novel.

“This study reveals important new information about how anesthesia affects our brains,” said Dr. Xu. “The results highlight a need for additional research into the effects of general anesthesia on learning and memory.”

A new way to monitor induced comas

After suffering a traumatic brain injury, patients are often placed in a coma to give the brain time to heal and allow dangerous swelling to dissipate. These comas, which are induced with anesthesia drugs, can last for days. During that time, nurses must closely monitor patients to make sure their brains are at the right level of sedation — a process that MIT’s Emery Brown describes as “totally inefficient.”

“Someone has to be constantly coming back and checking on the patient, so that you can hold the brain in a fixed state. Why not build a controller to do that?” says Brown, the Edward Hood Taplin Professor of Medical Engineering in MIT’s Institute for Medical Engineering and Science, who is also an anesthesiologist at Massachusetts General Hospital (MGH) and a professor of health sciences and technology at MIT.

Brown and colleagues at MGH have now developed a computerized system that can track patients’ brain activity and automatically adjust drug dosages to maintain the correct state. They have tested the system  — which could also help patients who suffer from severe epileptic seizures — in rats and are now planning to begin human trials.

Maryam Shanechi, a former MIT grad student who is now an assistant professor at Cornell University, is the lead author of the paper describing the computerized system in the Oct. 31 online edition of the journal PLoS Computational Biology.

Tracking the brain

Brown and his colleagues have previously analyzed the electrical waves produced by the brain in different states of activity. Each state — awake, asleep, sedated, anesthetized and so on — has a distinctive electroencephalogram (EEG) pattern.

When patients are in a medically induced coma, the brain is quiet for up to several seconds at a time, punctuated by short bursts of activity. This pattern, known as burst suppression, allows the brain to conserve vital energy during times of trauma.

As a patient enters an induced coma, the doctor or nurse controlling the infusion of anesthesia drugs tries to aim for a particular number of “bursts per screen” as the EEG pattern streams across the monitor. This pattern has to be maintained for hours or days at a time.

“If ever there were a time to try to build an autopilot, this is the perfect time,” says Brown, who is a professor in MIT’s Department of Brain and Cognitive Sciences. “Imagine that you’re going to fly for two days and I’m going to give you a very specific course to maintain over long periods of time, but I still want you to keep your hand on the stick to fly the plane. It just wouldn’t make sense.”

To achieve automated control, Brown and colleagues built a brain-machine interface — a direct communication pathway between the brain and an external device that typically assists human cognitive, sensory or motor functions. In this case, the device — an EEG system, a drug-infusion pump, a computer and a control algorithm — uses the anesthesia drug propofol to maintain the brain at a target level of burst suppression.

The system is a feedback loop that adjusts the drug dosage in real time based on EEG burst-suppression patterns. The control algorithm interprets the rat’s EEG, calculates how much drug is in the brain, and adjusts the amount of propofol infused into the animal second-by-second.

The controller can increase the depth of a coma almost instantaneously, which would be impossible for a human to do accurately by hand. The system could also be programmed to bring a patient out of an induced coma periodically so doctors could perform neurological tests, Brown says.

This type of system could take much of the guesswork out of patient care, says Sydney Cash, an associate professor of neurology at Harvard Medical School.

“Much of what we do in medicine is making educated guesses as to what’s best for the patient at any given time,” says Cash, who was not part of the research team. “This approach introduces a methodology where doctors and nurses don’t need to guess, but can rely on a computer to figure out — in much more detail and in a time-efficient fashion — how much drug to give.”

Monitoring anesthesia

Brown believes that this approach could easily be extended to control other brain states, including general anesthesia, because each level of brain activity has its own distinctive EEG signature.

“If you can quantitatively analyze each state’s signature in real time and you have some notion of how the drug moves through the brain to generate those states, then you can build a controller,” he says.

There are currently no devices approved by the U.S. Food and Drug Administration (FDA) to control general anesthesia or induced coma. However, the FDA has recently approved a device that controls sedation not using EEG readings.

The MIT and MGH researchers are now preparing applications to the FDA to test the controller in humans.

Study Expands Concerns About Anesthesia’s Impact on the Brain

As pediatric specialists become increasingly aware that surgical anesthesia may have lasting effects on the developing brains of young children, new research suggests the threat may also apply to adult brains.

Researchers from Cincinnati Children’s Hospital Medical Center report June 5 the Annals of Neurology that testing in laboratory mice shows anesthesia’s neurotoxic effects depend on the age of brain neurons – not the age of the animal undergoing anesthesia, as once thought.

Although more research is needed to confirm the study’s relevance to humans, the study suggests possible health implications for millions of children and adults who undergo surgical anesthesia annually, according to Andreas Loepke, MD, PhD, a physician and researcher in the Department of Anesthesiology.

“We demonstrate that anesthesia-induced cell death in neurons is not limited to the immature brain, as previously believed,” said Loepke. “Instead, vulnerability seems to target neurons of a certain age and maturational stage. This finding brings us a step closer to understanding the phenomenon’s underlying mechanism”.

New neurons are generated abundantly in most regions of the very young brain, explaining why previous research has focused on that developmental stage. In a mature brain, neuron formation slows considerably, but extends into later life in dentate gyrus and olfactory bulb.

The dentate gyrus, which helps control learning and memory, is the region Loepke and his research colleagues paid particular attention to in their study. Also collaborating were researchers from the University of Cincinnati College of Medicine and the Children’s Hospital of Fudan University, Shanghai, China.

Researchers exposed newborn, juvenile and young adult mice to a widely used anesthetic called isoflurane in doses approximating those used in surgical practice. Newborn mice exhibited widespread neuronal loss in forebrain structures – confirming previous research – with no significant impact on the dentate gyrus. However, the effect in juvenile mice was reversed, with minimal neuronal impact in the forebrain regions and significant cell death in the dentate gyrus.

The team then performed extensive studies to discover that age and maturational stage of the affected neurons were the defining characteristics for vulnerability to anesthesia-induced neuronal cell death. The researchers observed similar results in young adult mice as well.

Research over the past 10 years has made it increasingly clear that commonly used anesthetics increase brain cell death in developing animals, raising concerns from the Food and Drug Administration, clinicians, neuroscientists and the public. As well, several follow-up studies in children and adults who have undergone surgical anesthesia show a link to learning and memory impairment.

Cautioning against immediate application of the current study’s findings to children and adults undergoing anesthesia, Loepke said his research team is trying to learn enough about anesthesia’s impact on brain chemistry to develop protective therapeutic strategies, in case they are needed. To this end, their next step is to identify specific molecular processes triggered by anesthesia that lead to brain cell death.

“Surgery is often vital to save lives or maintain quality of life and usually cannot be performed without general anesthesia,” Loepke said. “Physicians should carefully discuss with patients, parents and caretakers the risks and benefits of procedures requiring anesthetics, as well as the known risks of not treating certain conditions.”

Loepke is also collaborating with researchers from the Pediatric Neuroimaging Research Consortium at Cincinnati Children’s Hospital Medical Center to examine anesthesia’s impact on children’s brain using non-invasive magnetic resonance imaging (MRI) technology.