Disruptive Effects of Anesthesia on Brain Cell Connections Only Temporary

The study, published in a recent 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.

University of California - San Diego - Biological Sciences

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.

- MFP News Services
- 12/8/14

Those with Autistism May Have Less Flexibility when Taking On Tasks

The brains of children with autism are relatively inflexible at switching from rest to task performance, according to a new brain-imaging study from the Stanford University School of Medicine.

Stanford University - School of Medicine

Instead of changing to accommodate a job, connectivity in key brain networks of autistic children looks similar to connectivity in the resting brain. And the greater this inflexibility, the more severe the child’s manifestations of repetitive and restrictive behaviors that characterize autism, the study found.

The study, which will be published online recently in Cerebral Cortex, used functional magnetic resonance imaging, or fMRI, to examine children’s brain activity at rest and during two tasks: solving simple math problems and looking at pictures of different faces. The study included an equal number of children with and without autism. The developmental disorder, which now affects one of every 68 children in the United States, is characterized by social and communication deficits, repetitive behaviors and sensory problems.

“We wanted to test the idea that a flexible brain is necessary for flexible behaviors,” said Lucina Uddin, PhD, a lead author of the study. “What we found was that across a set of brain connections known to be important for switching between different tasks, children with autism showed reduced ‘brain flexibility’ compared with typically developing peers.” Uddin, who is now an assistant professor of psychology at the University of Miami, was a postdoctoral scholar at Stanford when the research was conducted.

“The fact that we can tie this neurophysiological brain-state inflexibility to behavioral inflexibility is an important finding because it gives us clues about what kinds of processes go awry in autism,” said Vinod Menon, PhD, the Rachel L. and Walter F. Nichols, MD, professor of psychiatry and behavioral sciences at Stanford and the senior author of the study.

The researchers focused on a network of brain areas they have studied before. These areas are involved in making decisions, performing social tasks and identifying relevant events in the environment to guide behavior. The team’s prior work showed that, in children with autism, activity in these areas was more tightly connected when the brain was at rest than it was in children who didn’t have autism.

The new research shows that, in autism, connectivity in these networks that can be seen on fMRI scans is fairly similar regardless of whether the brain is at rest or performing a task. In contrast, typically developing children have a larger shift in brain connectivity when they perform tasks.

The study looked at 34 kids with autism and 34 typically developing children. All of the children with autism received standard clinical evaluations to characterize the severity of their disorder. Then, the two groups were split in half: 17 children with autism and 17 typically developing children had their brains scanned with fMRI while at rest and while performing simple arithmetic problems. The remaining children had their brains scanned at rest and during a task that asked them to distinguish between different people’s faces. The facial recognition task was chosen because autism is characterized by social deficits; the math task was chosen to reflect an area in which children with autism do not usually have deficits.

Children with autism performed as well as their typically developing peers on both tasks — that is, they were as good at distinguishing between the faces and solving the math problems. However, their brain scan results were different. In addition to the reduced brain flexibility, the researchers showed a correlation between the degree of inflexibility and the severity of restrictive and repetitive behaviors, such as performing the same routine over and over or being obsessed with a favorite topic.

“This is the first study that has examined how the patterns of intrinsic brain connectivity change with a cognitive load in children with autism,” Menon said. The research is the first to demonstrate that brain connectivity in children with autism changes less, relative to rest, in response to a task than the brains of other children, he added.

“The findings may help researchers evaluate the effects of different autism therapies,” said Kaustubh Supekar, PhD, a research associate and the other lead author of the study. “Therapies that increase the brain’s flexibility at switching from rest to goal-directed behaviors may be a good target, for instance.”

“We’re making progress in identifying a brain basis of autism, and we’re starting to get traction in pinpointing systems and signaling mechanisms that are not functioning properly,” Menon said. “This is giving us a better handle both in thinking about treatment and in looking at change or plasticity in the brain.”

- MFP News Services
- 12/5/14

Malaria Vaccine Preforming Well After 18 Months

A vaccine previously shown to reduce malaria in young infants and children reduces larger numbers of malaria cases in areas of higher malaria transmission, according to results from an ongoing clinical trial published in PLOS Medicine. The effect of vaccination diminished over time, but protection against clinical malaria remained evident 18 months after vaccination.

In the new report, the RTS,S Clinical Trials Partnership update estimates of vaccine efficacy (the reduction in the risk of malaria in participants who received the vaccine compared to those who received a comparator vaccine) and calculate the number of cases of malaria that the vaccine prevented in a phase 3, randomized, controlled clinical trial of the malaria vaccine RTS,S/AS01 given to young infants and children in Africa.

The study included 6,537 infants aged 6–12 weeks and 8,923 children aged 5–17 months who were randomly assigned to receive three doses of RTS,S/AS01 or comparator vaccine. During 18 months following vaccination, the researchers report vaccine efficacy of 45% [95% confidence interval (CI): 41%–49%, intention-to-treat analysis] in children age 5-17 months, and 27% vaccine efficiency [95% CI: 21%–33%, intention-to-treat analysis] in infants age 6-12 weeks. In both age groups, vaccine efficacy was highest in the first 6 months after vaccination. Across all 11 study sites, RTS,S/AS01 averted an average of 829 (range 37 to 2365) cases of clinical malaria per 1,000 children vaccinated, and 449 (Range -10 to 1402) cases in infants vaccinated, over 18 months following vaccination.

Safety analyses found overall serious adverse events (SAE) to occur less often in children age 5-17 months who received the vaccine [18.6% (95% confidence interval 17.6%–19.6%), compared with 22.7% (95% CI 21.2%–24.3%) in children who received a comparator vaccine]. In infants age 6-12 weeks overall SAE were not found to differ significantly with immunization. As noted in earlier reports, more meningitis cases were reported as SAE in participants who received the malaria vaccine than in those who received a comparator immunization (16 cases among the 5,949 children in the RTS,S/AS01 vaccine group and one case among the 2,974 children in the control group; and nine cases among 4,358 young infants in the RTS,S/AS01 group and three among 2,179 young infants in the control group) and no causal relationship to the vaccine has been established.

Going forward the study will analyze further efficacy and safety results following administration of a booster immunization given to study participants just after the time period analyzed in the current report. The authors note that “Translated to the population at risk of malaria, reductions in clinical cases on this scale as a result of vaccination with RTS,S/AS01 would have a major public health impact.”

-MFP News Services
- 12/4/14