Every year, twenty-four million Americans are put under general anesthesia. Still, much remains unknown about the mechanism and appropriate use of general anesthetics. An inadequate level of anesthesia has resulted in some patients waking up during surgery, while a higher dose of anesthesia has been linked to increased post-operative mortality in elderly patients.
These hazards underscore the importance of monitoring the level of anesthesia and better understanding how anesthesia works. Although monitors can help determine how much anesthetic should be administered clinically, doctors today continue to rely heavily on clinical observation.
The four end points of anesthesia — hypnosis, amnesia, analgesia, and reflex suppression — are highly subjective, but fMRI provides an alternative, objective method of description. Researchers at the Yale School of Medicine are using functional magnetic resonance imaging (fMRI) to probe the effects of anesthesia on the human brain. “Essentially, fMRI allows us to objectively measure the subjective effects of anesthesia,” explained Dr. Ramachandran Ramani, Associate Professor of Anesthesia at the Yale School of Medicine.
Working with Professor of Diagnostic Radiology and Neurosurgery and Director of the Yale Magnetic Resonance Research Center (MRRC) Robert Todd Constable, as well as Associate Research Scientist at the Yale MRRC Maolin Qiu, Ramani has conducted several fMRI studies with the commonly used inhalation anesthetic sevoflurane. These studies offer insight into the dose-dependent effects of general anesthetics on neuronal activity in the brain and may help doctors make more informed decisions about the administration of general anesthesia.
Objective Measurements of Subjective Effects
While traditional MRI uses the property of nuclear magnetic resonance to provide structural information such as the location of a brain tumor, fMRI provides functional information about the activity of different parts of the brain. With a spatial resolution of 0.5 mm and a temporal resolution of equal quality, fMRI allows precise measurement of brain activity. A few decades ago, researchers could only measure whole-brain activity, but fMRI allows investigation of the effects of anesthetics on specific regions in the brain.
Functional MRI produces two main outputs: blood oxygen level-dependent contrast (BOLD) and regional cerebral blood flow (rCBF). BOLD signals are influenced by the relative amounts of oxygenated and deoxygenated hemoglobin in the blood, and they provide a qualitative measure of regional cerebral metabolism and neuronal activity.
Ramani and colleagues used fMRI to measure the effects of low (sub-anesthetic) doses of general anesthetics on visual, auditory, motor, memory, and somatosensory activation in healthy adult subjects. Every study was conducted on 20–25 subjects, each imaged over the course of one to two hours. A baseline rCBF measurement was obtained in the awake state as well as in the anesthesia state. The subjects were instructed to perform visual, auditory, motor, memory, or somatosensory tasks, and fMRI measurements (BOLD and rCBF) in different parts of the brain were taken and compared to the baseline state.
A Non-uniform Effect on the Brain
“It has long been assumed that anesthesia uniformly decreases metabolism and blood flow in all the regions of the brain,” says Ramani. “But we see that at lower doses, there is non-uniformity. In some regions of the brain there is a decrease in blood flow; in other regions there is an increase. This implies that at lower doses some regions of the brain get activated, and some get deactivated.”
In the fMRI studies, visual, auditory, and motor activation resulted in a significant increase in CBF in associated regions of the brain. The primary and secondary visual cortices experienced greater CBF in response to visual activation. Anesthetic appeared to decrease the task-induced activation of the visual cortices, thalamus, hippocampus, and supplementary motor area. However, the task-induced activation of other regions of the brain, such as the primary and secondary auditory cortices, was unaffected by anesthetic.
One minimum alveolar concentration (1 MAC) is considered to be the minimum amount of anesthetic necessary to suppress reflex motor response in 50 percent of the subjects. In clinical anesthesia, the recommended dose of general anesthetic is at least 1 MAC, but Ramani and colleagues used lower doses to examine the effects of sevoflurane on the brain. They found that 0.25 MAC sevoflurane mostly affects the primary visual cortex, the related association cortices, and certain other higher order association cortices.
Similar studies with 0.5 MAC sevoflurane showed that this dose of anesthetic has an effect on a wider area of the brain. The researchers thus concluded that low doses of sevoflurane primarily affect the higher order memory-related regions and association areas.
The affected regions of the brain may also provide information regarding how sevoflurane impacts various aspects of brain functions. 0.25 MAC sevoflurane primarily influences the CBF of the occipital lobe of the brain, which contains the visual processing center, whereas 0.5 MAC sevoflurane primarily influences the CBF of the frontal and parietal lobes, which include areas that deal with memory and sensory functions.
The larger effect of anesthesia on higher order regions of the brain is consistent with the current understanding of the mechanism of action of general anesthetics. Most anesthetic agents, including sevoflurane, act primarily at the level of synaptic junctions in the brain. When a sensation is detected, the resulting neural signals go to the primary regions of the brain, and then to the secondary regions, before being transmitted to the tertiary regions in the frontal and temporal lobes, which process and combine multiple different types of stimuli.
For instance, visual signals received by the eyes are transmitted to the primary visual cortex and then to the secondary cortex in the occipital lobe, before arriving at the frontal and temporal lobes, where visual, auditory, sensory, and other information are integrated.
Because the neuronal signals must pass multiple synapses from the primary, secondary, and tertiary regions of the brain to reach the higher order regions, the anesthetic’s small effects on each synapse add up, so that the effect on rCBF is only observed at the more sensitive higher order regions.
Informing Clinical Practice
The results Ramani and colleagues obtained may also influence standard clinical practice. “We have been highlighting that the concentration we are using in routine practice — 1 MAC — may be too high,” says Ramani. The researchers’ fMRI findings suggest that all the regions of the brain relevant to the maintenance of anesthesia are already affected at 0.5–0.7 MAC.
Higher concentrations of anesthetics can have adverse effects on other parts of the body. They can affect breathing, depress the heart, and decrease blood pressure. Some studies suggest that keeping a patient under deep anesthesia can increase the mortality after surgery. In laboratory studies, it has been demonstrated that prolonged anesthesia could have neurotoxic effects in the brain of newborns. Some retrospective studies in humans also suggest that anesthesia early in life could lead to adverse neurological effects.
“You have to remember that our studies are being done with healthy young adults. With an older population, the requirement for anesthesia could be even less,” says Ramani. “Moreover, elderly people have other co-morbid conditions such as hypertension, diabetes, coronary artery disease, stroke, etc., which by themselves can increase the risk associated with anesthesia. The population in this country is getting older. As they get older, they get sicker also, and in light of this we have to be more cautious when we manage these patients.” The simultaneous use of multiple other medications during anesthesia may also require a further decrease in the dose of anesthetic used in clinical practice.
The researchers further recommend that doctors monitor the status of their patients under anesthesia and modulate the dose of anesthetic accordingly. Although fMRI is a very useful method for research on anesthesia, it is not practical for use as a monitor in clinical settings. Other research groups are currently studying how to correlate electroencephalogram (EEG) and fMRI measurements, to ultimately develope EEG-based monitors.
In the coming months, Ramani and colleagues hope to start a study on the neurotoxic effects of anesthetics. Rather than working with healthy subjects, they plan to study older populations, focusing specifically on orthopedic surgery patients. “In people over 65 years of age, there is a very high incidence of delirium following a surgery with anesthesia,” he says. Delirium can have negative effects on cardiovascular and respiratory function and often results in longer stays in the intensive care unit, hospital, or nursing facility.
Ramani and his collaborators will use fMRI to image patients prior to surgery and will monitor patients for signs of post-surgical delirium. “Older people have changes in cerebral blood flow, which cause cognitive dysfunction, and patients with cognitive dysfunction are more prone to delirium,” he explains. “We are trying to connect the first step, changes in cerebral blood flow, to the third step, delirium.”
With the fMRI studies, Ramani and his colleagues hope to find a fMRI biomarker that may help predict whether a patient is at risk of developing delirium, so that post-operative delirium can be treated proactively or even prevented. A biomarker for delirium susceptibility could help reduce morbidity and mortality as well as decrease health care costs for elderly patients requiring surgery.
About the Author
Katherine Zhou is a senior Molecular Biophysics & Biochemistry major in Saybrook College. She studies group II intron splicing in Professor Anna Pyle’s lab.
Acknowledgements
The author would like to thank Dr. Ramani for taking the time to explain his research and for his comments on this article.
Further Reading
Ramani R, Qiu M, Constable RT. Sevoflurane 0.25 MAC preferentially affects higher order association areas – fMRI study in volunteers. Anesth Analg 2007; 105: 648-655.
Qiu M, Ramani R, Swetye M, Constable RT. Spatial non uniformity of the resting CBF and BOLD responses to sevoflurane – in vivo study of normal humans subjects with Magnetic Resonance Imaging. Hum Brain Mapp 2008; 29: 1390-1399.
Ramani R. Effects of sub-anaesthetic and anaesthetic doses of Sevoflurane on regional cerebral blood flow in healthy volunteers. Acta Anaesthesiol Scand 2005: 49; 1223-1224.
Qiu M, Ramani R, Swetye M, Rajeevan N, Constable RT. Anesthetic effects on regional CBF and BOLD and the coupling between task induced changes in CBF and BOLD – fMRI study in normal human subjects. Magn Reson Med 2008; 60: 987-996.