Anesthesia and Brain Functional Connectivity: An Analysis of fMRI Changes in Chronic Pain and Refractory Depression

Background:

A phencyclidine derivative developed by Parke-Davis represented an attempt to mimic phencyclidine anesthesia without inducing the severe psychomimetic reactions of its parent compound. Initial reports were promising and received great enthusiasm. At high doses, the drug was found to provide profound analgesia whilst preserving airway reflexes. It induced reliable amnesia, yet could be delivered as a simple injection. It was claimed at the time that this anesthetic heralded a new phase in the history of anesthesia. Today, over 40 years since the anesthetic was introduced at Michigan, there has been a resurgence of interest in this old drug. A growing number of investigators are studying the effects of anesthesia on human subjects. There is currently tremendous interest in anesthesia as an opioid sparing agent, a model for schizophrenia, an antidepressant, and as an N-Methyl D-Aspartate (NMDA) antagonist in complex regional pain syndromes.

Functional connectivity is a measure of low-frequency oscillations (<0.08 Hz) that are inherent to brain tissue at rest. These oscillations are measured on fMRI, and appear to be synchronized between related areas of the brain. Although research in this area is still in its infancy, studies of the motor, auditory, visual, and sensorimotor systems, have shown that functionally related areas of the brain produce correlated low-frequency oscillations. This fascinating finding raises the possibility of a new approach to studying brain function as well as a potential tool for the diagnosis of disease. Recent fMRI studies of the precentral gyrus have demonstrated the ability of functional connectivity studies to differentiate healthy volunteers from patients with multiple sclerosis. Additional research is ongoing to determine whether functional connectivity will prove useful in the diagnosis of early Alzheimer's disease.

Recent research in functional connectivity has identified regions in the brain active at rest. These regions are often referred to at the "Default-mode network" (DMN). Activity in the DMN is increased in the brain at rest and decreased when a subject concentrates on a mental task. The first fMRI study examining functional connectivity in chronic pain patients was published in a recent issue of the Journal of Neuroscience. In this study abnormal patterns of functional connectivity were seen in chronic pain patients. Specifically, a dysfunction in down-regulating the DMN was seen. The chronic pain patients did not deactivate the medial prefrontal cortex, amygdala, or posterior cingulate cortex to the same degree as healthy controls.

The only fMRI study examining functional connectivity in major depression was published in September of 2007. This study also noted a dysfunction in the DMN. Depressed subjects were found to have increased network functional connectivity in the subgenual cingulate cortex, thalamus, orbitofrontal cortex, and the precuneus. Notably, the subgenual cingulate cortex is the location of a recent clinical trial suggesting that deep brain stimulation to this region may ameliorate symptoms of patients with severe refractory depression.