Massachusetts General Hospital

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Our 5 most important research advances over the past year are:

1. Purdon PL, Pierce ET, Mukamel EA, Prerau MJ, Walsh JL, Wong KFK, Salazar-Gomez, AF, Harrell PG, Sampson A, Cimenser A, Ching S, Kopell N, Tavares-Stoeckel CL, Habeeb K, Merhar R, Brown EN. Electroencephalogram signatures of loss and recovery of consciousness from propofol. Proceedings of the National Academy of Sciences, 2013 Mar 19;110(12):E1142-51. doi:10.1073/pnas.1221180110. Epub 2013 Mar 4.
PMID: 23487781.

This research provides a detailed characterization of how the electroencephalogram (EEG) changes as a patient loses consciousness and recovers consciousness under general anesthesia induced by propofol. This work demonstrates that that there are specific EEG signatures associated with unconsciousness. Tracking these signatures provides a clinically useful way of knowing how unconscious a patient is under general anesthesia.

2. Solt K, Van Dort CJ, Chemali JJ, Taylor N, Brown EN. Electrical stimulation of the ventral tegmental area induces reanimation from general anesthesia.
Anesthesiology, In Press, 2013.

In clinical practice, emergence from general anesthesia is treated as a passive process dictated by the pharmacokinetics of anesthetic drug clearance. Our group previously reported that methylphenidate (Ritalin) induces reanimation, or active emergence, from general anesthesia. Methylphenidate acts by blocking dopamine reuptake in the brain, so we hypothesized that intracranial electrical stimulation of dopamine neurons would induce reanimation from general anesthesia. The ventral tegmental area (VTA) and the substantia nigra (SN) are the two main dopamine nuclei in the brain. We discovered that VTA stimulation, but not SN stimulation, induces reanimation from general anesthesia. The role of dopamine neurons in behavioral arousal has not been well characterized previously, and our data suggest that VTA neurons (but not SN neurons) play a critical role in promoting wakefulness.

3. Stewart DS, Hotta M, Li GD, Desai R, Chiara DC, Olsen RW, Forman SA. Cysteine substitutions define etomidate binding and gating linkages in the alpha-M1 domain of gamma-aminobutyric acid type A (GABAA) receptors. J Biol Chem. 2013 Oct 18;288(42):30373-86. doi: 10.1074/jbc.M113.494583.Epub 2013 Sep 5.

Etomidate is a potent general anesthetic that acts through GABA-A receptors, binding at sites formed in part by alpha subunit transmembrane M1 domains. This study aimed to define amino acid residues on alpha-M1 that contact etomidate or otherwise mediate its effects at the molecular level. A series of 13 amino acids bracketing the etomidate-photolabeled residue alpha-M236 were mutated to cysteines. The cystenine substituted receptors were expressed in Xenopus oocytes and their function was studied using two-micro electrode voltage-clamp electrophysiology. Each mutant was characterized for GABA sensitivity, etomidate sensitivity, and functional effects of covalently modifying the engineered cysteine with para-chloromercuribenzene sulfonate (pCMBS). Modifiable mutants were firther tested to see how etomidate affected cysteine modification. In silico docking of etomidate to a structural homology model of wild-type GABA-A receptors was also performed.

4. Zhang X, Xin X, Dong Y, Zhang Y, Yu B, Mao J, Xie Z. Surgical incision-induced nociception causes cognitive impairment and reduction in synaptic NMDA receptor 2B in mice. J Neurosci 2013, 33:17737-17748.

Up to 80 percent of surgical patients in the U.S. have some level of postoperative pain, and several studies have suggested that pain could contribute to the development of postoperative cognitive dysfunction. This is the study to demonstrate that surgical incision-induced pain in mice selectively reduces the expression of synaptic NMDA receptor 2B in the medical prefrontal cortex. This leads to hippocampus-independent cognitive impairment, as measured by the Fear Conditioning Test. These effects may be due to an elevation of TNF-a and CDK-5 caused by pain from the surgical incision. These data suggest that pain may play a role in inducing postoperative cognitive dysfunction.

5. Lim G., Kim H, McCabe MF, Chou CW, Wang S, Chen L, Marota JJA, Blood A, Breiter HC, Mao J. A leptin-mediated central mechanism in analgesia-enhanced opioid reward in rats. J Neurosci, 2014, 34:9779-9788.

Opioid analgesics are commonly used in chronic pain management despite a potential risk of rewarding. However, it remains unclear whether opioid analgesia would enhance the opioid rewarding effect thereby contributing to opioid rewarding. This study showed that analgesia induced by morphine increased CPP score in arthritic rats, producing a phenomenon of analgesia-enhanced opioid reward. At the cellular level, administration of morphine activated a cascade of leptin expression, glial activation, and dopamine receptor upregulation in the nucleus accumbens (NAc), while administration of ibuprofen decreased glial activation with no effect on leptin expression in the NAc. Futhermore, the morphine rewarding effect was blocked in leptin deficient ob/ob mice or by neutralizing leptin or interleukin - 1ß in the NAc without diminishing morphine analgesia. The data indicate that systemic opioid can activate a leptin-mediated central mechanism in the NAc that led to the enhanced opioid rewarding effect. These findings provide evidence for an interaction between opioid analgesia and opioid rewarding, which may have implications in clinical opioid dose escalation in chronic pain management.