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THE LANCET Neurology Vol 2 December 2003 http://neurology.thelancet.com 717

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The neural mechanism involved in the unpleasant feeling of socialrejection is similar to that involved inthe experience of physical pain. Thislink may help explain why the death of a loved one or being a socialoutcast can be so “painful”, andsupports the idea that suchexperiences are evolutionarilyadvantageous.

Researchers used functionalMRI to see which parts of the brain became active whenvolunteers were “sociallyisolated” from a computer gameof catch. “In fact there were noother players, only a computer”,explains Naomi Eisenberger(University of California, LosAngeles, CA, USA), “but thevolunteers were made to believethey were playing with real people. Wemonitored their brain activity to seewhat happened when they wereincluded in the game, when they wereincluded but were the victims of mocktechnical problems preventing theirparticipation, and when they weredownright ignored by the ‘otherplayers’.” The volunteers were alsogiven a questionnaire to describe theirfeelings.

A significant increase in activity inthe anterior cingulate cortex (ACC)—the same area that lights up whenpeople feel physical pain—was seenduring outright exclusion. Self-reported

feelings of distress were also related toincreased ACC activity (Science 2003;302: 290–92).

Another area that became activeduring outright exclusion was the rightventral prefrontal cortex (RVPFC).Activity in this area has previously beenassociated with the control of physicalpain. “It would seem that the RVPFCkicked in to try to lessen the emotional‘pain’ felt by the volunteers when they

were socially excluded”, explainscoauthor Matthew Lieberman. “Noextra RVPFC activity was noticed,however, when the volunteers thoughtthey were just technically, rather than

socially, excluded. That distress isperhaps interpreted differentlyand elicits no self-regulatoryresponse.”

Similarities between theneural processing of social exclu-sion and pain could be beneficialto many mammals. “The bondthat keeps children withcaregivers, or attaches us tosocially cooperating groups isimportant to our survival”,explains Eisenberger. “Feeling‘emotional pain’ during socialexclusion could help us recogniseimperfect relationships and begin

reparatory behaviour.”“Although very interesting, the

authors’ extrapolations seem ratherstrong”, warns Alberto Fernández(Complutense University, Madrid,Spain). “One would expect activation ofpain-related areas other than the ACCor RVPFC which are also involved inthe attention processes if the notion that‘rejection hurts’ is to be claimed”.Adrian Burton

Social rejection may be pain to the brain

Mitochondrial dysfunction is known tocause striatal-neuron degeneration inmnd2 (motor neuron degeneration 2)mutant mice. Now, Emad Alnemri(Thomas Jefferson University,Philadelphia, PA, USA) and co-workers have shown that a missensemutation in the serine protease Omi,which is found in the intermembranespace of mitochondria, causes thisneurodegeneration.

At present, the exact physiologicalfunction of Omi is unclear. However,normal mitochondrial function seemsto depend on viable Omi, and loss ofOmi activity leaves cells more sensitiveto stress-induced cell death. Alnemriand co-workers postulate that Omimaintains mitochondrial homoeostasis,but participates in cell death under

apoptotic conditions (Nature 2003;425: 721–27).

The researchers crossed mnd2mutant mice with two other strains tolocalise the mutation to a 250 kbregion, which contained ten genes. Byuse of bacterial artificial chromosomeclones, they then narrowed down theinterval to a 40 kb region containingsix genes. They compared this 40 kbsequence in wild-type mice with thatin mutant mice and found only onedifference—in the code for the Omiprotease. A protease activity assayshowed the absence of substratecleaving activity of Omi extracted frommnd2 mutant mice.

“Since the neurodegenerativephenotype in the mnd2 mice is causedby a spontaneous loss of function

mutation in the Omi gene, I believe thatsimilar mutations might be responsiblefor some neurodegenerative diseases inhumans”, explains Alnemri.

Although the human OMI gene islocated near the PARK3 susceptibilitylocus for Parkinson’s disease onchromosome 2p13.1, so far no familieswith Parkinson’s disease mapped tothis locus have had mutations inhuman OMI.

“The next step is to find outwhether mutations in OMI are involvedin any human neurodegenerativediseases and to characterise the Omisignalling pathway at the molecularlevel to determine its exact physio-logical role in cell survival”, concludesAlnemri.Sarah Archibald

Mutated mitochondrial serine protease causes neurodegeneration

The pain of social rejection

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