Anger Management

Scientists probe the nature of wrath in the hope of devising cures

by ELIZABETH DOUGHERTY

Joson/Getty Images

WHEN EMOTIONAL BRAKES FAIL Depression and anger often go hand in hand

Flares and flashes. Outbursts and eruptions. The words used to describe anger tend to be
science may e!plain why.

olcanic. And

"hen an angry feeling coincides with aggressi e or hostile beha ior# it also acti ates the amygdala# an almond$shaped part of the brain associated with emotions# particularly fear# an!iety# and anger. This finding is one in a series from studies led by %arin %ougherty# an &M' associate professor of psychiatry at Massachusetts General &ospital# that aim to unco er why anger attac(s occur in patients with ma)or depressi e disorder. 'ome of these patients e!perience angry flare$ups that are inappropriate to the situation and out of character for the indi idual. *+eople will yell or throw things#, says %ougherty. *"e wanted to in estigate the mechanisms behind those reactions.,

For these patients# angry outbursts usually stop when the depression ends. -nderstanding this lin( could pro ide aluable insights into these disorders and their treatment. %ougherty began in ./// by in estigating healthy people with no signs of depression and no history of angry episodes. &e employed positron emission tomography imaging to e!amine which regions of the brain engage during angry moments. 'ub)ects simulated angry moments by recalling the moments in their li es when they felt rage. *0ou can try to spar( anger by showing upsetting pictures# for e!ample#, says %ougherty. *1ut the response isn2t as robust. The best way to induce emotion is through autobiographical scripts., %uring angry recollections# the amygdala fired. At the same time# a part of the orbital frontal corte!# )ust abo e the eyes# also engaged# putting the bra(es on emotion. *&ealthy people e!perience anger#, says %ougherty# *but they can suppress it before acting on it., In depressed people who are prone to anger attac(s# this neurological bra(e fails to engage. In another study# %ougherty found that in people with ma)or depressi e disorder and anger attac(s the orbital frontal corte! did not acti ate. 3ather# acti ity in the amygdala increased and angry outbursts ensued. More recently# %ougherty used functional magnetic resonance imaging to achie e a more fine$grained e!amination of the timing of the amygdala2s acti ation during angry moments. 4ow %ougherty is applying these research techni5ues to e!amine what happens in the brain during treatment for anger and depression using drugs or cogniti e beha ioral therapy to better understand how treatments wor( mechanistically. -ltimately he hopes this wor( will gi e clinicians better insights into which treatment options might be best for patients. STICKS AND STONES Verbal abuse injures young brains

6 eryone feels anger. Traffic snarls# unsympathetic colleagues# playground bullies7 we all ha e our triggers.
The problems start when anger boils o er into hostility and aggression# beha iors that cause harm.

T&6 8I%' A36 4OT A99 3IG&T: Martin Teicher# pictured abo e# has documented the damage that parental erbal abuse wrea(s on the brains of their children.
3ose 9incoln/&ar ard 4ews Office

According to research from Mc9ean &ospital# seemingly harmless anger may cause in isible damage to the brains of young children. Martin Teicher# an &M' associate professor of psychiatry at Mc9ean# has found that erbal abuse from parents and peers causes changes in de eloping brains tantamount to scarring that lasts into adulthood. Teicher began his in estigations by e!amining the effects of se!ual abuse# physical abuse# and harsh corporeal punishment on young brains. In ;<<=# he turned his attention to parental erbal abuse# finding that erbal abuse had deleterious effects on par with witnessing domestic iolence and other seemingly more iolent forms of maltreatment. In ;<</ he used diffusion$tensor magnetic resonance imaging to build an accurate map of the neural connections in the white matter of brains of adults who had e!perienced parental erbal abuse# but no other forms of abuse# as children. &e found three neural pathways that were disturbed in these adults: the arcuate fasciculus# in ol ed in language processing7 part of the cingulum bundle# altered in patients with post$traumatic stress disorder and associated with depression and dissociation7 and part of the forni!# lin(ed to an!iety. *The damage#, Teicher says# *was on par with that found in the brains of people who had e!perienced nonfamilial se!ual abuse.,

More recently# Teicher found that peer erbal abuse>whether teasing# belittling# or disparaging words>can cause similar damage. *8ids often hear many negati e things from their peers#, he says. Teicher2s latest research suggests that parental and peer erbal abuse may affect children differently throughout de elopment. "hen e!perienced during early childhood# erbal abuse can lead to somati?ation# the translation of emotions into physical illness. %uring middle school# it can increase the li(elihood of drug abuse# an!iety# and depression. In high school# it can lead to increased anger and hostility. *The e!pression of a lot of anger can be pathogenic#, Teicher says. *@hildren especially suffer when anger is ented. Openly e!pressed negati e# raw# and intense emotion is hard for many people to witness and can lea e scars., That is# children2s brains seem to turn down the olume on abusi e words# images# and e en pain. The result is diminished integrity in these sensory pathways. Teicher is now in estigating the effects of witnessing domestic iolence. 6arly findings suggest that all sensory systems may be ulnerable to iolence7 abuse that is heard may damage regions distinct from those in)ured by abuse that is seen or felt. &is wor( as a whole suggests that anger may deser e more attention from psychiatry. *"e2 e really focused on depression and an!iety as (ey emotions#, he says. *1ut anger is a big problem. It2s a problem when we e!press it too much and when we e!press it too little., THE SOUND OF THE FURY Turn off your phones. And televisions. And game consoles...

6 eryone# from children to great$grandparents# uses electronic media# and media use will only grow more
per asi e. At least# that2s how Michael 3ich 2/.# an &M' associate professor of pediatrics at @hildren2s &ospital 1oston# sees it. 0et since the earliest days of tele ision# electronic media has been a blame$ta(er. In the fifties# people worried that tele ision would turn children into delin5uents. Today# parents fear that iolent mo ie scenes and game scenarios will breed anger# aggression# and iolence. These accusations against media# 3ich belie es# come down to alues$based arguments# not scientific e idence.

In the fifties# people worried that tele ision would turn children into delin5uents. Today# parents fear that iolent mo ie scenes

and game scenarios will breed anger# aggression# and iolence.

6ri( %ungan/'toc(.Achng

In an effort to drill down to media2s true effects# 3ich has launched a longitudinal sur ey study. *"e2re trying to create the media e!posure e5ui alent of the Framingham &eart 'tudy#, he says. The pilot study# now in its third wa e of data collection# in ol es an ethnically and socioeconomically di erse group of .;B middle$ school students from Manchester# 4ew &ampshire. 3ich began the in estigation with computer$based self$inter iews to understand each child2s typical media use# health beha iors and health status. For one wee(# participants carry a +alm +ilot and ideo camcorder# soon to be replaced by a smartphone# which they are randomly signaled to use during wa(ing hours to capture their locations# companionship# media use# focus of attention# and emotional state. After completing the =C$ 5uestion form>which# gi en the media adeptness of the young participants# usually ta(es less than /< seconds >participants ma(e a 5uic( DB<$degree ideo of their en ironment. This ideo pic(s up en ironmental conte!ts# including media that go unnoticed by participants# such as loud music in the ne!t room# a brother playing a ideo game in the same room# or e en a billboard passing by outside a school bus.

Michael 3ich
@ourtesy of Michael 3ich

An early result of the study is the research team2s definition of an important new measure: the Media In ol ement Inde!# a measure of o erall media immersion. The team2s hypothesis is that as children use media de ices more fre5uently and concurrently# the children are more li(ely to show ris(s of ad erse outcomes. The first findings# published in the February ;<.. issue of the Journal of Adolescent Health# suggest that children with a higher Media In ol ement Inde! ha e an increased ris( of early alcohol use. Future results will e!plore how media in ol ement influences other adolescent health ris( beha iors# from smo(ing to iolence.

3ich aims to better understand the ways media affect people2s health and intends to share this information through his online parenting column# As( the Mediatrician. *In a way# urging responsible media consumption is li(e promoting food safety and traffic safety#, he says. *0ou don2t want to lecture people# but to gi e them facts so they can ma(e informed decisions., ALIEN THERAPY A video game trains angry children to keep their cool

+eewE +eew peewE Missed that alienE +eewE +eewE Oh# noE Just shot a good guy. +eewE +eew peewE

@ourtesy of Joseph Gon?ale?$&eydrich

"elcome to 3AG6 @ontrol F3egulate and Gain 6motional @ontrolG# a shoot$2em$up ideo game designed# as its name suggests# to teach anger management. This counterintuiti e game>the (ind often blamed for reinforcing beha iors that celebrate anger>wor(s. The (ey elementH "hen players2 heart rates rise# indicating the emotional arousal that can lead to anger# their guns start shooting blan(s. For adolescents who respond to minor stresses with angry and dangerous outbursts# the game may be an alternati e to pharmaceutical inter entions such as antipsychotics. In addition# says Joseph Gon?ale?$&eydrich# an &M' assistant professor of psychiatry at @hildren2s &ospital 1oston and leader of the 3AG6 @ontrol pro)ect# the game may enhance the effecti eness of beha ioral therapy. -nli(e traditional biofeedbac( training# in which people learn to calm themsel es by disengaging from reality# 3AG6 @ontrol re5uires players to stay internally calm during an intense and frustrating acti ity. In this game#

players must destroy googly$eyed aliens falling down the screen without harming the affable snails that s5uish past. *"e (new this type of game would force the (ids to ma(e decisions constantly while still (eeping their arousal in chec(#, says Jason 8ahn# an &M' instructor in psychiatry who built and helped design the prototype. *+lus it would be something they would want to play., The game# modeled after 'pace In aders# targets children aged eight and up. The researchers combine game play with beha ioral therapy that teaches such anger management techni5ues as deep breathing. The game also ser es as an icebrea(er for therapists. *The game pro ides patients with an opportunity to tal( about their actions and feelings in the conte!t of the game rather than ha ing to re isit uncomfortable# demeaning topics such as past bad beha ior#, says +eter %ucharme# a clinical social wor(er at @hildren2s &ospital 1oston who is in ol ed in the pro)ect. *+racticing the game lets them e!perience mastering the s(ills presented in therapy. This in turn allows them to open up about their difficulties., %uring the early stage of testing the game# the researchers recruited children who were inpatients in a psychiatric unit. *The alternati e treatment for these (ids would be antipsychotic drugs# which ha e a host of side effects and don2t get at the root of the problem#, says Gon?ale?$&eydrich. *0ou don2t learn to control your aggression by ta(ing antipsychotics., A recent trial of the game compared patients recei ing the normal course of treatment with those recei ing psychotherapy coupled with game play. Gon?ale?$&eydrich cautions that the study was small# and that a larger# randomi?ed controlled trial has started. At the same time# he says# *The game inter ention had a profound effect. The (ids reported feeling less angry., THEMS FIGHTIN WORDS erotonin and dopamine drive aggression in fruit flies

3aised in isolation# he had no role models. &e had ne er e en witnessed a fight. 0et when he stepped into the
ring# he had all the mo es. &e postured# lunged# and bo!ed# dancing li(e Muhammad Ali and )abbing li(e 'ugar 3ay. &ow did he feel when he faced his first foeH AngryH FrightenedH It is a 5uestion for the ages# for our ictorious pugilist is a fruit fly. *"e don2t (now when flies are angry#, says 6dward 8ra it?# the George +ac(er 1erry +rofessor of 4eurobiology at &M'# who studies fruit$fly aggression. *"e can2t as( the animals how they feel.,

@OM6 O-T '"I4GI4G: 6dward 8ra it?Is research team has found that during half$hour fights# fruit flies a erage ;J encounters of .. seconds each. The s(irmishing flies mo e so 5uic(ly that the researchers need slow$motion instant replay to score them.
ArlindoJ./istoc(photo.com

"hat 8ra it? can as(# howe er# is what dri es this innate aggressi e beha ior. 'uch research# although it does not translate directly to human anger# can pro ide insights into hostility and bullying. 8ra it? saw similar unlearned# unpracticed fighting instincts in lobsters# ma(ing the 5uestion about hardwired anger e en more curious. &e selected flies as a model for teasing out the genetics# though# because flies can be bred rapidly and raised in complete isolation. 8ra it? has found that flies show aggressi e beha iors when they face competition for resources# such as food or a mate. At first# they all fight the same way# but o er time# winners and losers emerge. *9osing flies de elop a loser mentality#, says 8ra it?. They fight less aggressi ely against opponents they2 e lost to before and# e en though they approach new foes with gusto# they tend to (eep losing. 6 en bullies# the ictors who (eep pic(ing fights and winning# will lose their competiti e ad antage after )ust one loss. In recent wor(# 8ra it? bred flies with *tunable, aggression. In these transgenic flies he can selecti ely turn on and off neurons that contain serotonin and dopamine to determine what roles these neurons play in aggression# fight intensity# and the creation of pec(ing orders. 'erotonin# he found# is crucial for fight intensity. "ithout it# flies will not do battle with gusto. %opamine appears to inhibit aggression: In its absence# flies fight at higher intensity le els. 8ra it? and colleagues plan to isolate the specific neurons in ol ed and wor( out the circuitry that go erns these beha iors. "hile it2s tempting to relate such findings to humans and their mood disorders# 8ra it? a oids such e5uations. *"e are after general principles of how these neural circuits wor(# and some of the chemicals are the same across species#, he says. *1ut the details of the circuitry are going to be completely different., !li"abeth Dougherty# a former science writer at H$ # is now a freelance science writer and novelist living in central $assachusetts.

The @hill of Fear

Dread requires only a tenth of a second to take root
by ANN MARIE MENTING

Ocean/@orbis

A copse can bec(en# with its dappled lea es and songbird trills. 1ut linger past twilight# and tree# bush# and
animal assume different dimensions. Trun(s thic(en and loom# bushes snatch at clothing# and the rustlings and s(itters of feather and claw magnify. 0ou become unsettled# unner ed. 0ou run. 0ou do this because you2re afraid. 6 en without direct e idence of danger# you2re compelled to flee# to protect yourself. "hy this compulsionH It2s the wor( of your amygdala# a tiny almond$shaped structure in your brain. 'ensory signals alert it7 in turn# it triggers a cascade of acti ity# deluging your body with messages that widen your eyes# pric( your ears# accelerate your heart# 5uic(en your breathing# wrench your stomach# moisten your palms# and launch a full$body# organ$clenching# corpuscle$filling chill. 0ou run 5uite simply because fear grips you. *0ou could call the amygdala a rele ance detector#, says 4ouchine &ad)i(hani# an &M' associate professor of radiology who speciali?es in capturing the acti ity of the brain as it reacts to fear$pro o(ing stimuli. *In less than .<< milliseconds# )ust one$tenth of a second# sensory information reaches the amygdala# which signals your brain to be aware. All your systems become more recepti e. 0ou2re now ready to fight# free?e# or flee.,

The good news is that# should the terror pro e benign# you2ll not long be in fear2s thrall. For while your amygdala is pro iding sur i al insurance by spurring action# sensory clues are also tra eling to your prefrontal corte!. The amygdala2s action buys you additional milliseconds# during which you might glimpse a light# stumble upon a tra eled road# or recei e other sensory stimuli that your prefrontal corte! will use to temper the initial response. 0ou will calm# completing an arc of reaction that has been (ey to mammalian sur i al through eons. In estigating what dri es that arc of reaction spurs much of today2s research into the molecular mechanisms of the fear response. &M' scientists are pro iding tantali?ing insights by e!plaining how we decipher danger in the ga?es or body mo ements of others# by informing treatments for conditions such as post$traumatic stress disorder# and e en by pro iding clues to the gender$based underpinnings of human response to fear. FEAR FACTORS A ;<<= poll of -.'. teenagers re ealed the power that emotion can ha e in searing fear$filled memories deeply7 despite the teens2 limited direct e!perience# terrorist attac(s# war# and nuclear war held top$ten berths in a list of fears. This finding hints at a phenomenon that &ad)i(hani and her colleagues study: the contagion of fear. In her research# &ad)i(hani has found that humans# li(e other animals# can e!perience fear indirectly# the result of another2s glance or muscle tensing# or# on a larger scale# that electric connection that turns a milling crowd into a stampeding throng.

4ouchine &ad)i(hani
Graham Gordon 3amsay

*"e2re born into this world with a system to read other people2s e!pressions#, says &ad)i(hani. *Ten minutes after we2re born# we2re already oriented more to faces than to ob)ects., In ;<<C# &ad)i(hani and colleagues

reported on their in estigation of one aspect of facial e!pression>the ga?e>and its role in communicating danger. They found that while a direct ga?e from a fear$filled face triggers acti ity in fear$response regions of the brain# the response is not as comple! as that elicited by a fear$filled face in which the eyes are a erted. A direct ga?e signals an interaction between participants who (now themsel es to be non$threatening. 1ut an a erted ga?e# *pointing with the eyes#, as the researchers call it# flags a possible en ironmental danger and spar(s acti ity in brain regions s(illed at reading faces# interpreting ga?es# processing fear# and detecting motion. In other research# &ad)i(hani found that the brain can recogni?e happy and fearful e!pressions in body mo ements. A fearful posture>hands held open and in front of the body li(e shields# for e!ample>acti ates brain regions that o ersee emotion# ision# and action# while postures of happiness>arms loosely held from the body as if opened to embrace>spur acti ity only in ision$processing regions. These physical communications of actual or percei ed danger offer one a enue to de eloping a conditioned fear# a learned response founded upon emotion and impressed so firmly within memory that it remains acti e for a lifetime. RAISING THE DREAD According to the 4ational Institute of Mental &ealth# roughly ./ million people in the -nited 'tates ha e mental illnesses that in ol e persistent# outsi?ed fear responses to seemingly ordinary stimuli. A door slam becomes a gun2s report to a shattered combat eteran# for e!ample# while smo(e from burning lea es might trigger smell$based memories of pyres for a genocide sur i or. Among the an!iety disorders lin(ed to conditioned fear responses is one that2s much in the news: post$traumatic stress disorder.

Kadim 1olsha(o
3ose 9incoln/&ar ard 4ews Office

For more than a decade# Kadim 1olsha(o # an &M' associate professor of psychiatry and director of Mc9ean &ospital2s @ellular 4eurobiology 9aboratory# has e!plored fear$dri en disorders by in estigating their molecular bases in the brains of rats. One early finding from his laboratory showed that learned fear changes the way the animals2 brains operate# offering a mechanism for conditioned fear2s persistence. 1olsha(o and colleagues taught rats to associate a harmless stimulus# a tone# with a painful e ent# a shoc( to their feet. The researchers found that neurons in the rodent amygdala e!hibited remar(able sensiti ity to the tone# so much so that the neurons continued to fire after the stimulus was remo ed. This sensiti ity# (nown as long$term potentiation# is important to memory ac5uisition. It is normally modulated by glutamate# a chemical that is released into the synaptic spaces between neurons when a message is being passed# but then is deacti ated to pre ent message o er$e!pression. 1olsha(o 2s team showed that the amygdala2s heightened sensiti ity was the result of too much glutamate# either because the clean$up process failed or# as the researchers postulated# because production of the chemical went into o erdri e. Other studies by 1olsha(o and colleagues identified two proteins essential to the innate and learned fear responses. "hen the researchers bloc(ed production of one of the proteins# stathmin# fear$conditioned mice were less able to recall the learned fear>and lost the ability to recogni?e dangers that normally would ha e (ic(ed their innate fear response into high gear. 1loc(ing the gene that produced a protein (nown as transient receptor potential channel =# normally found in high concentrations in the amygdala# decreased the rodents2 neurons2 sensiti ity to cholecysto(inin# a neuropeptide released when the innate fear response is triggered or a learned fear is recalled.

These insights are welcomed by 3oger +itman# an &M' professor of psychiatry# and Mohammed Milad# an &M' assistant professor of psychiatry. 1ased at Massachusetts General &ospital# these researchers see( to tease out treatments for people with an!iety disorders such as post$traumatic stress disorder. LOCATION, LOCATION, LOCATION *0ou can ne er completely abolish a learned fear#, says +itman. *9earned fears are deep and may strengthen by reconsolidating after recall. One way to help patients diminish the impact of an an!iety$producing memory is to guide them to form a new memory that inhibits# or e!tinguishes# e!pression of the fearful memory during any recall attempt.,

3oger +itman
John 'oares

Or# as +itman and colleagues disco ered se eral years ago# people might be helped to sta e off a fear$filled memory by pre enting it from consolidating in the first place. In a controlled study of patients entering Mass General2s emergency department after traumatic e!periences>assaults or car accidents# for e!ample>+itman pro ided some participants with a placebo and others with propranolol# a drug that bloc(s the effects of the hormone adrenaline. At follow$up inter iews participants listened to audiotapes of their own accounts of their trauma the day it occurred. +ropranolol recipients had wea(er physical responses to the tapes than placebo users# who showed physical signs of the stirring of their fearful memory despite time2s passage. 3eplicating these results has pro en difficult# howe er# so +itman and colleagues ha e shifted their focus to reacti ating traumatic memories in people with post$traumatic stress disorder and then administering an anti$ stress drug to try to wea(en the memory2s reconsolidation.

3eli ing a fear# e en a trauma$induced one# is not necessarily pathologic# Milad points out. 3ecalling the source of high emotion or in)ury can ser e as a safeguard# a warning that our brains can tap as needed. In addition# time often softens the intensity of response. *'ay you2re in a car accident#, Milad adds. *It occurs at a particular intersection at the same time a certain song is playing on the radio. For a period following that accident# whene er you go through that intersection or hear that song# you will re$e!perience at some le el your initial fear. If o er time nothing horrible happens to re(indle your memory# your conditioned response to either stimulus will lessen until the fear is e!tinguished. This e!tinction doesn2t erase the initial learned fear7 instead# it leads to forming a new memory# a Lsafety memory.2 The learned fear>the neuronal connections that the e!perience formed within your amygdala and between your amygdala and certain cortical structures>remains., For some# the trauma ne er lessens. In people with post$traumatic stress disorder# Milad and +itman ha e found that two brain regions in ol ed in e!tinction# the hippocampus and a region of the prefrontal corte!# function at a lesser capacity# while acti ity in the amygdala and the dorsal anterior cingulate# a region in ol ed in cognition and motor control# rachets up. These findings may e!plain the unending rawness that trauma$ induced fears bring to people with the disorder. X FACTOR Other research by these in estigators suggests that hormones and biological cycles may play significant roles in fear learning and e!tinction. *Although some data suggest that estrogen actually enhances fear learning#, says Milad# *other studies suggest the opposite# that it reduces fear and an!iety. -nfortunately# the area is underin estigated. An!iety disorders# for e!ample# are twice as high in women>and we can2t say precisely why.,

Mohammed Milad
John 'oares

The researchers2 wor( does pro ide intriguing clues# howe er. They ha e found that women with higher estrogen le els showed stronger acti ation of the entromedial prefrontal corte!# a brain region (ey to fear control. These high$estrogen women were good at e!tinguishing fear. "hen the researchers repeated the study in rats and manipulated estrogen le els# they found that bloc(ing estrogen impaired the animals2 ability to control fear. 3eintroducing estrogen caused the rats to beha e as if they felt safe. @uriously# the researchers found that men2s ability to control fear was a(in to that of high$estrogen women. &ow does it )ibe# then# that women ha e twice the pre alence of an!iety disordersH *"e don2t (now#, says Milad# *but the speculation is that estrogen alone doesn2t ma(e you a super$ e!tinguisher. It may be the lac( of the hormone that puts a woman at higher ris(. If a woman2s estrogen is high# she controls fear in a way comparable to men# but if her estrogen dips# as it would during a normal menstrual cycle# she may be at a higher ris( for fear ac5uisition following a trauma or another emotion$laden incident., 'uch studies by Milad and others highlight a growing interest in finely parsing the mechanisms of fear ac5uisition and e!tinction in humans. Fundamentally# though# our response to fear remains basic# a primiti e emotion essential to our sur i al and a core response that unifies our species. *The amygdala is the amygdala#, says Milad. *"hether it2s in Taipei or in @edar 3apids# it2s still a (nee$)er( response to danger., Ann $arie $enting is Associate !ditor of Harvard $edicine.

The %epths of %espair

Medicine tackles melancholia with new tools and understanding
by ELIZABETH DOUGHERTY

+i!onaut/istoc(photo.com

TUNING OUT SORROW Deep%brain stimulation offers hope for depression

'ome people with depression ha e tried e erything>beha ioral therapy# antidepressants# sleep depri ation#
electrocon ulsi e therapy>to no a ail. 4ow deep$brain stimulation is showing promise for people whose condition is refractory. The therapy# already used in some +ar(inson2s patients to control tremors# in ol es implanting electrodes in a region of the brain found to be acti e during sadness$induction studies.

T&3O"I4G A 9IF69I46: %arin %ougherty has found that deep$brain stimulation can offer hope to those with intractable depression.
3ose 9incoln/&ar ard 4ews Office

%arin %ougherty# an &M' associate professor of psychiatry at Massachusetts General &ospital# was principal in estigator of a study of fi e of the world2s first fifteen implantations e er attempted to control depression. The procedure# initial studies of which began at Mass General in ;<<D# in ol es the surgical insertion of electrodes into the brain2s entral capsule/ entral striatum. After implantation# the physician must tune the electrical stimulation for each patient# after which the de ice can stimulate the patient2s brain continually# e en indefinitely. If the de ice fails# as can happen when the person wal(s through a theft detector or airport screening de ice# the depressi e symptoms 5uic(ly return. In a follow$up study published by %ougherty and others in a ;<</ issue of &iological 'sychiatry# patients showed response rates of M< percent after si! months and =D percent after one to four years7 those responding showed significant impro ement. For a patient to consider such an in asi e treatment# their symptoms must be gra e. *The degree of illness really highlights the robustness of the treatment#, says %ougherty. A large$scale clinical trial of the techni5ue is now under way# in ol ing more than ;<< patients at ;< different sites. %ougherty is hopeful that an interim re iew of early results by the -.'. Food and %rug Administration will be one more step toward appro al of this e!perimental treatment. PRIMITIVE BRAINS Adults lose their reactivity to sad faces

Is sadness a sur i al emotionH In ;<<M# "illiam 8illgore# an &M' assistant professor of psychology at
Mc9ean &ospital# in estigated whether the perception of sadness might be go erned by the same unconscious

processing as fear or anger. *Our findings indicate that while other emotions ha e primiti e sur i al alue#, 8illgore says# *sadness appears to be more of a social emotion.,

istoc(photo.com

8illgore arri ed at this conclusion after in estigating whether the subliminal suggestion of sadness triggers acti ity in the brain2s amygdala# a region lin(ed with unconscious# sur i al$related responses# such as the startle refle! and the fight$or$flight response. In this study# 8illgore showed adult participants faces wearing sad e!pressions. 6ach sorrowful isage appeared for ;< milliseconds before 8illgore mas(ed it with one whose e!pression was neutral. "hile iewing the sad faces# participants had no conscious awareness of them# 8illgore found. -nli(e angry# frightened# and happy e!pressions# which in earlier research had all produced spi(es in amygdala acti ity# the subliminal sad e!pressions elicited no such response. In ;<<J 8illgore repeated his study with adolescents. These participants showed an unconscious response in the amygdala to sad e!pressions# suggesting# 8illgore says# that young brains may not be ready to distinguish some social emotions from threats. It may be that we learn as we mature to distinguish social cues from primiti e sur i al responses or that we learn to distinguish aroused happy# angry# and frightened faces from subdued# sad ones. Or# 8illgore adds# it could be both. &e recently found that the amygdala responds in the same way to both happy and frightened e!pressions# lending support to the arousal hypothesis. The difference between adults and adolescents does suggest# howe er# that in youth# *the amygdala is still responsi e to a broad range of emotional stimuli#, says 8illgore. *In adults# the prefrontal region puts the bra(es on to better modulate or control responses to social emotions., PERSONALIZED PSYCHIATRY (esearchers hope to be able to predict the success of antidepressants

More than half of clinically depressed patients don2t respond to their initial treatment# and wee(s often pass
before this failure becomes ob ious. 6ach subse5uent treatment re5uires additional wee(s to assess. 0et this process needn2t be a trial$and$error one# says %iego +i??agalli# an &M' associate professor of psychiatry at Mc9ean &ospital. +i??agalli hopes to speed the search for efficacious therapies for depression# not with new medications# but with biomar(ers.

1ernard 9elle/istoc(photo.com

*"e want to personali?e treatment in psychiatry#, he says# by gi ing psychiatrists the tools to find the best path to reco ery for each patient. The science is not there yet# he adds# but it may be soon. A decade ago# +i??agalli2s laboratory disco ered that a region of the brain called the rostral anterior cingulate corte! shows ele ated acti ity among people who# though not yet treated for depression# would go on to respond to the treatment months later. This biomar(er for ele ated acti ity identified C/ percent of e entual responders7 its absence was lin(ed with C/ percent of e entual nonresponders. More than a do?en studies ha e since replicated this finding. *The ne!t challenge#, +i??agalli says# *is to find a more treatment$specific predictor., &e is part of a group of researchers who recently recei ed funding to do )ust that. A 4ational Institute of Mental &ealth grant supports si! sites nationally# including Mc9ean &ospital# where +i??agalli is the principal in estigator# and Massachusetts General &ospital. The in estigators will recruit M<< patients nationally and collect a range of data# including genetic profiles# clinical symptoms# brain scans using electroencephalography and functional magnetic resonance imaging# and any e!perience with depression$lin(ed en ironmental factors# such as stress and early trauma. They will then correlate those data with treatment outcomes. *"e want to see if these data can be combined to deri e no el ways for guiding treatments for depression#, says +i??agalli. *"e hope to find the ne!t generation of predictors., THE PATH TO SADNESS The roots of depression can be uncovered

"hen it comes to triggering sadness and depression# which comes first# stress or
Auerbach# an &M' instructor in psychology at Mc9ean &ospital# suspects it2s both.

ulnerabilityH 3andy

-4%63 +36''-36: 3andy Auerbach has found that teens who recei e little support from their parents and classmates are more li(ely to be susceptible to stress$triggered depression.
John 'oares

*The presence of stress isn2t enough# and neither is the presence of ulnerability#, he says. *It2s the interaction of these two ris(s that con erge and pa e the path to sadness and depression., Auerbach2s research aims to tease out depression2s genesis by studying the interplay of stress with such ulnerabilities as low self$esteem# dysfunctional attitudes# self$referential processing# and a percei ed lac( of control in the face of ad erse e ents. &e focuses on adolescents because ;< percent of people in this age group e!perience a depressi e episode# and most will relapse in adulthood. Auerbach recently e!amined the relationship between social support and stress and the de elopment of depression among adolescents. &e found that young people with little support from parents and classmates are more li(ely to e!perience depressi e symptoms in the face of stress. A lac( of friends and supporti e peers# howe er# did not contribute to ris( for depression. This wor( appeared in the May ;<.. Journal of Abnormal )hild 'sychology. As a clinician# Auerbach applies his integrated# holistic model by helping patients learn to recogni?e their feelings# frailties# and susceptibilities so they can mo e from being reacti e to proacti e. 'omeone who feels test an!iety to the point of poor performance# for e!ample# may learn to predict that an!iety# employ rela!ation techni5ues# and interrupt the icious cycle of stress# a oidance# and impaired function. *%epression is comple!#, says Auerbach. *Once we ha e an understanding of the factors that affect the unfolding of depressi e symptoms# we can target them and reduce the despair.,

!li"abeth Dougherty# a former science writer at H$ # is now a freelance writer.

The 9oo( of 9o e
Loves many splendors begin with empathy and attachment
by DAVID CAMERON

+ainting: *+air of 9o ers#, by +al '?inyei Merse F+hoto by Alfredo %agli Ori/The Art Archi e/@orbisG

"hen second grader Jac5ueline Olds arri ed home from school one afternoon in ./==# she found the
atmosphere charged with e!citement. &er parents pointed to a headline on the front page of the $ontreal tar: *McGill opens ast new research field with brain Lpleasure area2 disco ery., Olds# now an &M' associate clinical professor of psychiatry at Massachusetts General &ospital# had only ague notions bac( then of what her father# James Olds# then a postdoctoral researcher at McGill -ni ersity# did during the day# yet she (new it had something to do with the brains of rats. The elder Olds had )ust published a paper in the Journal of )omparative and 'hysiological 'sychology describing how the rat brain was suffused with desire when a particular region of it was electronically stimulated. The rat would do whate er it could to reli e the cerebral oltage regardless of cost# li(e a )ilted lo er see(ing intimacy anew# or a gambler circling bac( to the roulette wheel. James Olds2s disco ery of the brain2s *pleasure center, has held up for more than half a century# and no scientific discussion on the phenomenon of human lo e can a oid it.

Most of us# e en those disciplined to interpret the world through the lens of e idence$based science# can2t help but imagine lo e as a ghost in the machine. 't. +aul2s famous meditation on the patience and (indess of lo e# recited in a seemingly nonstop wedding loop# personifies lo e as an entity embodying what we cra e most in others. 9o e as a spiritual alue has so permeated "estern culture that e en a science$drenched modern fable li(e the film !ternal unshine of the potless $indcouldn2t help but bust it out of its neurophysiologic sheathing. 1ut the scientific e idence is unmista(able: "hate er this thing called lo e is# we humans need it. %eep attachments to others>and the pleasure$center stimulation those lin(s cause>are as ital to our bodies and minds as food and sleep. Their absence carries catastrophic ris( to our health and well$being. I FEEL YOUR PAIN "hile many drugs# including antibiotics and certain chemotherapies# gradually lose effecti eness o er time# one treatment has manifested a steady rise in potency during the past few decades: the placebo.

@arl Marci
3ose 9incoln/&ar ard 4ews Office

Much to the e!ation of pharmaceutical companies trying to get antidepressants and pain medications appro ed for use# clinical trials conducted o er the years ha e re ealed the increasing power of the placebo effect. Our efforts to understand that trend throws light on the healing power of doctor/patient connectedness.

@arl Marci 2/J# an &M' assistant professor of psychiatry at Massachusetts General &ospital# began paying attention to the placebo effect in the early .//<s# while still a medical student. %uring a course on alternati e therapies# he was struc( by the amount of time these practitioners of homeopathy# 3ei(i# and acupuncture spent with their patients. *%ata showed that# with the e!ception of intense psychotherapy# people were spending far more time each year with alternati e practitioners than they were with other health care pro iders#, says Marci. *That got me thin(ing about the relationship., &e began to suspect that the success of these pro iders had less to do with their therapeutic approach than it did with the time they in ested in their patients. &e has since spent most of his professional life studying the doctor/patient relationship# using empathy as his framewor(. "hat is empathy# and why does it matterH The term# coined by a contemporary of Freud# goes bac( to the German word meaning *feeling into., The 6nglish no elist Ian Mc6wan once wrote# *Imagining what it is li(e to be someone other than yourself is at the core of our humanity. It is the essence of compassion# and it is the beginning of morality., A slightly more scientific paraphrase might describe empathy as the ability of the brain to accurately mirror the emotions it percei es in another. Marci2s contribution to this field is the disco ery that most empathy occurs at an unconscious le el# e idence that our brains are hardwired for it. 'e eral years ago Marci conducted a study in which he sought to 5uantify empathy. Ta(ing ;< patient/therapist pairs# he and colleagues measured the rate at which s(in conducted electrical impulses in these sub)ects# as determined through their sweat production during sessions. *'(in sweat mar(s arousal coming from the brain2s emotion center# and it accurately measures the depth of emotional response#, says Marci. *It can2t indicate what you2re feeling# but it indicates the depth and the cur e# the tra)ectory# of your emotion., Marci found that at the moments when the rate of electrical conducti ity on the s(in of patients and therapists synchroni?ed into matched lines of pea(s and gullies# the patients reported feeling most understood. FInterestingly# conducti ity was most dis)ointed precisely at those moments in which the therapists monopoli?ed the con ersation.G 'ince the mid$.//<s# when a group of Italian researchers first proposed the idea of *mirror neurons#, researchers ha e come to grasp that our brains contain dedicated neuronal networ(s that reflect the world around us. These networ(s# which reside primarily in the prefrontal corte!>the corner office of cerebral e!ecuti e function>imitate motions and emotions in a neurobiological mon(ey see# mon(ey do. "hen you witness someone wa ing# the ery part of your brain that acti ates arm motion and wrist action lights up# e en if you )am your hands into your poc(ets. And despite your efforts to (eep your isage impassi e# the neurons

that animate faces to form beaming smiles flare the nanosecond you glimpse a @heshire grin. *Our brains are so wired for empathy#, Marci says# *that there2s ?ero lag time., As far as the placebo effect goes# Marci suggests that one e!planation for its steady rise is the increasing comple!ity of clinical trials. The tighter the regulations# the more interactions patients ha e with a team of pro iders. The deeper human interaction that presumably results may help e!plain the increase in the placebo effect. "hich leads us bac( to the brain2s pleasure center# or reward center. 6mpathy triggers dopamine and serotonin# neurochemicals associated with the reward center2s con)oined twin# the brain2s emotion center. If# as the scientific literature indicates# mere laughter stimulates the reward center# how much more stimulating would be the act of immersing yourself in the world of anotherH From an e olutionary perspecti e# this ma(es perfect sense. *&uman babies ha e the most postnatal neuronal growth of any species#, says Marci. *"ithout empathy# there is no attachment# and attachment is essential for sur i al., GOOD CHEMISTRY "hat happens when empathy is absentH "hile Marci2s model is the doctor/patient relationship# 8arlen 9yons$ 3uth# an &M' associate professor of psychology at @ambridge &ealth Alliance# studies the physiological effects of human interactions in a relationship far more primordial: the one between mothers and infants. "ithin the field of de elopmental psychology# 9yons$3uth is a leading e!pert on attachment# with a particular focus on attachment gone wrong. *In a sense#, she says# *I2m most interested in what happens when lo e goes awry., 6mpathy and mirroring of the infant2s states by the parent is a powerful regulator of normal de elopment# says 9yons$3uth. The biomar(er she uses to measure the 5uality of a mother$infant relationship is cortisol. This steroid hormone has a number of functions# such as increasing blood sugar and helping the body metaboli?e fats and carbohydrates. It is also released in response to stress to help the body mobili?e to meet a challenge. 0et too much cortisol can lead to health problems. @ombat soldiers in particular are li(ely to e!perience long periods of e!treme stress. 'uch prolonged stress (eeps the hormone )ac(ed up# but the human organism2s capacity to tolerate such a powerful chemical is limited# so an emergency system clic(s in and dams the hormone2s flow. This chec( can result in an indi idual who goes through life with a blunted stress response system and attenuated emotional engagement. 4ormal cortisol le els and stress responses are essential for healthy attachment# says 9yons$3uth. "hen a mother2s cortisol le els are normal# she acts as an e!ternal regulator by being attuned to her baby2s fear and

discomfort and acting to relie e these negati e states. As a result# the baby e!periences minimal stress. 1ut when a mother2s cortisol response is blunted# her ability to act as an attuned e!ternal regulator for the infant may fail. *"e still ha e much wor( to do to understand this model of attachment#, says 9yons$3uth. *1ut our research has shown that mothers whose interactions with their infants are the most disrupted ha e the lowest cortisol le els., 'he and her colleague 1)arne &olmes ha e also obser ed that the infants of low$cortisol mothers present with low cortisol le els as well. "hen low$cortisol infants are stressed# though# their cortisol le els fly off the charts. *These babies lac( the ability to modulate their stress responses#, 9yons$3uth says. 1ecause antisocial children and adults also show blunted cortisol responses# low cortisol le els among mothers with ery young infants set off alarm bells about these babies2 future de elopment. Infants reared in orphanages may be most at ris( for blunted stress responses and associated disturbances in their ability to form deep emotional bonds. As Megan Gunnar and her colleagues at the -ni ersity of Minnesota ha e shown# many children adopted from orphanages show abnormally low hormone le els similar to those of combat eterans and antisocial adults. 1ut instead of acting antisocial# some of these children e!hibit what 9yons$3uth calls indiscriminate friendliness. They lac( the *stranger danger, instinct that is recogni?ed as a healthy component of early de elopment. Indiscriminate beha ior often persists throughout childhood# e en after adoption into healthy and stable homes. *The wor( that @harley Neanah has done at Tulane is pointing to a possible critical period for the formation of attachment bonds#, says 9yons$3uth. *%espite good care later# unless responsi e care is pro ided before the end of toddlerhood# blunted cortisol and attachment problems can persist., LONELY HEARTS CLUB

Jac5ueline Olds and 3ichard 'chwart?

John 'oares

3ichard 'chwart? has the distinction of being both an &M' associate clinical professor of psychiatry at Mc9ean &ospital and the husband of Jac5ueline Olds# the psychiatrist whose father disco ered the brain2s reward center. Together 'chwart? and Olds ha e car ed out a niche as e!perts in the study not only of lo e and marriage# but of loneliness as well. They had already written one boo( on loneliness when a -ni ersity of @hicago sur ey found# in ;<<M# that ;M.J percent of respondents had not spo(en to anyone o er the prior si! months on issues that were important to them. Most stri(ing was that nearly two decades earlier# only .< percent of respondents ta(ing the sur ey had reported this circumstance. This finding spurred 'chwart? and Olds to tac(le a second boo( on the sub)ect# The *onely American. Their thesis is straightforward: The -nited 'tates is suffering from a loneliness epidemic# and the feeling is leading to physical and mental stress. *To put it simply#, says 'chwart?# *loneliness is bad for you., And there2s plenty of e idence to support this notion. In ./CC# -ni ersity of Michigan sociologist James &ouse published a seminal re iew article in cience that detailed a lin( between loneliness and premature death. 6 en when circumstances such as accidents were factored out# socially isolated indi iduals were twice as li(ely to die within a ten$year period as were non$isolated people. Maintaining contact with others seems to be hardwired into our biology# such that our bodies become stressed when these connections are threatened. 9oneliness# in short# is a form of low$le el chronic stress. *"hen you2re disconnected# your immune system goes to hell#, 'chwart? obser es# citing another landmar( study# this one published in +enome &iology in ;<<J by 'te e @ole of the -ni ersity of @alifornia at 9os

Angeles. In this study# researchers found that chronic loneliness alters the e!pression of a networ( of genes associated with inflammation. *If we (now that loneliness affects our immune response#, 'chwart? says# *it2s not surprising that it would happen at the le el of %4A e!pression., As therapists# 'chwart? and Olds constantly encounter patients who suffer from chronic loneliness# yet most are hesitant to label it as such. As diagnoses go# depression and an!iety are less embarrassing. 1ut it2s hard to o erestimate the psychic pain that loneliness can cause. Thin( of the nibbling feelings you had as a child For an adultEG when you suspected you were being purposely left out. Then try to imagine the pain of ostracism or# ta(en to e!tremes# the outright torture of solitary confinement. *Few higher mammals are solitary#, obser es 'chwart?. *&umans are relati ely helpless as indi iduals in the natural world. +art of what ma(es us so powerful is that we2 e banded together in small groups. And part of the pain of loneliness is the recognition that without other people we simply can2t sur i e., 4or surprisingly# loneliness and substance abuse often go hand in hand. *Many drugs# particularly stimulants# trigger the dopaminergic reward center#, Olds says. *1ut we now (now that social connectedness and the feeling of being lo ed also acti ate that same reward center. If you lac( the relationships needed to stimulate that part of your brain# you2ll li(ely find it in a drug., 1lanche %u1ois2s legendary line in A treetcar ,amed Desire# *I ha e always depended on the (indness of strangers#, is e olutionarily and neurologically true. 6mpathy and attachment are at the core of human relatedness# and a small section of our prefrontal corte! dri es us to find it one way or another. "ithout it# we2re lost. *Attachment to others#, says Olds# *is the original reward., David )ameron is the Director of cience )ommunications at Harvard $edical chool.