Donna Chisholm goes un­der the wire for sci­ence.

North & South - - Cover Story -

Iam wired, not for sound, but for a sig­nal far more sub­tle – a brain wave from the right frontal cor­tex that has pos­si­bly been trig­gered deep in my hip­pocam­pus. It will ap­pear as a slight os­cil­la­tion on my EEG trac­ing; an un­con­scious re­sponse so slight that if I blink my eyes rapidly or grind my teeth, it will be lost in a ca­coph­ony of elec­tri­cal noise.

For in­ter­na­tion­ally noted Univer­sity of Otago anx­i­ety re­searcher Pro­fes­sor Neil Mcnaughton, who is mon­i­tor­ing this test at his Dunedin lab, the sig­nal is the cul­mi­na­tion of 50 years’ work. This brain wave – his brain wave – will, he be­lieves, be­come the world’s first biomarker of anx­i­ety.

The re­sult will have noth­ing to do with how stressed I feel or my abil­ity to “suc­ceed” at the com­puter test Mcnaughton has de­signed. “We can do this with lizards if nec­es­sary.” This is good news. Lizards are ap­par­ently less in­tel­li­gent than dol­phins, orang­utans, bears, par­rots, don­keys, cats, rac­coons and even naked mole rats.

The beauty of Mcnaughton’s rightclick, left- click, stop-go test is that it is pro­vid­ing new in­sights into the anx­ious brain – with­out the owner of the brain know­ing any anx­i­etyre­lated cir­cuitry is fir­ing up at all.

Anx­i­ety, he says, is not fear, but rather the adap­tive re­ac­tions that help us to ap­proach dan­ger rather than flee from it. Think of a hun­gry rat that wants food but must weigh up the risk of the cat sit­ting next to it. The brain rhythm Mcnaughton has found – first in rats and now in tests on peo­ple – con­trols goal-con­flict re­sponses and is re­duced by anti-anx­i­ety drugs even if they don’t work for de­pres­sion, pho­bia, panic or ob­ses­sion.

Crit­i­cally, says Mcnaughton, the biomarker will al­low us to de­fine a bi­o­log­i­cal type of anx­i­ety. At present, he says, guide­lines for the di­ag­no­sis of men­tal dis­or­ders lump to­gether symp­toms to de­fine them. “No­body has ever got a bi­o­log­i­cal def­i­ni­tion of any men­tal dis­or­der – we may have the first one of these.

The key prob­lem at the mo­ment is the way these are di­ag­nosed. You have a group of things that we cur­rently call high tem­per­a­ture spotty dis­or­der. We should be able to end up ef­fec­tively with a test which al­lows you to say, okay, this thing here is Ger­man measles.”

In EEG record­ings from hu­man vol­un­teers, Mcnaughton has been able to ac­cu­rately iden­tify groups who have been given small doses of anti-anx­i­ety drugs, based only on the lev­els of this right-frontal brain wave, which re­flects the goal- con­flict as­pect of anx­i­ety.

“My main claim to fame is to have at­tempted to nail down the idea that the hip­pocam­pus, which most peo­ple talk about as be­ing to do with con­trol­ling mem­ory, is ac­tu­ally a key area con­trol­ling anx­i­ety. What I think we are deal­ing with is a mech­a­nism that es­sen­tially can keep de­fen­sive, fear­ful, anx­ious mem­o­ries go­ing.

“This adds a par­al­lel anx­i­ety sys­tem (mov­ing to­wards dan­ger/ risk assess­ment) to the es­tab­lished fear sys­tems (mov­ing away from dan­ger). It sees anx­i­ety and fear as al­most op­po­sites of each other, rather than be­ing two words for the same fun­da­men­tal thing.

“The hip­pocam­pus is not only strongly con­nected to the amyg­dala but also to lower ( hy­po­thal­a­mus) and higher ( pre­frontal cor­tex) ar­eas in­volved in fear and anx­i­ety.”

So, to the test. It is, as Mcnaughton prom­ises, so sim­ple as to be al­most te­dious. Left click on the mouse when a left-fac­ing ar­row ap­pears on screen, right click when the right-fac­ing ar­row ap­pears. But when a beep sounds, do not click. The speed of the beep is ad­justed so that some­times it will be easy to stop, some­times al­most im­pos­si­ble, or evenly bal­anced 50-50. It’s those 50-50 calls which gen­er­ate the anx­i­ety-re­lated re­sponse. Tellingly, the sig­nal is un­af­fected by the an­noy­ance of fail­ure. Which is just as well: ex­ple­tives punc­tu­ate my test.

“You are try­ing to stop re­li­ably ev­ery time there is a stop sig­nal, and a lot of the time you can’t and that’s ir­ri­tat­ing, but a real ad­van­tage of the test is that we aren’t ex­pos­ing peo­ple to a ma­jor threat. This task, in terms of its na­ture and sur­round­ings, is very un­threat­en­ing. Then we ar­range con­flict, which is the key part of my the­ory.”

My EEG sug­gests I am not par­tic­u­larly, or overtly, anx­ious. I am, un­re­mark­ably, bor­ingly av­er­age, hav­ing a sim­i­lar-sized sig­nal “bump” to Mcnaughton’s “mid­dle of the road” group. “We ex­pect clin­i­cal cases to have a much larger pos­i­tive bump, with a spread to the lower fre­quen­cies.”

But what does all this mean for pa­tients? Surely it isn’t vi­able for ev­ery pa­tient to go through a brain scan to be di­ag­nosed with anx­i­ety? While that may be true of the present test, there is the prospect of cheap, clip-on EEG head­sets. “By the time we are down this track, there may well be EEG sys­tems that you could hand to your pa­tient and use for neuro-feed­back train­ing.”

His re­search is also be­ing used to bet­ter de­fine and tar­get the pa­tients who score most highly on the anx­i­ety brain sig­nals, to then see if he can de­vise a ques­tion­naire that iden­ti­fies them as be­ing anx­ious com­pared to hav­ing other types of men­tal dis­or­der.

“The prob­lem is dif­fer­ent peo­ple are be­ing given dif­fer­ent drugs and some of the drugs work for dif­fer­ent peo­ple some of the time, so the clin­i­cians have to keep swap­ping round. The ques­tion is whether they can be given the right ones first off.”

Mcnaughton, who co-au­thored a sem­i­nal work in the field, The Neu­ropsy­chol­ogy of Anx­i­ety, with renowned Ox­ford Univer­sity psy­chol­o­gist Jef­frey Gray (who died in 2004), is re­cruit­ing peo­ple who iden­tify them­selves as be­ing anx­ious but are not on drugs to treat it, and healthy con­trols, to take part in the EEG tri­als, which have the back­ing of a $1 mil­lion Health Re­search Coun­cil grant, in Auck­land and Dunedin. Any­one who’s in­ter­ested can find out more by email­ing anx­i­

The brain re­sponse typ­i­cally associated with anx­i­ety is known as “fight or flight”. This re­ac­tion starts in the amyg­dala – the cen­tre for emo­tional pro­cess­ing – which sends an SOS to the hy­po­thal­a­mus, the com­mand cen­tre.

One of the troops the hy­po­thal­a­mus dis­patches in re­sponse to stress and anx­i­ety is the cor­ti­cotropin-re­leas­ing hor­mone known as CRH. Ul­ti­mately, the hor­monal cas­cade through the adrenal and pi­tu­itary glands shows up in our blood with in­creased lev­els of cor­ti­sol. We need these phys­i­o­log­i­cal changes to help us cope with the dan­ger, but when the change be­comes chronic, or oc­curs in­ap­pro­pri­ately, the stage is set for anx­i­ety and stress dis­or­ders.

A few streets away from Mcnaughton’s lab, at the Univer­sity of Otago’s Cen­tre for Neu­roen­docrinol­ogy, As­so­ciate Pro­fes­sor Greg An­der­son and Dr Karl Ire­mon­ger have come to re­gard CRH neu­rons as the equiv­a­lent of the Prime Min­is­ter, and the many and var­ied pro­cesses that act on them

“What I think we are deal­ing with is a mech­a­nism that es­sen­tially can keep de­fen­sive, fear­ful, anx­ious mem­o­ries go­ing.”

as the PM’S spe­cial­ist ad­vis­ers and Cab­i­net. An­der­son has also iden­ti­fied a key mem­ber of the Cab­i­net with a pre­vi­ously un­recog­nised but im­por­tant role – to con­tinue the anal­ogy, a kind of bio­chem­i­cal Min­is­ter for Anx­i­ety, known in sci­en­tific cir­cles as RFRP neu­rons.

An­der­son stum­bled on the idea that RFRP might be af­fect­ing stress about five years ago, when he was re­search­ing (in rat mod­els) their role in sup­press­ing fer­til­ity.

“We were look­ing at sit­u­a­tions where peo­ple are known to be in­fer­tile – be­fore pu­berty, post­menopause, gen­er­ally when lac­tat­ing, and per­haps when stressed – to see whether this chem­i­cal might be ramped up. Some sit­u­a­tions didn’t fit our hy­poth­e­sis. There were times we were ex­pect­ing to find high lev­els of this chem­i­cal and they were re­ally low. But a much bet­ter ex­pla­na­tion for the lev­els we were see­ing was that they seemed to re­flect whether the an­i­mals were anx­ious or not,” he says.

The RFRP neu­rons seemed to be “re­ally ramped up” when the an­i­mals were stressed. “If the RFRP neu­rons are chron­i­cally el­e­vated, it means the CRH neu­rons are chron­i­cally el­e­vated.”

About five years ago, An­der­son’s group de­vel­oped a chem­i­cal, known as GJ14, which stops RFRP act­ing on its re­cep­tor on the CRH neu­ron. In 2015, they pub­lished their re­search show­ing how the drug com­pletely re­versed the anx­i­ety-pro­mot­ing ef­fects of RFRP, and changed the be­hav­iour of the mice treated with it. The be­havioural tests are rel­a­tively sim­ple – mice pre­fer dark en­closed spaces rather than be­ing ex­posed in lighted ar­eas and the ac­tiv­i­ties are mon­i­tored in a light-

When we’re un­der stress, phys­i­o­log­i­cal changes in our bod­ies help us cope with the dan­ger, but when the change be­comes chronic, or oc­curs in­ap­pro­pri­ately, the stage is set for anx­i­ety and stress dis­or­ders.

dark box. Mice treated with GJ14 spent sig­nif­i­cantly more time in the open than mice in­fused with RFRP.

The dis­cov­ery has changed An­der­son’s re­search fo­cus, from fer­til­ity to anx­i­ety, and his team is now work­ing to find out if the drug can suc­cess­fully cross the blood-brain bar­rier (at the mo­ment it’s in­jected into the brain), which would be es­sen­tial if it’s to be clin­i­cally ef­fec­tive.

Adding to the ex­cite­ment of the find is that the drug ap­pears to be “won­der­fully with­out ad­verse side ef­fects” and isn’t on the re­search radar of any other sci­en­tists in the field, in­ter­na­tion­ally.

An­other ad­van­tage is that it’s highly spe­cific in its tar­get. Ear­lier in the re­search, An­der­son says they tested an­other drug that blocked RFRP but also blocked other re­lated re­cep­tors, caus­ing un­wanted side ef­fects such as po­ten­tial fer­til­ity com­pli­ca­tions.

“Only one in 1000 re­search drugs will make it into clin­i­cal use; we are re­al­is­tic about that. We will have to line our drug up against the SSRIS [an­tide­pres­sants] and ben­zo­di­azepines [anti-anx­i­ety drugs] and show ours is bet­ter in or­der to get a drug com­pany ex­cited about de­vel­op­ing it fur­ther.”

Ire­mon­ger says a key goal of the re­search is to un­der­stand how stress neu­rons func­tion. We al­ready know about the cyclic na­ture of the re­ac­tions in the brain – that stress ac­ti­vates the CRH neu­rons, which ac­ti­vate the stress hor­mone lev­els, which feed back to the brain and reg­u­late how the brain func­tions. “The prob­lem seems to be that it’s not just a sin­gle stress that’s the prob­lem. Most peo­ple can cope with those quite well – it’s chronic el­e­va­tions in the cor­ti­sol which change brain ac­tiv­ity in a detri­men­tal way.”

He’s also look­ing at how neu­ral struc­tures within brain cells change after long-term ex­po­sure to cor­ti­sol. “Other labs around the world have shown quite con­vinc­ingly that in the emo­tional cir­cuits, you get quite dra­matic changes in struc­ture after long-term ex­po­sure to cor­ti­sol and to stress.”

Dr Karl Ire­mon­ger (left) and As­so­ci­ate Pro­fes­sor Greg An­der­son at the Univer­sity of Otago’s Cen­tre for Neu­roen­docrinol­ogy.

Univer­sity of Otago anx­i­ety re­searcher Pro­fes­sor Neil Mc­naughton.

Ex­ple­tives alert: Donna Chisholm takes the test.

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