Atlas, LY

Botvinick, MM

Chang, LJ

Coghill, RC

Davis, KD

Iannetti, GD

Poldrack, RA

Shackman, AJ

Wager, TD

Yarkoni, T

UCL Discovery

Pain	in	the	ACC?			TD	Wagera,b,1,	LY	Atlasc,d,	MM	Botvinicke,	LJ	Changf,	RC	Coghillg,	KD	Davish,i,j,	GD	Iannettik,	RA	Poldrackl,	AJ	Shackmanm,n,o,	T	Yarkonip			aDepartment	of	Psychology	and	Neuroscience,	University	of	Colorado	Boulder,	Boulder,	CO	80305;	bInstitute	of	Cognitive	Science,	University	of	Colorado,	Boulder,	CO	80305;	cNational	Center	for	Complementary	and	Integrative	Health,	National	Institutes	of	Health,	Bethesda,	MD	20892;	dNational	Institute	on	Drug	Abuse,	National	Institutes	of	Health,	Bethesda,MD	20892;	ePrinceton	University,	Princeton,	NJ	08544;	fDepartment	of	Psychological	&	Brain	Sciences,	Dartmouth	College,	Hanover,	NH	03755;	gDepartment	of	Anesthesiology,	Cincinnati	Children’s	Hospital,	Cincinnati,OH	45229;	hKrembil	Research	Institute,	TorontoWestern	Hospital,	University	HealthNetwork,	Toronto,ON,	CanadaM5G2C4;	iDepartment	of	Surgery,	University	of	Toronto,	Toronto,ON,	Canada	M5G	1V7;	jInstitute	of	Medical	Science,	University	of	Toronto,	Toronto,	ON,	Canada	M5G	1V7;	kUniversity	College	London,	London	WC1E	6BT,	United	Kingdom;	lStanford	University,	Stanford,	CA	94305;	mDepartment	of	Psychology,	University	ofMaryland,	College	Park,MD	20742;	nNeuroscience	and	Cognitive	Science	Program,	University	of	Maryland,	College	Park,	MD	20742;	oMaryland	Neuroimaging	Center,	University	of	Maryland,	College	Park,	MD	20742;	and	pUniversity	of	Texas	at	Austin,	Austin,	TX	78712				Lieberman	and	Eisenberger	 (1)	claim	that	 the	 “dorsal	anterior	cingulate	cortex	(dACC)	is	selective	for	pain.”	This	surprising	conclusion	contradicts	a	large	body	of	 evidence	 showing	 robust	 dACC	 responses	 to	 nonpainful	 conditions.	Electrophysiological	 and	 optogenetic	 studies	 have	 identified	 neuronal	populations	 activated	 during	 foraging	 behavior,	 attention,	 emotion,	 reward	expectancy,	 skeletomotor	 and	 visceromotor	 activity,	 and	 other	 functions	 (e.g.,	refs.	 2–5).	Only	 a	 small	minority	 of	 dACC	neurons	 are	 pain-related.	 Lieberman	and	Eisenberger	(1)	later	propose	that	the	dACC	responds	to	“enduring	survival-relevant	 goals,”	 including	 hunger	 and	 social	 rejection.	 This	 hypothesis	 appears	inconsistent	with	 selectivity	 for	pain,	with	 attention-	 (3)	 and	motor-coding	 (4)	dACC	neurons,	 and	with	demonstrations	of	 dissociable	 representations	of	 pain	and	 rejection	 in	 dACC	 (6).	 We	 agree	 that	 dACC	 subserves	 survival-relevant	functions;	 however,	 acceptance	 of	 dACC	 as	 “pain-selective”	 will	 lead	 the	 field	down	the	wrong	track.			Lieberman	and	Eisenberger’s	(1)	conclusions	are	based	on	Neurosynth.org	(7),	a	database	 of	 activation	 coordinates	 and	 words	 used	 in	 >11,000	 neuroimaging	studies.	The	claim	of	pain	selectivity	is	based	on	a	statistical	preference	in	dACC	activation	 studies	 for	 the	 use	 of	 pain-related	words,	 compared	with	 a	modest	number	of	alternatives	(e.g.,	“salience”).	Neurosynth	analyses	are	based	on	word	frequencies	 in	 published	 papers.	 They	 may	 not	 reflect	 the	 actual	 processes	studied,	 and	 are	 not	 linked	 specifically	 to	 particular	 brain	 locations.	 They	 are	subject	 to	 biases	 in	 how	 different	 literatures	 use	words	 and	 label	 brain	 areas	(e.g.,	 “salience”	 has	 multiple	 meanings,	 and	 dACC	 is	 also	 called	 anterior	 mid-cingulate	 cortex).	 Neurosynth	 is	 useful	 for	 exploring	 structure-to-function	mappings	 across	 a	 large	 literature,	 but	 it	 cannot	 provide	 definitive	 inferences	about	specific	brain	regions.		Nonetheless,	Lieberman	and	Eisenberger	(1)	wrote	that	the	“best	interpretation	of	dACC	activity	is	in	terms	of	pain.	.	.,”	implying	that	dACC	activity	can	be	used	as	an	 indicator	 for	 pain	 and/or	 related	 survivalrelevant	 functions.	 This	 sets	 a	dangerous	precedent,	and	would	yield	erroneous	conclusions	in	many	instances	(Fig.	 1A).	 In	 addition,	 Lieberman	 and	 Eisenberger’s	 claims	 of	 selectivity	 are	based	on	a	flawed	method	of	making	“reverse	inferences”	(RI),	inferences	based	on	the	posterior	probability	of	a	mental	state	(S)	given	regional	fMRI	activation.	Valid	 RI	 requires	 estimating	 the	 probability	 of	 S	 given	 activation	 using	 Bayes’	rule.	 Unlike	 priormetaanalyses	 testing	 RI	 (e.g.,	 ref.	 7),	 Lieberman	 and	Eisenberger’s	 analyses	 do	 not	 do	 this.	 Rather,	 they	 use	 a	 nonstandard	comparison	of	Z-scores	 for	pain	with	other	 individual	keywords.	This	has	been	extensively	 critiqued	 elsewhere	(www.talyarkoni.org/blog/2015/12/14/stillnot-selective-comment-on-comment-on-comment-onlieberman-eisenberger-2015/)	 and	 is	 not	 equivalent	to	 estimating	 posterior	 probabilities.	 In	 fact,	 using	 the	 same	 database,	 we	estimate	the	probability	of	a	study	inducing	physical	pain	given	activity	in	pain-selective	dACC	at	∼12%,	on	par	with	language,	emotion,	attention,	and	memory	(Fig.	1B).		Finally,	 the	seductive	notion	of	a	single,	one-	or	two-word	“best	 interpretation”	of	the	dACC’s	∼550	million	neurons	is	based	on	a	flawed	premise.	dACC	neurons	code	 for	 a	 broad	 spectrum	 of	 mental	 processes.	 Instead	 of	 trying	 to	 find	 the	single	 word	 or	 phrase	 that	 best	 characterizes	 dACC	 function,	 we	 should	 use	rigorously	 designed	 experiments	 to	 identify	 signals	 within	 dACC	 that	 are	common	and/or	specific	to	particular	information	processing	functions	(e.g.,	ref.	6),	 and	 use	 information	 distributed	 across	 multiple	 brain	 regions	 to	 perform	meaningful	structure-to-function	mapping.				 	References			1	Lieberman	MD,	Eisenberger	NI	(2015)	The	dorsal	anterior	cingulate	cortex	is	selective	for	pain:	Results	from	large-scale	reverse	inference.	Proc	Natl	Acad	Sci	USA	112(49):15250–15255.	2	Kvitsiani	D,	 et	 al.	 (2013)	Distinct	behavioural	 and	network	 correlates	of	 two	interneuron	types	in	prefrontal	cortex.	Nature	498(7454):363–366.	3	 Davis	 KD,	 et	 al.	 (2005)	 Human	 anterior	 cingulate	 cortex	 neurons	 encode	cognitive	and	emotional	demands.	J	Neurosci	25(37):8402–8406.	4	Picard	N,	 Strick	PL	 (1996)	Motor	 areas	of	 the	medial	wall:	A	 review	of	 their	location	and	functional	activation.	Cereb	Cortex	6(3):342–353.	5	 Shidara	 M,	 Richmond	 BJ	 (2002)	 Anterior	 cingulate:	 Single	 neuronal	 signals	related	to	degree	of	reward	expectancy.	Science	296(5573):1709–1711.	6	Woo	CW,	et	al.	 (2014)	Separate	neural	 representations	 for	physical	pain	and	social	rejection.	Nat	Commun	5:5380.	7	 Yarkoni	 T,	 Poldrack	RA,	Nichols	 TE,	 Van	 Essen	DC,	Wager	 TD	 (2011)	 Large-scale	automated	synthesis	of	human	functional	neuroimaging	data.	Nat	Methods	8(8):	665–670.	8	 Wager	 TD,	 et	 al.	 (2005)	 Common	 and	 unique	 components	 of	 response	inhibition	revealed	by	fMRI.	Neuroimage	27(2):323–340.	9	 Botvinick	 M,	 Nystrom	 LE,	 Fissell	 K,	 Carter	 CS,	 Cohen	 JD	 (1999)	 Conflict	monitoring	 versus	 selection-for-action	 in	 anterior	 cingulate	 cortex.	 Nature	402(6758):	179–181.	10	Bartra	O,	McGuire	 JT,	Kable	 JW	(2013)	The	valuation	system:	A	coordinate-based	meta-analysis	of	BOLD	fMRI	experiments	examining	neural	correlates	of	subjective	value.	Neuroimage	76:412–427.			 	Figure	and	legend				Fig.	1.	The	dACC	is	not	selective	for	pain.	(A)	dACC	activation	in	studies	of	(Top)	cognitive	 control	 [go/no-go	 (8)],	 (Middle)	 response	 conflict	 (9),	 and	 (Bottom)	reward	(10).	 If	pain	were	considered	the	“best	 interpretation”	of	dACC	activity,	these	 studies	 would	 be	 erroneously	 classified	 as	 pain-related.	 (B)	 Posterior	probabilities	 of	 study	 topic	 given	 activation	 in	 the	 pain-selective	 dACC,	 using	empirical	 priors.	 Center	 shows	Lieberman	 and	Eisenberger’s	 (1)	 pain-selective	dACC	coordinates.	They	find	that	seven	out	of	eight	of	these	locations	are	highly	selective	 for	 pain,	 including	 the	 one	 circled	 [Montreal	 Neurological	 Institute	(MNI)	coordinates	0,	10,	34].	The	top	terms	in	Neurosynth’s	“reverse	inference”	list	 are	 indeed	 pain-related.	 However,	 this	 does	 not	 reflect	 the	 actual	 topics	studied	 or	 the	 relevant	 posterior	 probabilities.	 We	 (T.D.W.	 and	 laboratory	members)	manually	 identified	 the	 topics	 of	 the	 first	 240	 (of	 647	 total)	 studies	reporting	brain	activation	within	8	mm	of	MNI	coordinates	0,	10,	34	based	on	the	paper	titles	and	abstracts,	and	used	them	to	calculate	the	posterior	probabilities	shown	 in	 the	 figure.	 The	 probability	 that	 the	 study	 topic	 was	 pain	 was	 12%.	More	broadly,	50%	of	dACC	activation	studies	were	focused	on	cognition	(blue),	20%	were	focused	on	socioemotional	processes	(green),	and	19%	were	focused	on	 pain,	 somatosensation,	 or	 other	 somatic	 referents	 (red).	 The	 remaining	studies	 were	 difficult	 to	 categorize	 or	 irrelevant	 (mainly	 resting	 state	 and	methodological	 studies).	 This	 analysis	 does	 not	 imply	 that	 there	 is	 no	 pain-related	 information	 in	 the	 dACC,	 but	 it	 does	 imply	 that	 dACC	 is	 not	 especially	selective	for	either	pain	or	a	special	class	of	survival-relevant	functions.	Images	courtesy	of	(A,	Top)	ref.	8,	with	permission	from	Elsevier,	and	(A,	Middle)	ref.	9.	A,	Bottom	is	a	schematic	based	on	findings	in	ref.	10.	

Pain in the ACC?

http://discovery.ucl.ac.uk/1566596/1/Iannetti-G_Pain_in_the_ACC_final_accepted_PNAS_2016.pdf

Pain in the ACC?

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