Pain in the ACC?

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 onNeurosynth.org (7), a databaseof 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 prior metaanalyses 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, oneor 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.