Sunday, November 18, 2012

Vicodin for Social Exclusion

Cyberball (with apologies to Kipling D. Williams).

Cyberball (not the Atari version) is a virtual game designed by social psychologists to be a model for social rejection and ostracism (Williams et al., 2000). The study participant is led to believe they are playing an online ball-tossing game with other people, who then proceed to exclude them from the game. The resultant negative feelings are meant to be a proxy for ostracism based on fundamental attributes such as race, disability, physical appearance, homelessness, etc. This simple game has lead to a burgeoning cottage industry on social pain and its close resemblance to physical pain.

Social Pain and Physical Pain Are Not Interchangeable

That statement may sound obvious to you, but an increasing number of neuroimaging studies would have us believe otherwise. Whenever I read an article proclaiming that "the brain bases of social pain are similar to those of physical pain" (Eisenberger et al., 2003), I am reminded of how phenomenologically DIFFERENT they are. Waking up from general anesthesia and feeling undermedicated for surgery that took your body apart and put it back together again feels absolutely nothing like being rejected by your long-term partner. Your anterior insula and anterior cingulate cortex might be very busy in both cases, but they're also activated in many different situations (Yarkoni et al, 2011).

Indeed, of the 2238 total papers in the BrainMap neuroimaging database, 735 of them contain the search term 'anterior cingulate' (see also Shackman et al., 2011). Besides pain and emotion, the behavioral domains that activate this brain region include motor learning, language, speech, explicit memory, working memory, bladder control, thirst, sexuality, and perception in all five senses. Sure, the affective components of pain might show some overlap with physical pain (Kross et al., 2011), but distinct networks are likely responsible for the unique aspects of these different qualia.1

The Aversive Brain

Hayes and Northoff (2012) described a core brain network involved in the processing of aversive stimuli (or states) that can be either painful or non-painful in nature. They relied on evidence from both the human and animal literatures. Aversion here refers to more than social and physical pain, and includes avoidance of stimuli that are unpleasant, frightening or disgusting. Meta-analysis of human neuroimaging data showed overlap in some of the structures involved in non-painful aversion and physical pain (shown in green below), which accounted for 35% of Aversion-related voxels and 24% of Pain-related voxels. These overlapping regions included mid-cingulate cortex, posterior cingulate cortex, anterior insula, right ventrolateral prefrontal cortex (PFC), dorsomedial PFC, thalamus, midbrain, secondary motor cortex, and areas related to memory (right hippocampus/parahippocampal gyrus) and even reward (dorsal striatum).2

It is important to note here that some of the social pain darlings (mid-cingulate cortex, anterior insula, right ventrolateral PFC) are also activated by unpleasant pictures, sounds, and smells.

- click on image for a larger view -

Fig. 2 (Hayes & Northoff, 2012). Overlap of pain- and aversion-related networks in humans. Results of meta-analyses for human pain- (blue) and aversion- (yellow) related studies (top row), overlapping activations (green; top row and isolated in bottom row), and a corresponding table of associated brain regions. All results are family-wise error rate whole-brain corrected at p < 0.05

Furthermore, although there was substantial overlap between Aversion and Pain, 65% and 76% of all activations (respectively) were not shared. Structures uniquely activated by Aversion included the amygdala, hypothalamus, more anterior regions of the anterior cingulate, and another reward-related area (ventral striatum). Brain regions uniquely activated by Pain included the cerebellum, rostral pons, somatosensory cortex, posterior insula, and yet another dopamine-rich, reward-related area (ventral tegmental area).3

Dave J Hayes, co-author of the study, wrote about this fruitful cross species network approach to The Aversive Brain in his blog.

But Depression Hurts, doesn't it?

It sure does according to Lilly, who would also like us to believe that their drug Cymbalta (duloxetine, an SNRI antidepressant) will cure your aches and pains along with your depression. But Duloxetine Does Not Relieve Painful Physical Symptoms in Depression, according to a meta-analysis of five available studies (Spielmans, 2008).

How much overlap is there between brain activity associated with physical pain and feelings of sadness? To answer this question, I performed a meta-analysis of my own that made use of the BrainMap database of published neuroimaging experiments. Using GingerALE software, I did two activation likelihood estimate (ALE) meta-analyses to look at brain regions activated by experimental manipulations to induce physical pain and sadness (see Laird et al., 2005 for methodological details of ALE). In brief, the procedure involves three steps to determine the likelihood of activation across experiments:
  1. ALE and Testing Significance: Compute the ALE values for each voxel in the brain and performs a test to determine the null distribution of the ALE statistic at each voxel.
  2. Thresholding: Take the P values from the previous step and computes the threshold for the ALE map using the Tom Nichol’s FDR algorithm.
  3. Cluster Analysis: Perform cluster analysis on the thresholded map, based on the minimum volume that is specified in the previous step.

Using Sleuth to search the BrainMap database revealed 94 papers related to pain perception or pain monitoring/discrimination, which involved 1334 subjects, 345 experimental contrasts, and 3455 locations. 4 The search for sadness identified 58 papers involving 1159 subjects, 193 experimental contrasts, and 1204 locations. The pinkish-colored regions in the figure below show the overlap between sadness (in blue) and pain (in red) — which is not very extensive! The slices were selected to highlight overlap in anterior cingulate (Left), mid-insula and basal ganglia (Middle), and anterior insula (Right).

The main points here are that:
  • Sadness is represented quite differently from physical pain.
  • The shared physical pain-social pain network also includes aversive responses to unpleasant sensory stimuli. Which are not painful.

So any treatment designed to ease the unpleasantness of physical pain would not help the concomitant  feelings of sadness, at least not directly. But treatments for social pain could generalize to the non-painful aversion network: disgusting and disturbing things might not seem as bad, either.

Have there been any effective manipulations to ease social pain? One unlikely study claimed that acetaminophen reduced the pain of social rejection (Dewall et al., 2010).  I was quite skeptical of this study, as outlined in Suffering from the pain of social rejection? Feel better with TYLENOL®:
 In Experiment 1, 30 participants (24 women, 6 men) took one 500 mg acetaminophen pill immediately after waking up and another 500 mg an hour before going to sleep (1,000 mg per day for 3 weeks). The other 32 participants (24 women, 8 men) took the same dosing of placebo for 3 weeks. Each evening, subjects filled out the the Hurt Feelings Scale (the "today" version) to report how much social pain they had experienced that day. Despite the fact that the half life of acetaminophen is 4 hours, it took about 10 days for the drug group to report significantly lower hurt feelings than the placebo group. The difference on day 21 was greatest (p < .005). However, the difference in change-over-time slopes between the two groups was only marginally significant (p ≤ .10). The explanation of the time course for these effects was unclear...
 Or as Time writer Maia Szalavitz said in a comment on the post:
This study would have made sense if they used opioids, which are known to reduce the emotional aspect of physical pain. There's also a high concentration of opioid receptors in the cingulate. Of course, the result wouldn't have been novel or surprising: junkies wouldn't exist if opioids didn't kill emotional pain.

Indeed, if acetaminophen could numb emotional pain, this would have been discovered by addicts by now. The fact that the drug remains boringly OTC suggests that this effect is either so small it can only be detected in the lab or nonexistent as the blog suggests.

Buffer the Pain Away 5

This brings us to a new study (by one of the same authors) that administered transcranial direct current stimulation (tDCS) over right ventrolateral PFC and reported a reduction in negative feelings caused by exclusion in a game of Cyberball  (Riva et al., 2012). This article, like the acetaminophen one, was published Psychological Science.

Rather than launch into a full-scale summary of this study, I refer the interested reader to a post by Andrew Wilson Psychological me at camera 3, which is not about this paper but summarizes some of the general issues that can be seen in 2-3 page short reports in Psych Science.

As for the specific findings of Riva et al. (2012), beyond asking whether all five of the rating scales confirmed the result (rather than just the two reported), I wonder about the specificity of the response to social exclusion. In other words, would tDCS reduce reactions to aversive stimuli in general (as noted above)? What do you think, does right frontal tDCS improve functioning in other domains? What do we know about its mechanisms of action?

And finally, do you buy the premise that social exclusion hurts, literally?


1 According to the Stanford Encyclopedia of Philosophy:
Philosophers often use the term ‘qualia’ ... to refer to the introspectively accessible, phenomenal aspects of our mental lives. ... Disagreement typically centers on which mental states have qualia, whether qualia are intrinsic qualities of their bearers, and how qualia relate to the physical world both inside and outside the head. The status of qualia is hotly debated in philosophy largely because it is central to a proper understanding of the nature of consciousness. Qualia are at the very heart of the mind-body problem. 

2 Presumably, the vast majority of subjects were not masochists or gluttons for punishment.

3 Another complicating factor is that this so-called "Pain Matrix" might not be specific to pain at all, but may instead reflect responses to highly salient stimuli in different modalities (Iannetti & Mouraux, 2010).

4 Compare this to 6 yrs ago, when my analysis for physical pain yielded only 35 studies (see Hypnosis and Pain Control).

5 OR you could F**k the Pain Away... Peaches would say.


Dewall CN, Macdonald G, Webster GD, Masten CL, Baumeister RF, Powell C, Combs D, Schurtz DR, Stillman TF, Tice DM, Eisenberger NI. (2010). Acetaminophen reduces socialpain: behavioral and neural evidence. Psychol Sci. 21:931-7.

Eisenberger NI, Lieberman MD, Williams KD. (2003). Does rejection hurt? An FMRI study of social exclusion. Science 302:290-2.

Hayes, D., Northoff, G. (2012). Common brain activations for painful and non-painful aversive stimuli. BMC Neuroscience, 13 (1) DOI: 10.1186/1471-2202-13-60

Iannetti GD, Mouraux A. (2010). From the neuromatrix to the pain matrix (and back). Exp Brain Res. 205:1-12.

Kross E, Berman MG, Mischel W, Smith EE, Wager TD. (2011). Social rejection sharessomatosensory representations with physical pain. Proc Natl Acad Sci 108(15):6270-5.

Laird AR, Fox PM, Price CJ, Glahn DC, Uecker AM, Lancaster JL, Turkeltaub PE, Kochunov P, Fox PT. (2005). ALE meta-analysis: controlling the false discovery rate and performing statistical contrasts. Hum Brain Mapp. 25:155-164.

Riva, P., Romero Lauro, L., DeWall, C., Bushman, B. (2012). Buffer the Pain Away: Stimulating the Right Ventrolateral Prefrontal Cortex Reduces Pain Following Social Exclusion. Psychological Science DOI: 10.1177/0956797612450894

Shackman AJ, Salomons TV, Slagter HA, Fox AS, Winter JJ, Davidson RJ. (2011). The integration of negative affect, pain and cognitive control in the cingulate cortex. Nat Rev Neurosci. 12:154-67.

Spielmans GI. (2008). Duloxetine does not relieve painful physical symptoms in depression: a meta-analysis Psychother Psychosom. 77:12-6.

Williams KD, Cheung CK, Choi W. (2000). Cyberostracism: effects of being ignored over the Internet. J Pers Soc Psychol. 79:748-62.

Yarkoni T, Poldrack RA, Nichols TE, Van Essen DC, Wager TD. (2011). Large-scale automated synthesis of human functional neuroimaging data. Nat Methods 8:665-70.

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At November 19, 2012 11:10 AM, Blogger Neuroskeptic said...

"Waking up from general anesthesia and feeling undermedicated for surgery that took your body apart and put it back together again feels absolutely nothing like being rejected by your long-term partner."

I dunno. They both feel 'bad', and that may seem like a trivial point but I don't think it is. 'Bad' is a distinct feeling - or kind of feeling - and it's possible to imagine life without it (take some morphine and physical pain no longer is 'bad')... I agree that 'Social pain is just like physical pain!' is a terrible way of expressing this, but if you reframed it as being about the neural basis of unpleasantness, then I've a lot time for it.

At November 19, 2012 2:43 PM, Blogger The Neurocritic said...

Really? I'd be hard pressed to tell you what's similar about them, in terms of bodily states and mental states. Sure, they're generically 'bad', but then the word 'bad' becomes an unhelpful descriptor for the associated qualia. You can also feel 'bad' while viewing unpleasant IAPS pictures or smelling a disgusting odor, but these don't hurt physically or psychologically. Or at least, not in the same way as social exclusion.

Of course, the whole point of the Hayes and Northoff (2012) meta-analysis was to point out that indeed, a general 'unpleasantness detector' encompasses responses to painful and non-painful aversive stimuli. Legrain, Iannetti et al. (2011) called the Pain Matrix a "salience detection system for the body". Taking this even further, Iannetti and Mouraux (2011) said that fMRI responses to physical pain cannot tell us why social rejection 'hurts' because the Pain Matrix is not even specific to pain:

"This network, although often referred to as the 'pain matrix,' has been shown to be largely unspecific for nociception and pain, and, instead, to reflect multimodal neural processes triggered by salient sensory stimuli regardless of their sensory modality, and probably related to attentional orienting toward these stimuli..."

The metaphorical language of a 'broken heart' loses some of its meaning if it's also part of a system that detects and avoids unpleasant odors.

At November 19, 2012 6:31 PM, Blogger Maia Szalavitz said...

Thanks for the cite ;-) .. I think opioids may again offer insight into where the overlap is: lots of people describe opioids as "distancing" them from both physical and emotional pain. A common (yet quite odd-sounding if you think about it} remark here is that "it still hurts but it doesn't bother me." I think the "bother" or angst or unpleasantness or sting— which could indeed be shared by disgust or aversion— is the commonality, similar to what Neuroskeptic wrote. In other words, what physical and emotional pain share is a sense of distressing impingement on or threat to the self, which can occur in many aversive experiences and can explain why drugs that relieve both emotional and physical pain also ease fear and disgust. Also, why people with opioid addictions may pre-existingly suffer oversensitivity to multiple aversive experiences. And so, the broken heart thing isn't so far off.. bad relationships are also "rotten."

At November 19, 2012 8:00 PM, Blogger The Neurocritic said...

Sure! You said:

A common (yet quite odd-sounding if you think about it} remark here is that "it still hurts but it doesn't bother me."

It is odd-sounding for the physical-emotional pain isomorphism if a drug that relieves the sensation of physical pain doesn't reduce feelings of emotional pain, but only makes you care less about them. Other drugs can do the same thing, but they're not pain relievers - benzodiazepines and alcohol, for example. Anxiolytics also reduce the distress of other aversive experiences.

As for the use of metaphorical language, I would like to see a cross-linguistic study of how hurt-related and aversion-related terms are used.

At November 20, 2012 4:41 AM, Blogger Maia Szalavitz said...

Hmm... What I meant was that opioids give the same "distance" and "not bothering" from *both* emotional and physical pain, rather than completely eliminating it. Alcohol also has strong effects on endogenous opioids.

As for benzos, they seem to reduce worry and fear more than pain, though they are often inextricably linked.

At November 20, 2012 11:04 AM, Anonymous Anonymous said...

Please, repeat with me:
1. Psychological Science publishes mostly false positive studies
2. Very little replicates in the tDCS field, in large part because of lack of proper reporting of procedures and absence of proper double blind studies


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