The Neurocritic

Recent technological developments in neuroscience have enabled rapid advances in our knowledge of how neural circuits function in awake behaving animals. Highly targeted and reversible manipulations using light (optogenetics) or drugs have allowed scientists to demonstrate that activating a tiny population of neurons can evoke specific memories or induce insatiable feeding.

But this week we learned these popular and precise brain stimulation and inactivation methods may produce spurious links to behavior!! And that “controlling neurons with light or drugs may affect the brain in more ways than expected”! Who knew that rapid and reversible manipulations of a specific cell population might actually affect (gasp) more than the targeted circuit, suggesting that neural circuits do not operate in isolation??

Apparently, a lot of people already knew this.

Here's the dire Nature News report:

...stimulating one part of the brain to induce certain behaviours might cause other, unrelated parts to fire simultaneously, and so make it seem as if these circuits are also involved in the behaviour.

According to Ölveczky, the experiments suggest that although techniques such as optogenetics may show that a circuit can perform a function, they do not necessarily show that it normally performs that function. “I don’t want to say other studies have been wrong, but there is a danger to overinterpreting,” he says.

But the paper in question (Otchy et al., 2015) was not primarily about that problem. The major theme is shown in the figure above — the difference between acute manipulations using a drug (muscimol) to transiently inactivate a circuit versus the chronic effects of permanent damage (which show remarkable recovery).¹In the songbird example, acute inactivation of the nucleus interface (Nif) vocal control area (and its “off-target” attachments) warped singing, but the “chronic” lesion did not.²

In an accompanying commentary, Dr. Thomas C. Südhof asked:

How should we interpret these experiments? Two opposing hypotheses come to mind. First, that acute manipulations are unreliable and should be discarded in favour of chronic manipulations. Second, that acute manipulations elicit results that truly reflect normal circuit functions, and the lack of changes after chronic manipulations is caused by compensatory plasticity.

But not so fast! said Südhof (2015), who then stated the obvious. “Many chronic manipulations of neural circuits (both permanent genetic changes and physical lesions) do actually produce major behavioural changes.” [as if no one had ever heard of H.M. or Phineas Gage or Leborgne before now.]

The acute/chronic conundrum is nothing new in the world of human neurology. But centuries of crudely observing accidents of nature, with no control over which brain regions are damaged, and no delineation of precise neural mechanisms for behavior, don't count for much in our store of knowledge about acute vs. chronic manipulations of neural circuits.

Let's take a look at a few examples anyway.

In his 1876Lecture on the Prognosis of Cerebral Hæmorrhage, Dr. Julius Althaus discussed recovery of function:

Do patients ever completely recover from an attack of cerebral hæmorrhage?
This question used formerly to be unhesitatingly answered in the affirmative.
. . .

The extent to which recovery of function may take place depends—

1. Upon the quantity of blood which has been effused. ...

2. Upon the portion of the brain into which the effusion has taken place. Sensation is more easily re-established than motion; and hæmorrhage into the thalamus opticus seems to give better prospects of recovery than when the blood tears up the corpus striatum. ...

[etc.]

In his 1913 textbook of neurology (Organic and Functional Nervous Diseases), Dr. Moses Allen Starr discussed aspects of paralysis from cortical disease, and the uniqueness of motor representations across individuals: “Every artisan, every musician, every dancer, has a peculiar individual store of motor memories. Some individuals possess a greater variety of them than others. Hence the motor zone on the cortex is of different extent in different persons, each newly acquired set of movements increasing its area.”

In 1983, we could read about Behavioral abnormalities after right hemisphere stroke and then Recovery of behavioral abnormalities after right hemisphere stroke.

More recently, there's been an emphasis on connectome-based approaches for quantifying the effects of focal brain injuries on large-scale network interactions, and how this might predict neuropsychological outcomes. So the trend in human neuroscience is to acknowledge the impact of chronic lesions on distant brain regions, rather than the current contention [in animals, of course] that “acute manipulations are probably more susceptible to off-target effects than are chronic lesions.”

But I digress...

Based on two Nature commentaries about the Otchy et al. paper, I was expecting “ah ha, gotcha, optogenetics is a fatally flawed technique.” This Hold Your Horses narrative fits nicely into a recap of neurogaffes in high places. One of the experiments did indeed use an optogenetic manipulation, but the issue wasn't specific to that method.

Ultimately, the neuroblunder for me wasn't the Experimental mismatch in neural circuits (or a failure of optogenetics per se), it was the mismatch between the-problem-as-hyped and a lack of historical context for said problem.

Footnotes

¹Here's a figure from the other experiment, which involved acute vs. chronic inactivation of motor cortex in rats. Basically, the tiny injection of muscimol impaired lever-pressing behavior (acutely), but the large lesion did not (chronically). Panel H shows a similar deleterious effect using optogenetic stimulation.

Modified from Fig. 1 (Otchy et al., 2015).

I can't stress this point enough – a human with a comparably sized lesion in primary motor cortex would not [likely] show that much spontaneous recovery of function in 5-10 days. Yes, of course there's plasticity in the central nervous system of adult humans, but I think Otchy et al. (2015) overstate the case here:

As in our experimental animals, patients with lesions to motor-related brain areas have motor deficits that resolve in the days and weeks following the injury. Aspects of this recovery are thought to be independent of rehabilitation, suggesting spontaneous processes at work.

²It isn't exactly true that the lesions had no effect on song: “A fraction of the initial post-lesion vocalizations were severely degraded and did not resemble pre-lesion song.”

References

Althaus J (1876). A Lecture on the Prognosis of Cerebral Haemorrhage. British medical journal, 2 (812), 101-4. PMID: 20748269

Otchy, T., Wolff, S., Rhee, J., Pehlevan, C., Kawai, R., Kempf, A., Gobes, S., & Ölveczky, B. (2015). Acute off-target effects of neural circuit manipulations. Nature DOI: 10.1038/nature16442

Reardon, S. (2015). Brain-manipulation studies may produce spurious links to behaviour. Nature DOI: 10.1038/nature.2015.19003

Südhof, T. (2015). Reproducibility: Experimental mismatch in neural circuits. Nature DOI: 10.1038/nature16323

My entire body of work has been called into question!

And what a fine week for technical neurogaffes it is. First was the threat that many trendy and important studies of neural circuits may need to be replicated using old-fashioned lesion methods, because of “off-target” effects:

Where do we go from here? Most acute manipulation studies that use optogenetics confirm, and so add valuable support to, existing hypotheses that were established in earlier studies. But for those studies that have proposed new circuit functions, it may be advisable to re-evaluate the conclusions using independent approaches.¹

Up next we have....

fMRI Neuroblunders in Brief

The most notable one of late is a new paper by Eklund et al. (2015), which demonstrated that common statistical tests used to analyze fMRI data can give wildly inflated false positive rates of up to 60%, as illustrated in the top figure.

“What they found is shocking”!

While voxel-wise error rates were valid, nearly all cluster-based parametric methods (except for FSL’s FLAME 1) have greatly inflated familywise Type I error rates. This inflation was worst for analyses using lower cluster-forming thresholds (e.g. p=0.01) compared to higher thresholds, but even with higher thresholds there was serious inflation. This should be a sobering wake-up call for fMRI researchers, as it suggests that the methods used in a large number of previous publications suffer from exceedingly high false positive rates (sometimes greater than 50%).

The problems (and recommended solutions) were expertly discussed already by Russ Poldrack, who is quoted above (see Big problems for common fMRI thresholding methods), and by Neuroskeptic (False Positive fMRI Revisited). I needn't belabor the issues any further.

Next question:

Is the ubiquitously activated dorsal anterior cingulate cortex (dACC) selective for pain (as opposed to conflict or cognitive control or salience)? That was the contention of a new paper by Lieberman and Eisenberger (2015) that made use of the Neurosynth meta-analytic framework developed by Tal Yarkoni.

It Depends on What “Selective” Means²

A 15,000 word debate between Yarkoni (No, the dorsal anterior cingulate is not selective for pain) and Lieberman (Comparing Pain, Cognitive, and Salience Accounts of dACC) ensued, with no end in sight.

It Also Depends on What “Pain” Means

Social Pain and Physical Pain Are Not Interchangeable. This may sound obvious to you, but Eisenberger and Lieberman have argued otherwise, with their neural alarm view of dACC function. Neurosynth uses text mining and machine learning to build maps based on terms that appear in published papers, along with activation coordinates. So the map above doesn't distinguish between different types of experimentally-induced physical pain (heat, cold, pressure, etc.) vs. emotional pain or social exclusion in a video game.

This might be one of L&E's major points, but pain researchers aren't on board; many don't even think the dorsal posterior insula is a pain-specific region.

Footnotes

¹If anyone can parse the bold red sentence that appears in the Naturecommentary (immediately after the first quoted passage in the post), please let me know.

In the future, it might be helpful always to correlate acute and chronic manipulations of specific neurons. If results from acute and chronic manipulations are discrepant, analyses of circuits that act in parallel to the manipulated circuit, or of similar neurons that are activated by different stimuli, might be more likely to provide an explanation for the discrepancy than examination of chains of hierarchically connected neurons, because off-target effects probably propagate throughout neural circuits by spilling over into adjacent, connected circuits.

²Sam Schwarzkopf addressed this in his post, What is selectivity?

Does the pain of mental anguish rely on the same neural machinery as physical pain? Can we treat these dreaded ailments with the same medications? These issues have come to the fore in the field of social/cognitive/affective neuroscience.

As many readers know, Lieberman and Eisenberger (2015) recently published a controversial paper claiming that a brain region called the dorsal anterior cingulate cortex (dACC, shown above) is “selective” for pain.¹This finding fits with their long-time narrative that rejection literally “hurts” — social pain is analogous to physical pain, and both are supported by activity in same regions of dACC (Eisenberger et al., 2003). Their argument is based on work by Dr. Jaak Panksepp and colleagues, who study separation distress and other affective responses in animals (Panksepp & Yovell, 2014).

Panksepp wrote The Book on Affective Neuroscience in 1998, and coined the term even earlier (Panksepp, 1992). He also wrote a Perspective piece in Science to accompany Eisenberger et al.'s 2003 paper:

We often speak about the loss of a loved one in terms of painful feelings, but it is still not clear to what extent such metaphors reflect what is actually happening in the human brain? Enter Eisenberger and colleagues ... with a bold neuroimaging experiment that seeks to discover whether the metaphor for the psychological pain of social loss is reflected in the neural circuitry of the human brain. Using functional magnetic resonance imaging (fMRI), they show that certain human brain areas that “light up” during physical pain are also activated during emotional pain induced by social exclusion [i.e., exclusion from playing a video game].

But as I've argued for years, Social Pain and Physical Pain Are Not Interchangeable. Whenever I read an article proclaiming that “the brain bases of social pain are similar to those of physical pain”, I am reminded of how phenomenologically DIFFERENT they are.

And subsequent work has demonstrated that physical pain and actual social rejection (a recent romantic break-up) do not activate the same regions of dACC (Woo et al., 2014). Furthermore, multivariate activation patterns across the entire brain can discriminate pain and rejection with high accuracy.²

Modified from Fig. 3 (Woo et al., 2014). Differences between fMRI pattern-based classifiers for pain and rejection.

Feelings of rejection were elicited by showing the participants pictures of their ex-partners (vs. pictures of close friends), and physical pain was elicited by applying painful heat to the forearm (vs. warm heat).

Does this mean there is no overlap between brain systems that can dampen physical and emotional pain (e.g., endogenous opioids)? Of course not; otherwise those suffering from utter despair, unspeakable loneliness, and other forms of psychic turmoil would not self-medicate with mind-altering substances.

Separation Distress: Of Mice and Psychoanalysis

Although Panksepp has worked primarily with rodents and other animals throughout his career, he maintains a keen interest in neuropsychoanalysis, an attempt to merge Freudian psychoanalysis with contemporary neuroscience. Neuropsychoanalysis “seeks to understand the human mind, especially as it relates to first-person experience.” If you think that's a misguided (and impossible) quest, you might be surprised by some of the prominent neuroscientists who have signed on to this agenda (see these posts).

Prof. Panksepp is currently collaborating with Prof. Yoram Yovell, a Psychoanalyst and Neuroscientist at the Institute for the Study of Affective Neuroscience (ISAN) in Haifa. A recent review paper addresses their approach of affective modeling in animals as a way to accelerate drug development in neuropsychiatry (Panksepp & Yovell, 2014). Their view is that current models of depression, which focus on animal behaviors instead of animal emotions, have hindered new breakthroughs in treatments for depression. It’s actually a fascinating and ambitious research program:

We admit that our conceptual position may be only an empirical/ontological approximation, especially when contrasted to affective qualia in humans … but it is at least a workable empirical approach that remains much underutilized. Here we advance the view that such affective modeling can yield new medical treatments more rapidly than simply focusing on behavioral processes in animals. In sum, we propose that the neglect of affect in preclinical psychiatric modeling may be a major reason why no truly new psychiatric medicinal treatments have arisen from behavior-only preclinical modeling so far.

They propose that three key primal emotional systems³may be critical for understanding depression: SEEKING (enthusiasm-exuberance), PANIC (psychic pain), and PLAY (joyful exuberance). If these constructs sound highly anthropormorphic when applied to rats, it's because they are!! Perhaps you'd rather “reaffirm classical behaviorist dogma” (Panksepp & Yovell, 2014) and stick with more traditional notions like brain reward systems, separation distress, and 50-kHz ultrasonic vocalizations (e.g., during tickling, mating, and play) when studying rodents.

Of interest today is the PANIC system (Panksepp & Yovell, 2014), which “mediates the psychic pain of separation distress (i.e. excessive sadness and grief), which can be counteracted by minimizing PANIC arousals (as with low-dose opioids).” Since low-dose opioids alleviate separation distress in animals (based on reductions in distress vocalizations), why not give them to suicidal humans suffering from psychic pain?

Well... because making strong inferences about the contents of animal minds is deeply problematic (Barrett et al., 2007). I've written about some of the problems with animal models of dread and despair. One might also question whether it's wise to give opioid drugs (even in very low doses) to severely ill people.

Low-Dose Buprenorphine for Suicidal Ideation

Recently investigators are increasingly entertaining the possibility of using ‘safe opioids’ for the treatment of depression, as well as the chronic ‘psychological pain’ that often promotes suicidal ideation. To be a ‘safe opioid’, the analgesic effects and the lethal (respiratory depression) effects of a particular opioid ligand need to be dissociated. Buprenorphine, a partial agonist at μ-opioid receptors (i.e. stimulating opioid receptors at low doses, but blocking them at high doses), is just such a drug.

Panksepp and Lovell's ideas led to a clinical trial (A Study of Nopan Treatment of Acute Suicidality) and a new paper in the American Journal of Psychiatry (Yovell et al., 2015). Nopan is sublingual buprenorphine hydrochloride 0.2 mg. At higher doses, buprenorphine is used as a treatment for opioid addiction, much like methadone.

Research on suicidal behavior is an important and tragically neglected topic, and many clinicians, organizations, and industry sponsors are reluctant to engage. So it's notable that the current study was funded by the Neuropsychoanalysis Foundation (which awards grants and sponsors the journal Neuropsychoanalysis), the Hope for Depression Research Foundation (whose Board is filled with some Heavy Hitters of Neuroscience – e.g., Akil, Mayberg, McEwen, Nestler, Hen), and ISAN.

It's interesting to track some of the changes in the study protocol and description over time. The initial ClinicalTrials.gov entry (dated 2010_01_11) dropped its psychoanalytic language on 2011_05_23:

The acutely suicidal patient presents a complex and dangerous clinical dilemma. Many suicidal patients receive antidepressant medications, but the onset of action of these medications is at least three weeks, and despite their established antidepressant effect, they have not shown a clear anti-suicidal benefit. Psychoanalysts hypothesized that depression (often leading to suicidality) shares important characteristics with the psychological sequelae of object loss and separation distress. Endogenous opioids (endorphins) have been implicated in mediating social bonding and separation distress in mammals.

On the same date, the Secondary Outcome Measure (Reduction in psychache as measured by the Holden Psychache Scale) was replaced by a more standard and non-psychoanalytic instrument, the Beck Depression Inventory (Reduction in depression as measured by the BDI). Dr. Beck conceptualized depression in a cognitive framework.

On the other hand, “psychache” (coined by suicidologist Dr. Edwin Shneidman) means “unbearable psychological pain—hurt, anguish, soreness, and aching. ... Psychache stems from thwarted or distorted psychological needs . . . every suicidal act reflects some specific unfulfilled psychological need.” Many of these views are at odds with neuropsychiatry (Schneidman, 1993):

Depression seems to have physiological, biochemical, and probably genetic components. The use of medications in treatment is on target. [so far so good] ... Suicide, on the other hand, is a phenomenological event... It is responsive to talk therapy and to changes in the environment. Suicide is not a psychiatric disorder. Suicide is a nervous dysfunction, not a mental disease.

But 90% of suicides are in people with clinically diagnosable psychiatric disorders; anxiety, depression, impulsivity, and alcohol abuse are major risk factors. While cases of psychache would certainly benefit from talk therapy and a change in environment, pharmacological (and/or brain stimulation) treatments seem to be essential. Which is the clearly the intention of Yovell et al. (2015), or else they wouldn't have conducted a drug study.

In short, I found it curious that the focus of their clinical trial changed so much mid-stream, and that the mental anguish of the original formulation is so completely and utterly human (given its genesis from the animal literature).

In the next post, I'll cover the actual study and the background on why anyone would think low-dose opioids are a good idea in cases of treatment-resistant depression and suicidality.

Further Reading

Vicodin for Social Exclusion

Suffering from the pain of social rejection? Feel better with TYLENOL®

Existential Dread of Absurd Social Psychology Studies

Does Tylenol Exert its Analgesic Effects via the Spinal Cord?

The Mental Health of Lonely Marijuana Users

Tylenol Doesn't Really Blunt Your Emotions

Of Mice and Women: Animal Models of Desire, Dread, and Despair

Footnotes

¹ In contrast, based on years of detailed neuroanatomical and neurophysiological experiments, most neuroscientists think the dACC is a functionally heterogeneous region (e.g., Vogt et al., 1992). Shortly after the Lieberman & Eisenberger (2015) paper was published, a number of researchers expressed their vehement disagreement in blog posts: Yarkoni-1, Lieberman reply, Yarkoni-2, Shackman, Wager.

²In contrast to these results, an earlier study by this group claimed that social rejection shares somatosensory representations with physical pain. It's always nice to see examples where scientists update their own theories based on new evidence.

³ In Panksepp's scheme, there are seven basic or primal emotions that are subcortically based and evolutionarily conserved: SEEKING, RAGE, FEAR, LUST, CARE, PANIC/GRIEF, and PLAY. Needless to say, this model has not gone unchallenged (Barrett et al., 2007; LeDoux, 2015). Barrett and colleagues have argued that emotions are not natural kinds, but rather emergent psychological events constructed from core affect (positive or negative states) and a human conceptual system for emotion.

References

Barrett LF, Lindquist KA, Bliss-Moreau E, Duncan S, Gendron M, Mize J, Brennan L. (2007). Of Mice and Men: Natural Kinds of Emotions in the Mammalian Brain? A Response to Panksepp and Izard. Perspect Psychol Sci. 2(3):297-312.

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

Panksepp, J., & Yovell, Y. (2014). Preclinical Modeling of Primal Emotional Affects (SEEKING, PANIC and PLAY): Gateways to the Development of New Treatments for Depression. Psychopathology, 47 (6), 383-393. DOI: 10.1159/000366208

Shneidman ES. (1993). Suicide as psychache. J Nerv Ment Dis. 181(3):145-7.

Woo CW, Koban L, Kross E, Lindquist MA, Banich MT, Ruzic L, Andrews-Hanna JR, & Wager TD (2014). Separate neural representations for physical pain and social rejection. Nature communications, 5. PMID: 25400102

Yovell, Y., Bar, G., Mashiah, M., Baruch, Y., Briskman, I., Asherov, J., Lotan, A., Rigbi, A., & Panksepp, J. (2015). Ultra-Low-Dose Buprenorphine as a Time-Limited Treatment for Severe Suicidal Ideation: A Randomized Controlled Trial. American Journal of Psychiatry DOI: 10.1176/appi.ajp.2015.15040535

The prescription opioid crisis of overdosing and overprescribing has reached epic proportions, according to the North American media. Just last week, we learned that 91% of patients who survive opioid overdose are prescribed more opioids! The CDC calls it an epidemic, and notes there's been “a 200% increase in the rate of overdose deaths involving opioid pain relievers and heroin.” A recent paper in the Annual Review of Public Health labels it a “public health crisis” and proposes “interventions to address the epidemic of opioid addiction” (Kolodny et al., 2015).

In the midst of this public and professional outcry, why on earth would anyone recommend opioid drugs as a treatment for severe depression and suicidal ideation??

Let's revisit the questions posed in my previous post:

Does the pain of mental anguish rely on the same neural machinery as physical pain?

Can we treat these dreaded ailments with the same medications?

The opioid-for-depression proponents would answer both of those questions in the affirmative,¹ with some qualifications. First off, the actual medication in question (and its dose) is different from the typically abused opiate / opioid drug. As far as I can tell, no one is clamoring for narcotic analgesics like OxyContin and Vicodin to be used as antidepressants.

In his 2008 paper on the Psychotherapeutic Benefits of Opioid Agonist Therapy, Dr. Peter L. Tenore reviewred the history of the Opium Cure and declared, “Opioids have been used for centuries to treat a variety of psychiatric conditions with much success.” However, these drugs can be highly addictive (obviously) so he issued this caveat at the end of the paper:

It should be noted that opioids do not have FDA approval for the treatment of psychiatric disorders. The intent of this paper was not to suggest that practitioners should prescribe opioids in a manner not approved by the FDA, but rather it was to explore the mechanisms and develop hypotheses that might explain the observation that opioid-dependent psychiatric patients in appropriately certified opioid replacement therapy programs (i.e., methadone treatment programs) stabilize on higher opioid dosages than those without psychiatric diagnoses.

Methadone and especially low-dose buprenorphine are the drugs being tested for their antidepressant efficacy, even in those who have no opioid abuse issues. Buprenorphine is a mixed partial μ/κ agonist with complex actions, including:

Antagonist (blocker) of κ-opioid receptors (KORs) that bind dynorphins (endogenous opioids associated with anxiety and dysphoria)
Partial agonist at μ-opioid receptors (MORs), producing analgesic effects but with less euphoria and less respiratory depression than full agonists

Basic research in rodents suggests that KORs may be a promising target for potential psychiatric treatments in humans, based on improvements shown in standard behavioral assays such as the forced swim test and the elevated maze test (Crowley & Kash, 2015).²But there's still a long way to go. In addition to the difficulty of modeling mental anguish in animals, the complexity of the dynorphin/KOR system — which can exhibit paradoxical and “convoluted” effects on behavior³— presents a barrier to clinical translation.

In contrast, a very different approach uses affect modeling in an effort to accelerate drug development in neuropsychiatry (Panksepp & Yovell, 2014). In this view, current models of depression have hindered new breakthroughs because of their focus on animal behaviors, instead of animal emotions. Panksepp maintains that separation distress and infant versions of psychic pain, excessive sadness, and grief are mediated by the PANIC system, which is soothed by opioids. Chicks, kittens, puppies, and other infant animals emit distress vocalizations when separated from their mothers. Rat pups emit ultrasonic vocalizations and baby monkeys“coo”. These innate, reflexive, and adaptive behaviors are reduced with low doses of morphine.⁴

Panksepp and colleagues have inferred that very strong and human-like emotions are associated with distress vocalizations.

By way of example, here is my adult cat. He's very affectionate and chatty. He requires a lot of attention and doesn't like to be alone. Does he meow and miss me when I'm on vacation? I imagine he does. Do I think he feels psychic pain and grief while I'm gone? No.

Watt and Panskepp (2009) argue that depression is an evolutionarily conserved mechanism to terminate separation distress, drawing on psychoanalytic concepts like object relations theory as well as the literature on neuropeptides and neuromodulators implicated in major depression.

Nopan Treatment of Acute Suicidality

The research on separation distress in animals helped motivate a clinical trial that was recently published in the American Journal of Psychiatry (Yovell et al., 2015). The initial daily dose of Nopan (0.1 or 0.2 mg sublingual buprenorphine hydrochloride) was relatively low, reaching a maximum dose of 0.8 mg daily by the end of the four week trial (mean = 0.44 mg). By way of comparison, the maintenance dose for opioid dependence is 4 to 24 mg/day.⁵ Analgesic effects are obtained at 0.1– 8 mg (according to Heit, 2010), although Yovell et al. said their doses were subanalgesic.

Eighty-eight severely suicidal patients were enrolled in the double-blind, placebo-controlled trial, about 2/3 of whom had made at least one suicide attempt. Over half met criteria for borderline personality disorder (BPD), which includes symptoms like affective instability, self-harm, high rates of substance abuse, and fear of abandonment (i.e., heightened separation distress). Although 50 patients had BPD, the other 48 did not. If separation distress is a major motivating construct for the trial, it seems problematic to have a heterogeneous population on that dimension. Nevertheless...

Almost all were clinically unstable, and their ability to cooperate with the study team was compromised, as reflected in a high dropout rate (29.5%) during the first week of treatment.

This sort of study is very difficult to conduct, so it's not surprising that the completion rate was low (57%): 33 patients on buprenorphine, 17 on placebo (the original randomization was deliberately 2:1).

- click on image for a larger view -

Modified from Fig. S2 (Yovell et al., 2015). A portion of the flow diagram (starting from those who were enrolled).

Importantly, participants with a lifetime history of opioid abuse were excluded. Buprenorphine is a Schedule III controlled substance in the US (same as ketamine), with a lower potential for abuse than heroin (Schedule I) and morphine, methadone, OxyContin, etc. (Schedule II).⁶As we know, individuals with BPD have high rates of substance abuse. In one study, 44% of patients seeking buprenorphine treatment for opioid addiction were diagnosed with BPD. Therefore, the investigators had to screen the participants very closely, in partnership with their regular clinical providers. Other exclusionary criteria were schizophrenia, current psychosis, and ECT within the past month. Finally, there could be no substance or alcohol abuse or benzodiazepine dependence within the past 2 years.

Regarding patient demographics, 70% were female, 43% had major depression, 25% were currently hospitalized, 49% had experienced major stressors in the last year (but separation during past month in only 24%), 70% on antidepressants, 49% on benzos, and about 20% on mood stabilizers and antipsychotics.

A week’s supply of medication (<5.6 mg, usually <2.8 mg) was not considered to present a high risk for suicide by overdose. Outpatients received the study medication for the following week during their weekly visits, and took it independently at home.

Another difficulty is that opioids have notable side effects, and this was true with the “ultra-low-dose” used here (Yovell et al., 2015) — which isn't really all that low.

One or more adverse events were reported in 77.2% of participants in the buprenorphine group and 54.8% of those in the placebo group (p=0.03). Among participants in the buprenorphine group, there were more reports of fatigue (49.1% compared with 22.6% in the placebo group), nausea (36.8% compared with 12.9%), dry mouth (29.8% compared with 9.7%), and constipation (26.3% compared with 9.7%).

The primary outcome measure was change in suicidal ideation after four weeks of treatment. To make up for high dropout, the Last Observation Carried Forward (LOCF) was used. In this way, data from all participants who received at least one dose of drug and one suicidal ideation score were included. However, LOCF is a flawed procedure that can overestimate effect sizes.⁷

The buprenorphine group had lower suicidal ideation than the placebo group at weeks 2 and 4, but an analysis restricted to patients who completed the study was not reported. Furthermore, the suicidal ideation scores were highly variable, and improvements in many secondary outcome measures (e.g., depression severity) didn't reach statistical significance (Fig. S3 below).

The authors acknowledged seven critical limitations, summarized below (the most egregious in red):

Outcome measures based on self-report. Clinician ratings of suicidality, depression, and overall functioning should be part of any future trial.
Participants were unstable and severely suicidal; many had BPD; high dropout rates. Are the findings applicable to more stable, less severely suicidal patients?
Flexible and gradual dosing limits inferences about the optimal dosage of buprenorphine to treat suicidal ideation.
Heterogeneity of the study population [e.g., why were both BPD and non-BPD included?] and its modest size limited ability to stratify results by dose, gender, and diagnosis.
Study did not assess nonsuicidal self-injury, which is associated with BPD, mental pain, and abnormalities in the endogenous opioid system.

I'll add that a case series on buprenorphine for NSSI was not cited.

Trial did not include an extended follow-up period to allow assessment of possible long-term effects, including the possibility of developing drug craving or rebound suicidality.

Despite its favorable safety profile, buprenorphine is potentially addictive and possibly lethal.

The authors end by stating the “results do not support the widespread, long-term, or nonexperimental use of buprenorphine for suicidality.” In other words, don't open buprenorphine clinics to treat severe depression and suicidal ideation! [ketamine infusion clinics, I'm looking at you].

People suffering from suicidal thoughts and actions deserve the best possible care, yet many researchers and clinicians shy away from conducting clinical trials. Ketamine seems to be the exception, where 24 studies are listed in ClinicalTrials.gov. While the present study has a long list of admitted flaws that make me wonder why it was published in AJP, the authors are in the admirable position of trying to help an extremely vulnerable population.

Read Part 1, Social Pain Revisited: Opioids for Severe Suicidal Ideation.

Footnotes

¹ But not surprisingly, many others don't agree with this strategy — e.g., Opioids in Depression: Not Quite There Yet (Xin et al. 2015), Psychiatry is the missing P in chronic pain care (Howe & Sullivan, 2014), and my previous post.

² These tests measure “depression-like” and “anxiety-like” behaviors, respectively. We could certainly debate whether these are adequate models of depression and anxiety, and this was in fact the topic of an interesting discussion on Twitter. The problem of anthromorphism is greatly magnified with concepts like the “psychic pain” of separation distress (the PANIC system of Panksepp and colleagues). For now, I'll refer you to my old post, Of Mice and Women: Animal Models of Desire, Dread, and Despair.

³The world of dynorphin and KORs has gotten even more complicated since the discovery that subpopulations of dynorphin neurons in the nucleus accumbens have opposing effects (aversion vs. reward). Crowley and Kash (2015) suggest that translation to humans may be..... uh difficult, to say the least:

“Important studies using modern genetic approaches have highlighted the multiple ways that KORs effect behavior, and paradoxical effects have emerged when manipulating the dynorphin system.”

...and...

“In addition, circuit and site-specific manipulations...provide some clarity as to the convoluted effect seen with systemic administration of KOR agonists. This provides key important information as to how KOR modulation can be used to shift anxiety-related behaviors: both low doses of KOR agonists, as well as KOR antagonists, may prove to be effective.”

...finally...

“Despite of an abundance of literature showing KORs to be a promising therapeutic target for the treatment of drug addiction ... few drugs impacting the KOR system have been taken to the level of human clinical trials.”

⁴ I haven't heard that morphine or buprenorphine is recommended for human babies who cry persistently and excessively.

⁵ @debe: in addiction it's 2 to 32 mg (pure bup) or to 24 (bup+nalox). 0.2 mg cps are for pain.

⁶The clinical trial was conducted in Israel, where buprenorphine is used to treat opioid dependence (as in many other countries) Litigiousness might be one possible reason such a study hasn't been conducted in the US?

⁷Caution is needed when interpreting results using Last Observation Carried Forward (LOCF) analyses – filling in missing values based on existing data – because of the problematic nature of this method for handling missing data. See Appendix below.

References

Crowley NA, Kash TL. (2015). Kappa opioid receptor signaling in the brain: Circuitry and implications for treatment. Prog Neuropsychopharmacol Biol Psychiatry 62:51-60.

Howe CQ, Sullivan MD. (2014). The missing 'P' in pain management: how the current opioid epidemic highlights the need for psychiatric services in chronic pain care. Gen Hosp Psychiatry 36(1):99-104.

Kolodny A, Courtwright DT, Hwang CS, Kreiner P, Eadie JL, Clark TW, Alexander GC. (2015). The prescription opioid and heroin crisis: a public health approach to anepidemic of addiction. Annu Rev Public Health 36:559-74.

Panksepp, J., & Yovell, Y. (2014). Preclinical Modeling of Primal Emotional Affects (SEEKING, PANIC and PLAY): Gateways to the Development of New Treatments for Depression. Psychopathology, 47 (6), 383-393. DOI: 10.1159/000366208

Tenore, P. (2008). Psychotherapeutic Benefits of Opioid Agonist Therapy. Journal of Addictive Diseases, 27 (3), 49-65. DOI: 10.1080/10550880802122646

Watt, D., & Panksepp, J. (2009). Depression: An Evolutionarily Conserved Mechanism to Terminate Separation Distress? A Review of Aminergic, Peptidergic, and Neural Network Perspectives Neuropsychoanalysis, 11 (1), 7-51 DOI: 10.1080/15294145.2009.10773593

Yovell, Y., Bar, G., Mashiah, M., Baruch, Y., Briskman, I., Asherov, J., Lotan, A., Rigbi, A., & Panksepp, J. (2015). Ultra-Low-Dose Buprenorphine as a Time-Limited Treatment for Severe Suicidal Ideation: A Randomized Controlled Trial. American Journal of Psychiatry DOI: 10.1176/appi.ajp.2015.15040535

Yin X, Guven N, Dietis N. (2015). Opioids in Depression: Not Quite There Yet. UK Journal of Pharmaceutical and Biosciences 3(1):12-7.

Appendix

Reasons to avoid Last Observation Carried Forward (LOCF):

Streiner 2014: “...LOCF has serious and, in some cases, fatal problems.”

Olsen et al. 2012: “Although these methods are simple to implement, they are deeply flawed in that they may introduce bias and underestimate uncertainty, leading to erroneous conclusions.”

www.missingdata.org.uk: “For full longitudinal data analyses this is clearly disastrous: means and covariance structure are seriously distorted. For single time point analyses the means are still likely to be distorted, measures of precision are wrong and hence inferences are wrong. Note this is true even if the mechanism that causes the data to be missing is completely random.”

Molnar et al. 2008: “If there were a prize for the most inappropriate analytical technique in dementia research, 'last observation carried forward' would be the runaway winner.”

Molnar et al. 2009: “The published results of some randomized controlled trials of dementia drugs may be inaccurate (i.e., drug effectiveness may be exaggerated) or invalid (i.e., there may be false-positive results) because of bias introduced through the inappropriate use of LOCF analyses.”

doi:10.1371/journal.pone.0129659.g003

Did you know that SPECT imaging can diagnose PTSD with 100% accuracy (Amen et al., 2015)? Not only that, out of a sample of 397 patients from the Amen Clinic in Newport Beach, SPECT was able to distinguish between four different groups with 100% accuracy! That's right, the scans of (1) healthy participants, and patients with (2) classic post-traumatic stress disorder (PTSD), (3) classic traumatic brain injury (TBI), and (4) both disorders..... were all classified with 100% accuracy!

TRACK-TBI investigators, your 3T structural and functional MRI outcome measures are obsolete.

NIMH, the hard work of developing biomarkers for mental illness is done, you can shut down now. Except none of this research was funded by you...

The finding was #19 in a list of the top 100 stories by Discover Magazine.

How could the Amen Clinics, a for-profit commercial enterprise, accomplish what an army of investigators with billions in federal funding could not?

The authors¹ relied on a large database of scans collected from multiple sites over a 20 year period. The total sample included 20,746 individuals who visited one of nine Amen Clinics from 1995-2014 for psychiatric and/or neurological evaluation (Amen et al., 2015). The first analysis included a smaller, highly selected sample matched on a number of dimensions, including psychiatric comorbidities (Group 1).

- click on image for larger view -

You'll notice the percentage of patients with ADHD was remarkably high (58%, matched across the three patient groups). Perhaps that's because...

I did not know that.

Featuring Johnny Cash ADD.

SPECT uses a radioactive tracer injected 30 minutes before a scan that will assess either the “resting state” or an “on-task” condition (a continuous performance task, in this study). Clearly, SPECT is not the go-to method if you're looking for decent temporal resolution to compare two conditions of an active attention task. The authors used a region of interest (ROI) analysis to measure tracer activity (counts) in specific brain regions.

I wondered about the circularity of the clinical diagnosis (i.e., were the SPECT scans used to aid diagnosis), particularly since “Diagnoses were made by board certified or eligible psychiatrists, using all of the data available to them, including detailed clinical history, mental status examination and DSM-IV or V criteria...” But we were assured that wasn't the case: “These quantitative ROI metrics were in no way used to aid in the clinical diagnosis of PTSD or TBI.” The rest of the methods (see Footnote 2) were opaque to me, as I know nothing about SPECT.

A second analysis relied on visual readings (VR) of about 30 cortical and subcortical ROIs. “Raters did not have access to detailed clinical information, but did know age, gender, medications, and primary presenting symptoms (ex. depressive symptoms, apathy, etc.).” Hmm...

But the quantitative ROI analysis gave superior results to the clinician VR. So superior, in fact, that the sensitivity/specificity in distinguishing one group from another was 100% (indicated by red boxes below). The VR distinguished patients from controls with 100% accuracy, but was not as good for classifying the different patient groups during the resting state scan — only a measly 86% sensitivity, 81% specificity for TBI vs. PTSD, which is still much better than other studies. However, results from the massively sized Group 2 were completely unimpressive. ³

- click on image for larger view, you'll want to see this -

Why is this so important? PTSD and TBI can show overlapping symptoms in war veterans and civilians alike, and the disorders can co-occur in the same individual. More accurate diagnosis can lead to better treatments. This active area of research is nicely reviewed in the paper, but no major breakthroughs have been reported yet. So the claims of Amen et al. are remarkable. Stunning if true. But they're not. They can't be. The accuracy of the classifier exceeds the precision of the measurements, so this can't be possible. What is the test-retest reliability of SPECT? What is the concordance across sites? Was there no change in imaging protocol, no improvements or upgrades to the equipment over 20 years? SPECT is sensitive to motion artifact, so how was that handled, especially in patients who purportedly have ADHD?

SPECT has been noted for its poor spatial resolution compared to other functional neuroimaging techniques like PET and fMRI. A panel of 16 experts did not include SPECT among the recommended imaging modalities for the detection of TBI. Dr. Amen and his Clinics in particular have been criticized in journals (Farah, 2009; Adinoff & Devous, 2010a, 2010b; Chancellor &, Chatterjee, 2011) and blogs (Science-Based Medicine, The Neurocritic, and Neurobollocks) for making unsubstantiated claims about the diagnostic accuracy and usefulness of SPECT.

Are his latest results too good to be true? You can check for yourself! The paper was published in PLOS ONE, which has an open data policy:

PLOS journals require authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception.

When submitting a manuscript online, authors must provide a Data Availability Statement describing compliance with PLOS's policy. If the article is accepted for publication, the data availability statement will be published as part of the final article.

Before you get too excited, here's the Data Availability Statement:

Data Availability: All relevant data are within the paper.

But this is not true. NONE of the data are available within the paper. There's no way to reproduce the authors' analyses, or to conduct your own. This is a problem, because...

Refusal to share data and related metadata and methods in accordance with this policy will be grounds for rejection. PLOS journal editors encourage researchers to contact them if they encounter difficulties in obtaining data from articles published in PLOS journals. If restrictions on access to data come to light after publication, we reserve the right to post a correction, to contact the authors' institutions and funders, or in extreme cases to retract the publication.

So all you “research parasites” out there⁴— you can request the data. I thought this modest proposal would create a brouhaha until I saw a 2014 press release announcing the World's Largest Database of Functional Brain Scans Produces New Insights to Help Better Diagnose and Treat Mental Health Issues:

With a generous grant from the Seeds Foundation [a Christian philanthropic organization] in Hong Kong, Dr. Amen and his research team led by neuroscientist Kristen Willeumier, PhD, have turned the de-identified scans and clinical information into a searchable database that is shared with other researchers around the world.

In the last two years, Amen and colleagues have presented 20 posters at the National Academy of Neuropsychology. The PR continues:

The magnitude and clinical significance of the Amen Clinics database – being the world's largest SPECT imaging database having such volume and breadth of data from patients 9 months old to 101 years of age – makes it a treasure trove for researchers to help advance and revolutionize the practice of psychiatry.

Does this mean that Dr. Amen will grant you access to the PLOS ONE dataset (or to the entire Amen Clinics database) if you ask nicely? If anyone tries to do this, please leave a comment.

Footnotes

¹ The other authors included Dr. Andrew “Glossolalia” Newberg and Dr. Theodore “Neuro-Luminance Synaptic Space” Henderson.

² Methods:

To account for outliers, T-score derived ROI count measurements were derived using trimmed means [91] that are calculated using all scores within the 98% confidence interval (-2.58 < Z < -2.58). The ROI mean for each subject and the trimmed mean for the sample are used to calculate T with the following formula: T = 10*((subject ROI_mean - trimmed regional_avg)/trimmed regional_stdev)+50.

³ Results from the less pristine Group 2 were not impressive at all, I must say. Group 2 had TBI (n=7,505), PTSD (n=1,077), or both (n=1,017) compared to n=11,147 patients without either (these were not clean controls as in Group 1). Given the massive number of subjects, the results were clinically useless, for the most part (see Table 6).

⁴ A brand new editorial in NEJM by Longo and Drazen (who decry “research parasites”) is causing a twitterstorm with the hashtags #researchparasites and #IAmAResearchParasite.

References

Adinoff B, Devous M. (2010a). Scientifically unfounded claims in diagnosing and treating patients. Am J Psychiatry 167(5):598.

Adinoff B, Devous M. (2010b). Response to Amen letter. Am J Psychiatry 167(9):1125-1126.

Amen, D., Raji, C., Willeumier, K., Taylor, D., Tarzwell, R., Newberg, A., & Henderson, T. (2015). Functional Neuroimaging Distinguishes Posttraumatic Stress Disorder from Traumatic Brain Injury in Focused and Large Community Datasets PLOS ONE, 10 (7) DOI: 10.1371/journal.pone.0129659

Chancellor B, Chatterjee A. (2011). Brain branding: When neuroscience and commerce collide. AJOB Neuroscience2(4): 18-27.

Farah MJ. (2009). A picture is worth a thousand dollars. J Cogn Neurosci. 21(4):623-4.

Today, The Neurocritic celebrates ten years as a blog. Given the ongoing use of a pseudonym, how should I commemorate the occasion?

1. Should I finally update my blog template? (“Hey, 2004 wants their Blogger template back”).

2. Should I throw a party? Popular London-based blogs Mind Hacks and BPS Research Digest held big public bashes in November 2014 and December 2015, respectively. My audience is only a fraction of theirs, however. I doubt a local gathering of fans would fill more than a broom closet.

3. How about a Happy Hour, where I privately invite social media folks who live nearby? I know where many of you live, but not vice versa.

4. Or I could publicly announce the location of an informal gathering or night on the town with an open invitation to readers. In either of those scenarios, you'd get to meet me in person. Other pseudonymous bloggers appear in public all the time, why shouldn't I?

5. Another idea was inspired by the cooking competition show Top Chef, which is celebrating its 10th Anniversary this season. In the most recent elimination challenge, the contestants were asked to recall what they were like 10 years ago. The goal was to prepare a dish that represents themselves, professionally and emotionally, at that stage of their lives.

Top Chef 13: The chefs must create a dish that tells the story of who they were 10 years ago.

This was not a pleasant experience for some of the contestants. Chef Isaac, from New Orleans, had to remember the devastation after Hurricane Katrina. He prepared duck gumbo with roasted jalapeno andouille sausage, crispy rice cake and duck cracklings — the type of a dish he made for large numbers of displaced people 10 years ago.

Front runner Chef Kwame was quite upset by recalling his estranged relationship with his father. He made jerk broccoli with corn bread pudding and smokey blue cheese as an homage to his Jamaican father. This wasn't a wise decision, however. He ended up at the bottom.

I thought about how I might write a post based on a similar theme: to tell the story of who I was 10 years ago and why I started to blog. I remembered some of the major things in my life at the time, and decided it would be too personal. For 10 years, I've avoided revealing anything about myself.

“I tried my best to stay under the radar and hoped that no one would think of me as a real person,” I said two years ago.

Why did I decide to start a neuroscience blog?

It was out of sheer frustration. I was facing some rejection of my own work, and felt I didn't have much of a voice in the neuroscience community. I was annoyed by flawed journal articles and overblown press coverage, and decided that blogging would be a cathartic outlet for my complaints. I didn't expect that many people would actually read it, but at least writing might make me feel a bit better.

6. I could do a retrospective of my most popular and commented-on posts, but that would be boring. Nobody cares, no one would read it.

7. Perhaps a look back at how the science blogosphere has evolved would have broader appeal? Or not. I wrote an opinion piece in 2013 during a time of #scicomm upheaval, that was enough. Although lifestyle pieces on the rise of social media and the decline of blogs are ever-popular...

8. Should I write a personal reflection on the greatest advances in Human Brain Imaging, Cognitive Neuroscience, and Psychopharmacology since 2006? Such a piece would be time consuming, and needs no special ties to a 10 year blogiversary celebration. Any specific requests for this type of post?

9. Or I could mention other neuro/psych blogs that have been around for 8-10 years, like Neurophilosophy (Mo Costandi soon celebrates his 10th), BPS Research Digest, SciCurious, Neuroskeptic, Neuron Culture (now here), Providentia (now nine), Addiction Inbox, Talking Brains, NeuroDojo (established in 2002), BrainBlog, Deric's MindBlog, and of course Shrink Rap. I could also recognize some influential legacy blogs of the era, including Neurofuture, Developing Intelligence, Mixing Memory, Cognitive Daily, and Omni Brain. Finally, I could credit major influences like Bad Neuro-Journalism (which dates back to 1998) and Mind Hacks.

10. Finally, I may announce a new occasional feature in the coming days or weeks.

Thank you for reading!

More Navel Gazing

Eight Years of Neurocriticism

The Decline of Neurocriticism

The Brain From Beyond Infinity

In honor of The Neurocritic's 10th anniversary, I'd like to announce a new occasional feature:

Was I Wrong?

In science, as in life, we learn from our mistakes. We can't move forward if we don't admit we were wrong and revise our entrenched theory (or tentative hypothesis) when faced with contradictory evidence. Likewise, it's possible that some of the critiques in this blog are no longer valid because additional evidence shows that the authors were correct. And vindicated. At least for now...

I've been collecting possible instances of this phenomenon for months, and I'll preview two of these today.

(1) In November 2015, I said that Obesity Is Not Like Being "Addicted to Food". Drugs of abuse are consistently associated with decreases in D2 dopamine receptors, but D2 receptor binding in obese women is not different from that in lean participants (Karlsson et al., 2015). Conversely, μ-opioid receptor (MOR) binding is reduced, which supports lowered hedonic processing. After the women had bariatric surgery, MOR returned to control values, while the unaltered D2 receptors stayed the same.

However, a recent study in mice “points to a causal link between striatal dopamine signaling and the outcomes of bariatric interventions” (Han et al., 2016). How relevant is this new finding for clinical studies in humans?

(2) In another post, I poo-pooed the notion that there is One Brain Network for All Mental Illness. However, a subsequent paper in Molecular Psychiatry claimed that common psychiatric disorders share the same genetic origin (Pettersson et al., 2015). If so, could this result in common brain ~~abnormalities~~ alterations across disorders?

In the future, I'll take a closer look at these and other examples to see if I should revise my opinions.

As you might have gathered, my brain is taking a rest from blogging after the excitement of The Neurocritic's tenth anniversary. Regular blogging will resume shortly.

Thank you for your patience.

Fig. 1 (Buckner, 2013). The brain's default network. The default network was discovered serendipitously when experimenters using neuroimaging began examining brain regions active in the passive control conditions of their experiments. The image shows brain regions more active in passive tasks as contrast to a wide range of simple, active task conditions.⁶

Dialogues Clin Neurosci. 2013 Sep; 15(3): 351–358.

Who is this, wandering around the crowded street, afraid of everything, trusting no one?

“There must be something wrong, somewhere.”
But maybe I’m safer since I look disheveled.

Who are these people? Where is this place?
Did I write that? When did that happen? I don’t remember.

I can’t stop writing. I can’t stop walking, either, which is a problem because it’s hard to write and walk at the same time.

In the early 1940s, Austrian Psychiatrist Dr. Erwin Stengel wrote a pair of papers on fugue states, a type of dissociative disorder involving loss of personal identity and aimless wandering (Stengel, 1941):

THE peculiar condition designated “fugue state,” of which the main symptom is compulsive wandering, has puzzled psychiatrists since it was first described. Nothing is known of the aetiology of this well-defined condition. Fugue states occur in epileptics, hysterics, and certain psychopaths. Bleuler has described their occurrence in schizophrenia, and they have been recorded in cases of general paralysis and of altered personality due to brain tumour. ... Kraepelin recognized that it was impossible to distinguish between the states of compulsive wandering associated with various mental disorders. Janet tried to distinguish between hysterical and epileptic fugues by pointing out that short fugues are more likely to be epileptic than hysterical.

He was disturbed by inaccurate use of the term, which was widespread (Stengel, 1943):

...the following conditions have been described as fugues: States of wandering, in accordance with the classical conception; states of double personality; all kinds of transitory abnormal behaviour of functional origin; hysterical loss of consciousness and of memory; twilight states; confusional states of hysterical nature; delirious states in schizophrenia. The tendency to call transient states of altered consciousness fugues, irrespective of the behaviour of the patient, is obvious. This is a most unsatisfactory state of affairs.

Stengel presented dozens of cases in these papers and was obsessed with finding common etiological factors, no matter what the underlying medical condition (e.g., epilepsy, “hysteria”, schizophrenia):

The intimate similarity of fugue states associated with different mental disorders suggests that there must be aetiological factors common to all. However, no attempt has been made hitherto to ascertain such factors. I have been engaged in investigations concerning this problem for more than eight years...

...and (Stengel, 1943):

Clinical studies carried out over many years have convinced me that there is no justification in differentiating between hysterical and epileptic wandering states, as the behaviour of the patients and the majority of the etiological factors are fundamentally the same in all fugues with the impulse to wander (Stengel, 1939, 1941).

Since Stengel was trained as a psychoanalyst and considered Freud as a mentor, you might guess the common etiology:

This was a disturbance of the environment of child life. A serious disturbance in the child-parent relationship, usually of such a nature that the relationship to one or both parents was either completely lacking or only partially developed, had occurred in nearly every case.

Beyond the mommy/daddy issues, symptoms of severe depression (suicide attempts, failure to eat, lack of hygiene) and/or mania (elation, hypersexuality) were commonplace. Here's one especially tragic example:

CASE 9. — M. E —, female, born 1906. The patient was normal until her twenty first year. At that time she suddenly became unstable and wanted to live apart from her mother, with whom she had been happy hitherto. She went to Paris, where she found employment as a secretary, but after some months she returned home again. When she was 22 she experienced for the first time an urge to wander, which reappeared subsequently two or three times every year. For no adequate reason, sometimes after an insignificant quarrel, she left home and wandered about for some days. During these states she was not fully conscious, slept little, and neglected herself. When normal consciousness returned, after three or four days, she found herself in the country far away from home. These states were followed by profound depression, lasting for several weeks, when the patient indulged in self-reproaches, ate very little, lost weight, and could not work. ... The patient was a typical daydreamer. In her daydreams a fantasy of a man disappointed in love committing suicide often appeared. (Her father had committed suicide.) ... The patient, who was of unusual intelligence, suffered very much from her abnormal states, which appeared at intervals of four to five months, and were always followed by melancholic depression. In one of these depressions she committed suicide by poisoning.

Period Fugue

Stengel (1941) asserted that the majority of his female patients started their wandering premenstrually, but his definition of what this meant was kind of loose (and meaningless): “usually appear before menstruation”, “usually just before menstruation”, “usually commences shortly before her menstrual period”, “at the onset of menstruation”, “about the time of menstruation”.

He had no explanation for this, other than the implication that it's an unstable lady thing. One particularly fun case (Case 14) was a young woman with a previous bout of encephalitis lethargica. But it was determined that her menstrual period and an Oedipus Complex drove her to wander, not her illness.

The report for Case 35 (Miss May S. M—, aged 18, member of the women's military service) was accompanied by a four page excerpt from her diary, which is illuminating for what it tells us about bipolar disorder (but fugue, not so much):

“ 1940. 12.1: Had a drink, sang all the way home. —13.1: The matinee went off well. Feeling so horribly sad, a terribly empty feeling, felt like crying my heart out. Home is like the end of the world. —21.1: Tried to commit suicide. Instead wrote to G. telling him to give me some ideas how to get to America. Feeling just frightful, feel dead. —27.1: No feelings at all. —30.1: Have a mad desire to go really common, lipstick, scarlet nails and with as little clothes as possible.

Modern conceptions of fugue states (including dissociative amnesia) focus on trauma, memory systems, and underlying neurobiological causes, instead of dysfunctional child-parent relationships (MacDonald & MacDonald, 2009).

Who is this? How did I end up here?

You mean there’s a world outside my head, beyond the computer, exceeding all page limits and formatting errors?

— Writing-Induced Fugue State

ADDENDUM (March 7 2016): I should clarify that in DSM-5, dissociative fugue no longer has its own category. Now it's a subtype of dissociative amnesia(DSM-5 diagnostic code 300.12):

Sub-Specifier: Dissociative Amnesia with dissociative fugue (300.13)

This occurs when an individual travels or wanders, either in a seemingly purposeful or bewildered fashion, without knowing who they are. Dissociative fugue involves amnesia of a person’s entire identity or for other important autobiographical information.

Another salient difference from Stengel's day is that the fugue state must not due to a general medical condition, like temporal lobe epilepsy.

References

Stengel, E. (1941). On the Aetiology of the Fugue States The British Journal of Psychiatry, 87 (369), 572-599 DOI: 10.1192/bjp.87.369.572

Stengel, E. (1943). Further Studies on Pathological Wandering (Fugues with the Impulse to Wander) The British Journal of Psychiatry, 89 (375), 224-241 DOI: 10.1192/bjp.89.375.224

from Kopelman et al. (2000)

Our bodily sense of self contributes to our personal feelings of awareness as a conscious being. How we see our bodies and move through space and feel touched by loved ones are integral parts of our identity. What happens when this sense of self breaks down? One form of dissolution is Depersonalization Disorder (DPD).¹ Individuals with DPD feel estranged or disconnected from themselves, as if their bodies belong to someone else, and “they” are merely a detached observer. Or the self feels absent entirely. Other symptoms of depersonalization include emotional blunting, out-of-body experiences, and autoscopy.

Autoscopy for dummies - Antonin De Bemels (cc licence)

Transient symptoms of depersonalization can occur due to stress, anxiety, sleep deprivation, or drugs such as ketamine (a dissociative anesthetic) and hallucinogens (e.g., LSD, psilocybin). These experiences are much more common than the official diagnosis of DPD, which occurs in only 1-2% of the population.

Research by Olaf Blanke and colleagues (reviewed in Blanke et al., 2015) has tied bodily self-consciousness to the integration of multi-sensory signals in fronto-parietal and temporo-parietal regions of the brain.

from Neuron 88(1):145-66.

The fragmentation or loss of an embodied self raises philosophically profound questions. Although the idea of “mind uploading” is preposterous in my view (whether via whole brain emulation or cryonics), proponents must seriously ask whether the uploaded consciousness will in any way resemble the living person from whom it arose.²“Minds are not disembodied logical reasoning devices” (according to Andy Clark). And...

Increasing evidence suggests that the basic foundations of the self lie in the brain systems that represent the body (Lenggenhager et al., 2012).

Lenggenhager et al. asked whether the loss of sensorimotor function alters body ownership and the sense of self. Persons with spinal cord injuries scored higher on Cambridge Depersonalization Scale (CDS) items such as “I have to touch myself to make sure that I have a body or a real existence.” This suggests that disconnecting the brain from somatosensory input can change phenomenological aspects of self-consciousness.

Source: misswhite.blogcu.com

The Stranger in the Mirror

Patients with depersonalization not only feel a change in perception concerning the outside world, but they also have clear-cut changes concerning their own body. ... The patient sees his face in the mirror changed, rigid and distorted. His own voice seems strange and unfamiliar to him. ... It is in this respect especially remarkable that the estrangement concerning the outside world is often an estrangement in the optic sphere (Schilder, 1935, p. 139).

Depersonalization can involve perceptual distortions of bodily experience in different sensory modalities (e.g., vision, hearing, touch, and pain). Recent research has examined interactions between visual and somatosensory representations of self in the tactile mirroring paradigm (also called visual remapping of touch). Here, the participant views images of a person being touched (or not) while they themselves are touched. Tactile perception is enhanced by simultaneously receiving and observing the same stimulation, especially when the image is of oneself.

Are the symptoms of depersonalization associated with reduced or absent responses in the tactile mirroring paradigm? If so, at what stage of processing (early or late) does this occur? A new study recorded EEG to look at somatosensory evoked potential (SEP) responses to tactile stimuli during mirroring (Adler et al., 2016). The participants scored high (n=14) or low (n=13) on the CDS.

One SEP of interest was the P45, which occurs shortly (25-50 msec) after tactile stimulation. Although the spatial resolution of EEG does not allow firm conclusions about the neural generators, we know from invasive studies in epilepsy patients and animals that P45 originates in the primary somatosensory cortex (S1).

When the participants viewed the other-face, P45 did not differ on touch vs. no-touch trials. But the later N80 component was enhanced for touch vs. no-touch, and the enhancement was similar for low and high depersonalization (DP) participants.

Modified from Figs. 3 and 4 (Adler et al. 2016). SEPs in response to tactile stimuli for low DP (top) and high DP (bottom) while observing touch (thick line) or no-touch (thin line) on another person's face. SEPs are shown for components P45 and N80 at a cluster of central-parietal electrodes located over somatosensory cortex.

Results were different when subjects viewed images of themselves. P45 was enhanced in the low DP group when viewing themselves being touched (vs. no-touch trials). However, those with high DP scores did not show this P45 enhancement.

Modified from Figs. 3 and 4 (Adler et al. 2016). SEPs in response to tactile stimuli while observing touch (thick line) or no-touch (thin line) on the participant's own face. Red arrow indicates no self-mirror enhancement of P45.

These results suggest a very early disturbance in sensory integration of the self in depersonalization:

Measurable effects of mirroring for tactile events on the observer's own face may be absent over P45 because deficits in implicit self-related processing prevent the resulting visual enhancement of tactile processing from taking place in the context of self-related information. An alternative, or additional, explanation for the absence of P45 mirroring effects may be that seeing their own body causes depersonalised individuals to actively inhibit the processing of bodily stimulation via this pathway. This may cause feelings of disembodiment, and is akin to the suggestion that fronto-limbic inhibitory mechanisms acting on emotional processes cause the emotional numbing experienced in depersonalisation (Sierra and David, 2011).

[Although I'm not so sure how much “active inhibition” can occur within 25 msec...]

A later component (P200) did not show the expected effect in the high DP group, either. While these results are intriguing, we must keep in mind that this was a small study that requires replication.³

Our Bodies, Our Selves

Predictive coding models hypothesize that the anterior insular cortex (AIC) provides top-down input to somatosensory, autonomic, and visceral regions and plays a critical role in integrating exteroceptive and interoceptive signals (Seth et al., 2012; Allen et al., 2016). DPD is associated with “pathologically imprecise interoceptive predictive signals,” leading to a disruption of conscious presence (the subjective sense of reality of the world and of the self within the world). Here's the predictive coding model of conscious presence (Seth et al., 2012):

It has been suggested that DPD is associated with a suppressive mechanism grounded in fronto-limbic brain regions, notably the AIC, which “manifests subjectively as emotional numbing, and disables the process by which perception and cognition become emotionally colored, giving rise to a subjective feeling of unreality” (Sierra and David, 2011)...

In our model, DPD symptoms correspond to abnormal interoceptive predictive coding dynamics. ... the imprecise interoceptive prediction signals associated with DPD may result in hypoactivation of AIC since there is an excessive but undifferentiated suppression of error signals.

In contrast, Adler et al. (2016) adopt a very different (Freudian) view:

We speculate that the abnormalities related to depersonalisation may be based on a lack of mirroring interactions in early childhood. Several recent papers culminated in the idea that mirroring experiences in early life - the process of moving and being moved by others, both physically and affectively - give rise to our sense of bodily self... This bodily self forms the core of other forms of self-consciousness, from body ownership to the sense of agency and the ability to mentalise (e.g. Fonagy et al., 2007; Gallese & Sinigaglia, 2010; Markova and Legerstee, 2006; Stern, 1995). ... Depersonalisation could be a potential consequence of such developmental experiences.

I don't buy it... none of the participants in their study had a clinical diagnosis, and we know nothing of their early childhood. In the end, any model of chronic DPD still has to account for the transient phenomena of disconnection and unreality experienced by so many of us.

Further Reading

Feeling Mighty Unreal: Derealization in Kleine-Levin Syndrome

Fright Week: The Stranger in the Mirror

Footnotes

¹ In DSM-5, the syndrome is known as Depersonalization/Derealization Disorder. I wrote about the symptoms of derealization– a subjective alteration in one's perception or experience of the outside world – in another blog post.

² For a discussion of the relevant issues, see The False Science of Cryonics and Silicon soul: The vain dream of electronic immortality.

³ Given the requirements for specialized equipment and a specialized population, I don't imagine this study is on the Many Labs or Replication Project lists.

References

Adler, J., Schabinger, N., Michal, M., Beutel, M., & Gillmeister, H. (2016). Is that me in the mirror? Depersonalisation modulates tactile mirroring mechanisms. Neuropsychologia DOI: 10.1016/j.neuropsychologia.2016.03.009

Allen M, Fardo F, Dietz MJ, Hillebrandt H, Friston KJ, Rees G, Roepstorff A. (2016). Anterior insula coordinates hierarchical processing of tactile mismatch responses. Neuroimage 127:34-43.

Blanke O, Slater M, Serino A. (2015). Behavioral, Neural, and Computational Principlesof Bodily Self-Consciousness. Neuron 88(1):145-66.

Lenggenhager, B., Pazzaglia, M., Scivoletto, G., Molinari, M., & Aglioti, S. (2012). The Sense of the Body in Individuals with Spinal Cord Injury. PLoS ONE, 7 (11) DOI: 10.1371/journal.pone.0050757

Schilder, P. (1935). The Image and Appearance of the Human Body. London: Kagan, Paul, Trench, Trubner & Co.

Seth AK, Suzuki K, Critchley HD. (2012). An interoceptive predictive coding model of conscious presence. Front Psychol. 2:395.

from Jhené Aiko, Mirrors. gif via genius.com

Dopamine is love. Dopamine is reward. Dopamine is addiction.

Neuroscientists have a love/hate relationship with how this monoamine neurotransmitter is portrayed in the popular press.

wwlp.com

thestranger.com

[The claim of vagus nerve-stimulating headphones is worth a post in its own right.]

observer.com

“You can fold your laundry, but you can’t fold your dopamine.”
- James Cole Abrams, M.A. (in Contemplative Psychotherapy)

The word dopamine has become a shorthand for positive reinforcement, whether it's from fantasy baseball or a TV show.

But did you know that a subset of dopamine (DA) neurons originating in the ventral tegmental area (VTA) of the midbrain respond to obnoxious stimuli (like footshocks) and regulate aversive learning?

Sometimes the press coverage of a snappy dopamine paper can be positive and (mostly) accurate, as was the case with a recent paper on risk aversion in rats (Zalocusky et al., 2016). This study showed that rats who like to “gamble” on getting a larger sucrose reward have a weaker neural response after “losing.” In this case, losing means choosing the risky lever, which dispenses a low amount of sucrose 75% of the time (but a high amount 25%), and getting a tiny reward. The gambling rats will continue to choose the risky lever after losing. Other rats are risk-averse, and will choose the “safe” lever with a constant reward after losing.

This paper was a technical tour de force with 14 multi-panel figures.¹ For starters, cells in the nucleus accumbens (a VTA target) expressing the D2 receptor (NAc D2R⁺ cells) were modified to express a calcium indicator that allowed the imaging of neural activity (via fiber photometry). Activity in NAc D2R⁺ cells was greater after loss, and during the decision phase of post-loss trials. And these two types of signals were dissociable.² Then optogenetic methods were used to activate NAc D2R⁺ cells on post-loss trials in the risky rats. This manipulation caused them to choose the safer option.

- click to enlarge -

Noted science writer Ed Yong wrote an excellent piece about these findings in The Atlantic (Scientists Can Now Watch the Brain Evaluate Risk).

Now, there's a boatload of data on the role of dopamine in reinforcement learning and computational models of reward prediction error (Schultz et al., 1997) and discussion about potential weaknesses in the DA and RPE model. So while a very impressive addition to the growing pantheon of laser-controlled rodents, the results of Zalocusky et al. (2016) aren't massively surprising.

More surprising are two recent papers in the highly sought-after population of humans implanted with electrodes for seizure monitoring or treatment of Parkinson's disease. I'll leave you with quotes from these papers as food for thought.

1. Stenner et al. (2015). No unified reward prediction error in local field potentials from the human nucleus accumbens: evidence from epilepsy patients.

Signals after outcome onset were correlated with RPE regressors in all subjects. However, further analysis revealed that these signals were better explained as outcome valence rather than RPE signals, with gamble gains and losses differing in the power of beta oscillations and in evoked response amplitudes. Taken together, our results do not support the idea that postsynaptic potentials in the Nacc represent a RPE that unifies outcome magnitude and prior value expectation.

The next one is extremely impressive for combining deep brain stimulation with fast-scan cyclic voltammetry, a method that tracks dopamine fluctuations in the human brain!

2. Kishida et al. (2016). Subsecond dopamine fluctuations in human striatum encode superposed error signals about actual and counterfactual reward.

Dopamine fluctuations in the striatum fail to encode RPEs, as anticipated by a large body of work in model organisms. Instead, subsecond dopamine fluctuations encode an integration of RPEs with counterfactual prediction errors, the latter defined by how much better or worse the experienced outcome could have been. How dopamine fluctuations combine the actual and counterfactual is unknown. One possibility is that this process is the normal behavior of reward processing dopamine neurons, which previously had not been tested by experiments in animal models. Alternatively, this superposition of error terms may result from an additional yet-to-be-identified subclass of dopamine neurons.

Further Reading

As Addictive As Cupcakes– Mind Hacks (“If I read the phrase ‘as addictive as cocaine’ one more time I’m going to hit the bottle.”)

Dopamine Neurons: Reward, Aversion, or Both?– Scicurious

Back to Basics 4: Dopamine!– Scicurious (in fact, anything by Scicurious on dopamine)

Why Dopamine Makes People More Impulsive– Sofia Deleniv at Knowing Neurons

2-Minute Neuroscience: Reward System– video by Neuroscientifically Challenged

Footnotes

¹ For example:

Because decision-period activity predicted risk-preferences and increased before safe choices, we sought to enhance the D2R⁺ neural signal by optogenetically activating these cells during the decision period. An unanticipated obstacle (D2SP-driven expression of channelrhodopsin-2 eYFP fusion protein (D2SP-ChR2(H134R)-eYFP) leading to protein aggregates in rat NAc neurons) was overcome by adding an endoplasmic reticulum (ER) export motif and trafficking signal²⁹ (producing enhanced channelrhodopsin (eChR2); Methods), resulting in improved expression (Extended Data Fig. 7). In acute slice recordings, NAc cells expressing D2SP-eChR2(H134R)-eYFP tracked 20-Hz optical stimulation with action potentials (Fig. 4c).

² The human Reproducibility Project: Psychology brigade might be interested to see Pearson’s r² = 0.86 in n = 6 rats.

References

Kishida KT, Saez I, Lohrenz T, Witcher MR, Laxton AW, Tatter SB, White JP, Ellis TL, Phillips PE, Montague PR. (2016). Subsecond dopamine fluctuations in human striatum encode superposed error signals about actual and counterfactual reward. Proc Natl Acad Sci 113(1):200-5.

Schultz W, Dayan P, Montague PR. (1997). A neural substrate of prediction and reward. Science 275:1593–1599. [PubMed]

Stenner MP, Rutledge RB, Zaehle T, Schmitt FC, Kopitzki K, Kowski AB, Voges J, Heinze HJ, Dolan RJ. (2015). No unified reward prediction error in local field potentials from the human nucleus accumbens: evidence from epilepsy patients. J Neurophysiol. 114(2):781-92.

Zalocusky, K., Ramakrishnan, C., Lerner, T., Davidson, T., Knutson, B., & Deisseroth, K. (2016). Nucleus accumbens D2R cells signal prior outcomes and control risky decision-making Nature DOI: 10.1038/nature17400

New in the journal journal Cortex: four shocking cases of practicing medicine while exhausted (Dharia & Zeman, 2016). The authors called this newly discovered syndrome “fatigue amnesia.” Why this is is any different from countless other examples of not remembering things you did while exhausted — I do not know. Except amnesia for performing a complex medical procedure is a lot more disturbing than forgetting you did the dishes the night before.

Here are the cases in brief:

Case 1: A consultant geriatrician, while working as house officer, treated a patient with chest pain and severe pulmonary oedema in the middle of night. She made an entry in the notes, demonstrating successful initial memory acquisition. She does not remember going to bed that night. On the ward round on the following morning the patient was pointed out to her but she had no recollection of seeing the patient or writing the note.

Case 2: A senior house officer, now a consultant neurologist, went to bed in the early hours after a busy shift. She was woken soon afterwards to manage a patient with cardiac arrest. The resuscitation was complex and included an intracardiac adrenaline injection. She documented events in the medical notes immediately, demonstrating successful initial memory acquisition. She returned to bed. She was told on the morning ward round that the patient was well and had his breakfast following the cardiac arrest. She was startled by this information, as she had no recollection of the previous night's events.

Case 3: A consultant microbiologist who was working on a night shift as a house officer clerked in a patient at 11:00 pm and continued to work thereafter throughout the night. On the morning ward round when the patient was pointed out to her she had no recollection of seeing or managing him.

Case 4: A paediatrician reported memory loss for a complex decision made and instructions given over the phone. While working as a registrar he went to bed in the early hours of morning when on call. He was woken by a call about a complex patient. He went to the ward soon afterwards to find out that the trolley was laid out for Swan Ganz catheterisation. Although he was assured that he had done so, he did not remember giving instructions to prepare the trolley.

The incidents were not due to alcohol or drugs. Long hours and sleep deprivation were to blame. And fortunately, the amnesic episodes were isolated and did not recur in any of the doctors. Dharia & Zeman (2016) suggested that:

While the resulting memory gaps can reasonably be described as resulting from a ‘transient amnesic state', the evidence from the medical notes suggest that this phenomenon reflects a novel form of accelerated long-term forgetting (Elliott, Isaac, & Muhlert, 2014), whereby a memory for events is acquired normally but then decays more rapidly than usual.

Sleep Blogging

By tomorrow, I will have forgotten that I wrote this...

Reference

Dharia, S., & Zeman, A. (2016). Fatigue amnesia Cortex DOI: 10.1016/j.cortex.2016.03.001

Recent studies of transcranial electrical stimulation in human cadaver heads showed a 90% loss of current when delivered through the skin (Buzsáki, 2016 CNS meeting).

Siren Song

By Margaret Atwood

This is the one song everyone
would like to learn: the song
that is irresistible:

the song that forces men
to leap overboard in squadrons
even though they see the beached skulls

the song nobody knows
because anyone who has heard it
is dead, and the others can't remember.

Better living through electricity. The lure of superior performance, improved memory, and higher IQ without all the hard work. Or at least, in a much shorter amount of time.

Transcranial direct current stimulation (tDCS), hailed as a “non-invasive”¹ way to alter brain activity,² has been hot for years. In fact, peak tDCS is already behind us, with a glut of DIY brain stimulation articles in places like Fortune, CBC, Life Hacker, New Statesman, Wall Street Journal, Wired, Slate, Medical Daily, Mosaic, The Economist, Nature, IEEE Spectrum, and The Daily Dot.

Simply apply a weak electrical current to your head via a pair of saline soaked sponges connected to a 9 volt battery. Current flows between the positive anode, or stimulating electrode (in blue below), and the negative cathode (in red below). Low levels of electrical stimulation travel through the scalp and skull to a region of cortex underneath the anode. Modeling studies suggest that the electric field generated by tDCS in humans is about 1 mV/mm (Neuling et al., ). The method doesn't directly induce spiking (the firing of action potentials), but it's thought to alter neuronal excitability. By facilitating neuroplastic changes during cognitive training, tDCS may improve learning, memory, mental arithmetic, and target detection.

Modified from Fig. 1b (Dayan et al., 2013). Bipolar tDCS electrode configuration, with one electrode over left dorsolateral prefrontal cortex and a reference electrode over the contralateral supraorbital region.

And there you have it. High tech performance enhancement for less than $40. Or a siren song for wannabe brain hackers?

In Symposium Session 7 of the Cognitive Neuroscience Society meeting last week, Dr. György Buzsáki threw a bit of cold water on non-invasive transcranial electrical stimulation (TES) methods, which include tDCS and transcranial alternating current (tACS).

My understanding of his remarks: Studies of transcranial electrical stimulation (TES) in human cadaver heads showed there's a 90% loss of current when delivered through the skin (which is obviously the case in living humans) vs. through the skull. This implies that a current of at least 5 mA on the scalp would be necessary to generate a 1 mV/mm electric field in the human brain. Based on his personal experience, Dr. Buzsáki reported that 4 mA was hard to tolerate even with anesthetized skin. For comparison, 2 mA is the maximum current recommended by an international panel of experts.

Others in the audience had similar interpretations:

90% loss of electrical current between skin and scalp -György Buzsáki #CNS2016
— CNS News (@CogNeuroNews) April 5, 2016

90% charge loss skin-skull using TES. Need 5 mA to affect spiking, FDA approved 2mA, Buzsáki first hand 4mA hard to tolerate. #CNS2016
— Renee M. Symonds (@DatabaseDragons) April 5, 2016

This revelation was in the context of work on focused beam stimulation, which is designed to improve the spatial selectivity of TES (Voroslakos et al., 2015):

We recorded TES-generated field potentials in human cadavers and anesthetized rats. Stimulation was applied by placing Ag/AgCl EEG electrodes over the external surface of the skull. ... We also measured the shunting effect of the skin during transcutaneous stimulation. In addition to our earlier results, we found that the skin dramatically reduced the generated intracranial electric fields, and alters its geometry.

image via Sue Peters, @nomorewires

In turn, the cadaver studies were an extension of very cool research on Closed-Loop Control of Epilepsy by Transcranial Electrical Stimulation. This paper used a rodent model of generalized epilepsy to test a system that (1) records neural activity and (2) triggers TES to quell abnormal activity once it is detected.

Having such a system that works in humans would be a huge advance for those who suffer from intractable seizures. Human heads are very different from rat heads, hence the need for human cadavers. And hence the bombshell that 1-2 mA current may have less of an effect on neurons than previously expected.

“But wait!” you say. “Aren't there literally thousands of peer-reviewed articles on tDCS? Surely it must be doing something.”

How Does It Work?

Shall I tell you the secret
and if I do, will you get me
out of this bird suit?

–Atwood, Siren Song

If the effects of tDCS are not directly via neurons, what's the mechanism of action? It's glia! And calcium! Gliotransmission! Maybe.

“Using a transgenic mouse expressing G-CaMP7 in astrocytes and a subpopulation of excitatory neurons, we find that tDCS induces large-amplitude astrocytic Ca²⁺ surges across the entire cortex with no obvious changes in the local field potential. Moreover, sensory evoked cortical responses are enhanced after tDCS. These enhancements are dependent on the alpha-1 adrenergic receptor and are not observed in IP₃R2 (inositol trisphosphate receptor type 2) knockout mice, in which astrocytic Ca²⁺ surges are absent. Together, we propose that tDCS changes the metaplasticity of the cortex through astrocytic Ca²⁺/IP₃ signalling.” (Monai et al., 2016)

The pre-astrocyte version of purported mechanism — based on direct modulation of the affected neurons' resting membrane potential — is described in the schematic below (click on image for a larger view).

from Fertonani & Miniussi (2016).

But maybe tDCS doesn't really do much in humans after all, as claimed in two recent review articles (Horvath et al., 2015a,b).³

And remember, transcranial devices are not playthings! (warn Bikson et al., 2013).

This gentleman discusses his burn injuries at the tDCS reddit.

Footnotes

¹ But see “Non-invasive” brain stimulation is not non-invasive (Davis & van Koningsbruggen, 2013):

These techniques [TMS and tCS] have collectively become known as “non-invasive brain stimulation.” We argue that this term is inappropriate and perhaps oxymoronic, as it obscures both the possibility of side-effects from the stimulation, and the longer-term effects (both adverse and desirable) that may result from brain stimulation.

² But see Evidence that transcranial direct current stimulation generates little-to-no reliable neurophysiologic effect beyond MEP amplitude modulation in healthy human subjects: A systematic review (Horvath et al., 2015a):

Our systematic review does not support the idea that tDCS has a reliable neurophysiological effect beyond MEP amplitude modulation... This work raises questions concerning the mechanistic foundations and general efficacy of this device – the implications of which extend to the steadily increasing tDCS psychological literature.

³ Not too surprisingly, these papers have not gone unopposed...

ADDENDUM (April 15 2016)– Antal et al. (2015)published one potent rebuttal to Horvath et al. (2015a):

...We are concerned about the validity of the conclusions for various reasons. Since this paper reviews a whole field of research and comes to debatable assumptions, it is especially important that basic quality requirements are fulfilled, which is unfortunately not the case.

First, this review suffers from numerous conceptual flaws and misunderstandings. Second, the work contains relevant design problems, several errors and many incompletely or incorrectly cited data.
. . .

In summary, as shown by the examples given above, this review suffers from important flaws with regard to citing and interpreting available literature, non-transparent, and in many cases erroneous data aggregation, citation of study specifics, and discussion of the results.

References

Berényi A, Belluscio M, Mao D, Buzsáki G. (2012). Closed-loop control of epilepsy by transcranial electrical stimulation. Science 337(6095):735-7.

Fertonani A, & Miniussi C (2016). Transcranial Electrical Stimulation: What We Know and Do Not Know About Mechanisms. The Neuroscientist. PMID: 26873962

Monai H, Ohkura M, Tanaka M, Oe Y, Konno A, Hirai H, Mikoshiba K, Itohara S, Nakai J, Iwai Y, & Hirase H (2016). Calcium imaging reveals glial involvement in transcranial direct current stimulation-induced plasticity in mouse brain. Nature communications, 7. PMID: 27000523

M. VOROSLAKOS, A. OLIVA, K. BRINYICZKI, T. ZOMBORI, B. IVÁNYI, G. BUZSÁKI, A. BERÉNYI. (2015). Targeted transcranial electrical stimulation protocols: Spatially restricted intracerebral effects via improved stimulation and recording techniques. Society for Neuroscience. Poster# 257.17/Y3.

Further Reading

Invading the brain to understand and repair cognition– CNS Press Release

When the Hype Doesn’t Pan Out: On Sharing the Highs-and-Lows of Research with the Public– by Jared Cooney Horvath

Non-invasive direct current brain stimulation for depression:  the evidence behind the hype– by Camilla Nord and Jonathan Roiser

Neurostimulation: Bright sparks– by Katherine Bourzac

DIY tDCS– Keeping Tabs On Transcranial Direct Current Stimulation

Why 2.0 mA as the limit for TDCS?– reddit thread

Brunoni AR, Nitsche MA, Bolognini N, Bikson M, Wagner T, Merabet L, Edwards DJ, Valero-Cabre A, Rotenberg A, Pascual-Leone A, Ferrucci R, Priori A, Boggio PS, Fregni F. (2012). Clinical research with transcranial direct current stimulation (tDCS): challenges and future directions. Brain Stimul. 5(3):175-95.

Davis NJ. (2016). The regulation of consumer tDCS: engaging a community of creative self-experimenters. Journal of Law and the Biosciences. Apr 5:lsw013.

Davis NJ, van Koningsbruggen MG. (2013). "Non-invasive" brain stimulation is not non-invasive. Front Syst Neurosci. 7:76.

Dayan E, Censor N, Buch ER, Sandrini M, Cohen LG. (2013). Noninvasive brain stimulation: from physiology to network dynamics and back. Nat Neurosci. 16(7):838-44.

Edwards D, Cortes M, Datta A, Minhas P, Wassermann EM, Bikson M. (2013). Physiological and modeling evidence for focal transcranial electrical brain stimulation in humans: a basis for high-definition tDCS. Neuroimage 74:266-75.

Horvath JC, Forte JD, Carter O. (2015a). Evidence that transcranial direct current stimulation (tDCS) generates little-to-no reliable neurophysiologic effect beyond MEP amplitude modulation in healthy human subjects: A systematic review. Neuropsychologia 66:213-36.

Horvath JC, Forte JD, Carter O. (2015b). Quantitative Review Finds No Evidence of Cognitive Effects in Healthy Populations From Single-session Transcranial Direct Current Stimulation (tDCS). Brain Stimul. 8(3):535-50.

Kuo MF, Nitsche MA. (2012). Effects of transcranial electrical stimulation on cognition. Clin EEG Neurosci. 43(3):192-9.

Parkin BL, Ekhtiari H, Walsh VF. (2015). Non-invasive human brain stimulation in cognitive neuroscience: a primer. Neuron 87(5):932-45.

Santarnecchi E, Brem AK, Levenbaum E, Thompson T, Kadosh RC, Pascual-Leone A. (2015). Enhancing cognition using transcranial electrical stimulation. Current Opinion Behav Sci. 4:171-8.

Woods AJ, Antal A, Bikson M, Boggio PS, Brunoni AR, Celnik P, Cohen LG, Fregni F, Herrmann CS, Kappenman ES, Knotkova H, Liebetanz D, Miniussi C, Miranda PC, Paulus W, Priori A, Reato D, Stagg C, Wenderoth N, Nitsche MA. (2016). A technical guide to tDCS, and related non-invasive brain stimulation tools. Clin Neurophysiol. 127(2):1031-48.

MORE! (added April 15 2016): Two recent meta-analyses on tDCS and working memory reported “a mix of significant and nonsignificant small effects” and “some evidence of a beneficial effect ... [but] the small effect sizes obtained, coupled with non-significant effects on several analyses require cautious interpretation” (respectively):

Mancuso LE, Ilieva IP, Hamilton RH, Farah MJ. Does Transcranial Direct Current Stimulation Improve Healthy Working Memory?: A Meta-analytic Review.J Cogn Neurosci. 2016 Apr 7:1-27. [Epub ahead of print]

Hill AT, Fitzgerald PB, Hoy KE. Effects of Anodal Transcranial Direct Current Stimulation on Working Memory: A Systematic Review and Meta-Analysis of Findings From Healthy and Neuropsychiatric Populations. Brain Stimul. 2016; 9(2):197-208.

I don't enjoy it here
squatting on this island
looking picturesque and mythical

with these two feathery maniacs,
I don't enjoy singing
this trio, fatal and valuable.

I will tell the secret to you,
to you, only to you.
Come closer. This song

is a cry for help: Help me!
Only you, only you can,
you are unique

at last. Alas
it is a boring song
but it works every time.

–Atwood, Siren Song

image:Mihály Vöröslakos / University of Szeged

“Don't Lose Your Head Over tDCS,” I warned last time. Now the infamous cadaver study has reared its ugly hot-wired head in Science News (Underwood, 2016).

The mechanism of action of transcranial direct current stimulation (tDCS) had been called into question by Dr. György Buzsáki during his presentation at the Cognitive Neuroscience Society meeting.

...Or had it?

To recap, my understanding was that an unpublished study of transcranial electrical stimulation (TES) in human cadaver heads showed a 90% loss of current when delivered through the skin vs. through the skull. This implies that a current of at least 5 mA on the scalp would be necessary to generate a 1 mV/mm electric field in the human brain. Based on his personal experience, Dr. Buzsáki reported that 4 mA was hard to tolerate even with anesthetized skin. For comparison, 2 mA is the maximum current recommended by an international panel of experts.

But Dr. Tiziana Metitieri left a comment on my post saying this is nothing new. She translated the remarks of Dr. Carlo Miniussi, who said:

...but what is reported appear to me not so “new” (http://www.ncbi.nlm.nih.gov/pubmed/?term=Miranda+PC+2006). Of course, if the findings obtained by Buzsáki are confirmed, you may think that tDCS has an effect nearly homeopathic on the brain. Certainly, these type of research is the most needed: systematic studies of animal and human models, comparable in terms of the amount of current that stimulates the brain. Luckily, they are coming out, or, well, we know they exist and we are waiting to read them, as for Buzsáki. [read more]

Why is this important to cognitive neuroscientists? Because the behavioral effects of tDCS have been vastly overstated, according to some investigators (e.g., Horvath et al., 2015), and the “homeopathic” level of brain stimulation is one likely explanation.

But a common refrain of experts in the field [I am not an expert] is that Buzsáki's results are not surprising — the low amount of current is old hat. For instance, Dr. Marom Bikson explained in Science News that...

...many in the field already accepted that the 1 or 2 milliamps the methods use don't directly trigger firing. It can make neurons more likely to fire or form new connections, he and others believe. Unlike techniques that rely on magnetic fields or higher current to actively trigger neurons ... tDCS and tACS likely subtly alter ongoing brain activity, Bikson says. Using cadavers to test these methods is a “complicated choice” because dead tissue conducts electricity differently from living tissue, he adds.

Also quoted is Dr. Vince Clark, who...

...has found that applying 2 milliamps of current to a person’s scalp for just 30 minutes can double the speed at which they learn a game in which players must detect a concealed “threat”... Several labs have replicated those results, he says, adding that the idea that 10% or less of the current gets through to the brain is not new, and doesn’t necessarily mean the methods are ineffective. “If it works, you know 10% is enough,” Clark says.

Although some effects may be replicable, Dr. Vince Walsh dropped a stink bomb by saying that the tDCS field is “a sea of bullshit and bad science—and I say that as someone who has contributed some of the papers that have put gas in the tDCS tank. ... It really needs to be put under scrutiny like this.” In Wired, Walsh basically said the reason for the “sea of bullshit and bad science” is that the barrier to enter tDCS research is so darn low.

When Can TES Influence Spiking?

Returning to Buzsáki's talk, he mentioned a study in rats (Ozen et al., 2010) where a TES-induced voltage gradient of 1 mV/mm at the recording sites could phase-locked spiking (action potentials). However, the current was delivered via electrodes placed directly on the skull or even the dura covering the brain. The stimulation protocol was low frequency sinusoid patterns that mimic slow cortical oscillations, to entrain neuronal spiking activity. That was the goal in humans, but similar TES applied to the scalp produced no discernible change in oscillatory activity. Hence, the cadaver tests.

These studies used transcranial alternating current stimulation (tACS), which is designed to influence ongoing cortical oscillations by “entraining” or phase-locking to specific EEG frequency bands (as in Kanai et al., 2008). Buzsáki himself actually commented on the Science piece (which I will quote at length):

"The real question: Is the current which does reach the brain sufficient to perform this ‘extremely weak coupling’ in neural systems?" This is exactly what we investigated. Since we failed to entrain neuronal activity (local fields) repeatedly in the living human brain with the commonly used current intensities, whereas we were very successful in rodents using stimulation electrodes directly on the bone, we looked for answers. The cadaver is the next best possible thing to a living human brain if one wants to know how the currents are distributed inside the brain. We found that most current is lost by the shunting effect of the extracranial tissue. As a result, the voltage gradients that we measured in the brain were way below the values we found in rodents needed to affect population neuronal oscillations. The weak electric fields were just too weak. Of course, there is the principle of stochastic resonance and thus some super weak effect can have some effects occasionally - we cannot and do not want to deny it, but cannot prove it either, therefore cannot rely on it as an explanation for the reported behavioral effects of TES.

In his talk he mentioned possible effects on astrocytes, and my previous post cited the study of Monai et al. (2016). In his Science comment Buzsáki said, “Glia may be more sensitive to polarized currents than neurons and muscles.” He also mentioned possible effects on peripheral nerves in the scalp (like the vagus nerve), which is something that Dr. Jamie Tyler (formerly of Thync) has said for years:

Thync tried to replicate some basic tDCS findings on cognition but could not do so. Dr Tyler now believes that tDCS may not directly stimulate the brain at all but instead modulates cranial nerves in the skull...

During the discussion period at the CNS meeting, Buzsáki was asked about the phenomenon of DIY tDCS. He compared it to alternative medicine.

On that note, I'll conclude with a nod to the tDCS reddit community, some of whom didn't trash my last critical post as much as I expected. Yay! Others? Not so much. Boo: “There are so many inaccuracies in this article, I don't know where to begin.” And then they don't bother to begin...

So any- and all-comers can begin by pointing out my inaccuracies in the comments section of this post.

References

Horvath JC, Forte JD, Carter O. (2015). Quantitative Review Finds No Evidence of Cognitive Effects in Healthy Populations From Single-session Transcranial Direct Current Stimulation (tDCS). Brain Stimul. 8(3):535-50.

Kanai R, Chaieb L, Antal A, Walsh V, Paulus W. (2008). Frequency-dependent electrical stimulation of the visual cortex. Curr Biol. 18(23):1839-43.

Ozen, S., Sirota, A., Belluscio, M., Anastassiou, C., Stark, E., Koch, C., & Buzsaki, G. (2010). Transcranial Electric Stimulation Entrains Cortical Neuronal Populations in Rats Journal of Neuroscience, 30 (34), 11476-11485. DOI: 10.1523/JNEUROSCI.5252-09.2010

Underwood, E. (2016). Cadaver study challenges brain stimulation methods. Science, 352 (6284), 397-397 DOI: 10.1126/science.352.6284.397

NINETY-TWO percent of retired National Football League players have decreased cognitive function, according to a new study:

“In the NFL group, baseline neuropsychological assessments showed 92% of players had decreased general cognitive proficiency, 86% had decreased information processing speed, 83% had memory loss, 83% had attentional deficits, and 85% had executive function impairment.”

The Truth?

The study reported on a self-selected sample of 161 current and retired NFL players recruited via a blog (“The NFL concealed the danger of brain injuries!!”), the Los Angeles Chapter of the Retired NFL Players Association, The Summit (??), and possibly other sources. Perhaps these players were motivated to participate because they had cognitive complaints, or because they wanted an evaluation in advance of the $1 billion concussion settlement. The League's Baseline Assessment Program is a required part of the settlement.¹

The quote above is the full extent of the report on the players' neuropsychological assessments. These were done using computerized test batteries (MicroCog or WebNeuro), which are largely unknown to most clinical neuropsychologists. Was there an adequately matched control population? What norms were used? They don't say.

THE TRUTH IS, we don't know the extent of cognitive impairment in these football players, or the percentage of all players who are affected, or the severity of impairment in those who are. This new paper (by Daniel Amen, Bennet Omalu, and others) doesn't give us enough information, but it succeeds in sounding the alarm about the dangers of football and the inevitability of memory loss and attention deficits.

Are blows to the head bad for your brain? Can repeated concussions cause cognitive impairment and chronic traumatic encephalopathy (CTE)?² Yes, almost certainly, but we can't rely on biased samples, appeal to celebrity, and Frontline documentaries (“researchers have identified CTE in 96 percent of NFL players that they’ve examined”) as conclusive scientific evidence. What's needed are better sampling methods (in the short term) and longitudinal studies that follow a diverse cohort over time (in the long term).

The Scans

Caption for top figure: SPECT brain scans showing abnormal low blood flow in an NFL player compared to a normal healthy control subject.

The new paper by Amen et al. (2016) was actually focused on SPECT scans, not surprisingly, since these are the backbone of his business at the Amen Clinics. The article claims “90% sensitivity, 86% specificity, and 94% accuracy” in discriminating NFL players from controls. I won't elaborate here, but check out This Neuroimaging Method Has 100% Diagnostic Accuracy (or your money back) and The Dark Side of Diagnosis by Brain Scan for detailed critiques of the methods used here. I will flag one tiny issue, however:

“All NFL players were male, while 56% of the control group were women.”

Why?? The authors have a database of 100,000 SPECT scans...

Footnote

¹ 11. What is the Baseline Assessment Program (“BAP”)?

. . .
Retired players who are diagnosed with Level 1 Neurocognitive Impairment (i.e., moderate cognitive impairment) are eligible to receive further medical testing and/or treatment (including counseling and pharmaceuticals) for that condition during the ten-year term of the BAP or within five years from diagnosis, whichever is later.

14. What diagnoses qualify for monetary awards?

Monetary awards are available for the diagnosis of ALS, Parkinson’s Disease, Alzheimer’s Disease, Level 2 Neurocognitive Impairment (i.e., moderate Dementia), Level 1.5 Neurocognitive Impairment (i.e., early Dementia) or Death with CTE (the “Qualifying Diagnoses”). A Qualifying Diagnosis may occur at any time until the end of the 65-year term of the Monetary Award Fund.

²ADDENDUM (May 1 2016): I should say, “...cause CTE and/or other neurodegenerative disorders and dementias.”

Also see: Here’s What We Don’t Know About Head Injuries And Sport
...and A Clinical Approach to the Diagnosis of Traumatic Encephalopathy Syndrome

Reference

Daniel G. Amen, Kristen Willeumier, Bennet Omalu, Andrew Newberg, Cauligi Raghavendra, & Cyrus A. Raji (2016). Perfusion Neuroimaging Abnormalities Alone Distinguish National Football League Players from a Healthy Population Journal of Alzheimer's Disease : 10.3233/JAD-160207

Caption (from press materials): SPECT brain scans showing improvement of abnormal low blood flow in an NFL player compared after 3.5 months on a customized brain rehabilitation program.

ADDENDUM #2 (May 1 2016): The authors'Conflict of Interest statements.

When you hear the word “apple”, do you picture a Red Delicious apple or a green Granny Smith? Or neither, because you can't conjure up a visual image of an apple (or of anything else, for that matter)?
Aphantasia is the inability to generate visual images, which can be a congenital condition or acquired after brain injury (Farah, 1984). The most striking aspect of this variation in mental life is that those of us with imagery assume that everyone else has it, while those without are flabbergasted when they learn that other people can “see” pictures in their head.

Programming prodigy Blake Ross created a sensation recently with his eloquent essay on what's it's like to discover that all your friends aren't speaking metaphorically when they say, “I see a beach with waves and sand.”

Aphantasia: How It Feels To Be Blind In Your Mind

I just learned something about you and it is blowing my goddamned mind.
. . .

Here it is: You can visualize things in your mind.

If I tell you to imagine a beach, you can picture the golden sand and turquoise waves. If I ask for a red triangle, your mind gets to drawing. And mom’s face? Of course.
. . .

I don’t. I have never visualized anything in my entire life. I can’t “see” my father’s face or a bouncing blue ball, my childhood bedroom or the run I went on ten minutes ago. I thought “counting sheep” was a metaphor. I’m 30 years old and I never knew a human could do any of this. And it is blowing my goddamned mind.

It's worth reading Ross's account in its entirety to gain insight into the vast individual variation in our internal mental lives.

Although the term aphantasia is new (coined by Zeman et al., 2015), the condition isn't; Francis Galton published a paper on the Statistics of Mental Imagery in 1880. Similar to Ross, many of Galton's s friends (male scientists) were shocked to learn that others had imagery:¹

To my astonishment, I found that the great majority of the men of science to whom I first applied, protested that mental imagery was unknown to them, and they looked on me as fanciful and fantastic in supposing that the words 'mental imagery' really expressed what I believed everybody supposed them to mean. They had no more notion of its true nature than a colour-blind man who has not discerned his defect has of the nature of colour. They had a mental deficiency of which they were unaware, and naturally enough supposed that those who were normally endowed, were romancing.

The nature of mental images has been a topic of philosophical debate in cognitive science since the 1970s. Are mental images quasi-perceptual representations that activate visual areas of the brain (Kosslyn and colleagues), or non-pictorial, abstract, symbolic descriptions (Zenon Pylyshyn)? The Stanford Encyclopedia of Philosophy's entry on Mental Imagery provides an indispensable background on the philosophical, theoretical, and empirical debates in the field. As well, extensive research on individual differences in mental imagery (e.g., Kosslyn et al., 1984) can inform new studies on aphantasics.

Aphantasia and Paivio's Dual Coding Theory

To investigate the role of imagery in verbal memory, I propose a return to classic cognitive psychology experiments of the 1970s. Alan Paivio's Dual Coding Theory specifies two types of mental representations, or codes, for words and mental images (Paivio, 1971). The verbal code and imagery code are both activated by pictures, which can account for the picture superiority effect: pictures are better remembered than their verbal referents (i.e., words). The picture superiority effect should be abolished in those who cannot generate visual images.²

Even more interestingly, words that are highly imageable (concrete nouns like elephant) are better remembered than words that are rated low in imageability (abstract nouns like criterion). The original ratings from 1968 and the expanded 2004 version (concreteness, imageability, meaningfulness, familiarity) are available online: Clark and Paivio (2004) Norms. Lists of high and low imageable nouns that are carefully matched on other lexical factors (e.g., number of letters, word frequency, complexity) can be presented in a memory test. The recognition memory (or free recall) advantage for concrete, highly imageable words should be diminished or abolished in relation to self-reported imagery abilities.

I believe this experiment would address the objection of psychogenic aphantasia (“refusing to imagine”), because the concreteness advantage (using imagery during encoding) could not be mobilized as an explicit (or perhaps implicit) strategy. Given the hundreds (if not thousands) of Aphantasics who have made blog comments, joined Facebook groups and other communities, taken surveys, and of course contacted Dr. Zeman, the sample size might be quite respectable.

Quick poll (please RT!): Can you draw up an image in your mind's eye...?
— Kevin Mitchell (@WiringTheBrain) May 3, 2016

Mental images poll. Is 'mental image' a misnomer? Pls RT, this stuff is weird. (CC: @WiringTheBrain; @blakeross).
— Ed Berry (@ed_berry) May 3, 2016

Footnote

¹Aphantasia seems bizarrely overrepresented in Galton's cronies. Here's his explanation:

My own conclusion is, that an over-readiness to perceive clear mental pictures is antagonistic to the acquirement of habits of highly generalised and abstract thought, and that if the faculty of producing them was ever possessed by men who think hard, it is very apt to be lost by disuse. The highest minds are probably those in which it is not lost, but subordinated, and is ready for use on suitable occasions.

²Of note here, some with aphantasia report severe deficits in autobiographical memory.

References

Farah MJ. (1984). The neurological basis of mental imagery: A componential analysis. Cognition 18:245-72.

GALTON, F. (1880). I.--STATISTICS OF MENTAL IMAGERY Mind, os-V (19), 301-318 DOI: 10.1093/mind/os-V.19.301

Kosslyn SM, Brunn J, Cave KR, Wallach RW. (1984). Individual differences in mental imagery ability: a computational analysis. Cognition 18:195-243.

Paivio A. (1969). Mental imagery in associative learning and memory. Psychological Review 76: 241-263.

Paivio A. (1971, 2013). Imagery and verbal processes. Holt, Rinehart & Winston / Psychology Press.

Zeman, A., Dewar, M., & Della Sala, S. (2015). Lives without imagery – Congenital aphantasia Cortex, 73, 378-380 DOI: 10.1016/j.cortex.2015.05.019

ADDENDUM (May 7 2016): via @vaughanbell, a new review article by the University of Exeter group (part of their project, The Eye's Mind):

MacKisack M, Aldworth S, Macpherson F, Onians J, Winlove C, Zeman A. (2016). On Picturing a Candle: The Prehistory of Imagery Science. Front Psychol. 7:515.

Not only Galton, Paivio, Kosslyn, and Pylyshyn but also Aristotle, Plato, Thomas Aquinas, and more.

- click on image for a larger view -

Left: Belgian physician Dr. Wim Distelmans, a cancer specialist, professor in palliative care and the president of the Belgian federal euthanasia commission.Right: Generic acetaminophen.

What (or who) is an “Empathy Killer“? An Angel of Death Kevorkian-type who helps terminally ill patients with ALS or cancer put an end their excruciating pain? This is a very selfless act that shows extreme empathy for the suffering of others.

Or is an “Empathy Killer” a medication that dulls your numerical ratings of empathic concern for fictional characters ever so slightly? If you guessed the latter, you are correct. Here's the actual title of a new paper in SCAN: “From Painkiller to Empathy Killer: Acetaminophen (Paracetamol) Reduces Empathy for Pain.”

Oh the headlines. Truly painful.

Paracetamol doesn't just kill pain - it makes us less CARING

America's Most Common Drug Ingredient Could Be Making You Less Empathetic

Why Would a Headache Medication Make You Less Empathetic?

A popular line of research in Social Cognitive and Affective Neuroscience examines the commonalities between physical and social/psychological pain. IFthere is indeed an overlap,¹ one might ask some provocative questions about the underlying neural mechanisms. Do drugs that ease physical pain also soothe the pain of social rejection and existential angst?² Several recent papers have reported that acetaminophen does exactly that (Dewall et al., 2010; Randles et al., 2013; Durso et al., 2015) — although some pundits may beg to differ.³

The latest psychological study on this popular over-the-counter painkiller looks at empathy for another person's pain (Mischkowski et al., 2016). This work is based on the premise that the same neural machinery responsible for feeling our own physical and psychological pain (ACC, AI, mirror neurons— don't ask — but see Zaki et al., 2016) is invoked when observing the pain of others.

The Mystery of the Sliding Scales

[NOTE: Perceived Pain scores standardized in Tables 1, 3, 4 but not Table 2]

Can Tylenol (aka Parecemetol) lessen the pain you feel for others? I'll go out on a limb here and say probably not. Or not much, especially in a real-world sense. Here's why.

First, you have to understand that the experimental ratings of empathy were based on two different scales that varied from 1 (No pain at all) to 5 (Worst possible pain) OR from -4 (Worst possible pain) to +4 (Most possible pleasure). For the latter scale, the authors “reverse-coded participants’ ratings, so higher ratings indicated higher empathy for pain.”

Participants in Experiment 1 were given a placebo drink (n=40) or 1000 mg liquid acetaminophen (n=40). An hour later, they read short scenarios depicting other people in physical pain (e.g., cutting a finger) or social pain (e.g., getting rejected from college). Two major scores were obtained for perceived pain and personal distress. My reading is that these should yield a mean score between 1 and 5 for each measure.

ADDENDUM (May 18 2016): As pointed out by two Anonymous commenters, the Perceived Pain scores were standardized in Table 1. The same measure was not standardized in Table 2.

PERCEIVED PAIN — For each scenario, we measured perceived pain with two measures. First, participants rated the pain of each protagonist using a scale from 1 (No pain at all) to 5 (Worst possible pain). Second, participants rated on three items how much each protagonist felt hurt, wounded, and pained on scales ranging from 1 (Not at all) to 5 (Extremely). We averaged items to create perceived hurt feeling measures across physical and social pain scenarios... Within each scenario type, both perceived pain ratings correlated highly... Therefore, we standardized and averaged these measures into indices of perceived physical and social pain.

PERSONAL DISTRESS — Participants also rated their personal distress when reading each scenario. On a scale from 1 (Not at all) to 5 (Extremely), participants rated the extent to which they felt uncomfortable, pained, bothered, unpleasant, distress, as well as wanted to cringe while imagining the feelings of each scenario protagonist. We averaged items to create separate personal distress measures for physical and social pain scenarios...

My guess is that the authors made a mistake in their Tables, or else I misunderstood the scoring scheme. Let's take a look (click on image for a larger view).

For the first Dependent Variable, participants rated their own positive and negative feelings on the PANAS. General Affect ratings didn't differ between drug and placebo.

Next, look at Perceived Pain for Physical Pain Scenarios and Social Pain Scenarios. I won't belabor the p values here. Instead, focus on the red rectangles.[My mistake, Perceived Pain scores were standardized in Table 1. However, this does not affect my next comment.]These values are both close to zero (perhaps not significantly different from zero)~~. But they don't seem to be on the 1 to 5 scale described above.~~ The Personal Distress values ranged from “kind of a little bit” distressed for drug (2.15 and 2.00) to “kind of a little bit more” distressed for placebo (2.75 and 2.45). The participants who received acetaminophen are hardly in the land of the cruel and heartless psychopath. How much would these slight variations in personal distress ratings translate to real world empathy? We simply don't know.

Next, let's figure out the sliding scale issue. In Experiment 2:

Participants read the same eight physical and social pain empathy scenarios as in Experiment 1. After reading each scenario, participants rated perceived pain of the protagonist, using a scale from -4 (Worst possible pain) to +4 (Most possible pleasure). We reverse-coded participants’ ratings, so higher ratings indicated higher empathy for pain.

So here we have a scale that does include negative numbers, perhaps that scale was used for Perceived Pain in Exp. 1. Except ratings in Exp. 2 seems to use the 1 to 5 scale? It's hard to tell at this point. [Perceived Pain scores were not standardized in Table 2.] At any rate, the differences are small, and not significant for some of the comparisons.

There were other conditions involving noise blasts and watching a person being excluded from a round of cyberball (an old-school ball-tossing video game). Some of the values here were confusing as well. Or maybe I'm just confused... [Yes, I was confused. Perceived Pain scores were standardized in Tables 3 and 4.]

Noise blasts rated on a scale from 1 (Not unpleasant at all) to 10 (Extremely unpleasant).

Once again, in Table 4 we see mean values for Perceived Pain that are very close to zero. What does it mean? I will be happy to correct any erroneous interpretations of these Tables.

Now that I have corrected my mistakes, I still think it's hyperbole to say these differences mean that acetaminophen is an empathy killer in real life.

Neuroskeptic points out:

Something odd about some of the datapoints... In Table 1, the mean for "perceived pain" for placebo is equal to the mean for acetaminophen * -1 (e.g. 0.22 vs -0.22, 0.19 vs. -0.19). The same is true in Table 4, two different values (e.g. 0.06 vs. -0.06, 0.04 vs -0.04).

Furthermore, does an Empathic Concern for Ostracized Player score of 1.68 (compared to 2.05) mean you're a less caring person? That acetaminophen has dulled your empathy? An empathy score of 2.05 (out of 5) while on placebo isn't exactly a heart-rending level of concern...

Cyberball 4.0

I could be wrong, but I don't think the Tylenol-fueled collapse of civilization is neigh. Next up? Ibuprofen! ⁴

Footnotes

¹ Many have argued that the physical-emotional pain isomorphism is vastly overstated (e.g., Hayes and Northoff, 2012; The Neurocritic, 2012; Iannetti et al., 2013; Woo et al., 2014; Wager et al., 2016).

²Well sure, you say, people have been self-medicating with opiates and alcohol for centuries. BUT here I mean mild nonprescription medications not known for having psychoactive properties.

³ Yeah, I've written about this a lot.

Tylenol Doesn't Really Blunt Your Emotions

Suffering from the pain of social rejection? Feel better with TYLENOL®

Existential Dread of Absurd Social Psychology Studies

Does Tylenol Exert its Analgesic Effects via the Spinal Cord?

Vicodin for Social Exclusion

⁴ I've wanted to see that study for years.

References

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 social pain: behavioral and neural evidence. Psychological Science 21:931-937.

Durso G, Luttrell A, Way B. (2015). Over-the-Counter Relief From Pains and Pleasures Alike: Acetaminophen Blunts Evaluation Sensitivity to Both Negative and Positive Stimuli.Psychological Science 26:750-758.

Mischkowski, D., Crocker, J., & Way, B. (2016). From Painkiller to Empathy Killer: Acetaminophen (Paracetamol) Reduces Empathy for Pain. Social Cognitive and Affective Neuroscience DOI: 10.1093/scan/nsw057

Randles D, Heine SJ, Santos N. (2013). The common pain of surrealism and death: acetaminophen reduces compensatory affirmation following meaning threats. Psychological Science 24:966-73.

Zaki J, Wager TD, Singer T, Keysers C, Gazzola V. (2016). The Anatomy of Suffering: Understanding the Relationship between Nociceptive and Empathic Pain. Trends Cogn Sci. 20(4):249-59.

You may have seen headlines such as: Florida Man Woke Up In A Motel Room Speaking Only Swedish. Or: Englishman wakes up speaking Welsh after stroke (“Rare brain disorder left English-speaking Alun Morgan only able to communicate in Welsh”). The first case was likely due to a fugue state, a type of dissociative disorder involving loss of personal identity and aimless wandering (Stengel, 1941). The second seems like an unusual example of bilingual aphasia involving loss of the ability to speak one's native language (rather than the more commonly affected second language).

Perhaps you've even seen paranormal claims like:

Under Hypnosis or Past Life Regression, A Physician's Wife Starts Speaking Swedish

. . . In sessions conducted from 1955 to 1956, when Tania was under hypnosis, a personality emerged who spoke Swedish, a language that neither Tania nor Ken knew. As such, this represents a case of xenoglossy, where an individual can speak a language that has not been learned through normal means.

Tania was born in Philadelphia and as such, English was her native language. Her parents, who were Jewish, were born in Odessa, Russia. No one in the family had ever been to Scandinavia and they knew no one who could speak Swedish.

Xenoglossy is “the putative paranormal phenomenon in which a person is able to speak or write a language he or she could not have acquired by natural means.” Of course, there's always a logical explanation for such cases, but magical thinking leads people to believe that such phenomena are proof of past lives and reincarnation.

A New Case of False Xenoglossy

An amusingly written clinical report describes a 50 year old Italian man who stopped speaking his native Italian and insisted on speaking broken and somewhat fake French after a neurological event (Beschin et al., 2016). An abnormality in his basilar artery blocked the necessary flow of cerebrospinal fluid (CSF), with hydrocephalus and brainstem vascular encephalopathy as a result. A typical example of the condition (known as megadolicho basilar artery) in another patient is shown below.

Fig. 1 (Thiex & Mull, 2006). (A) CSF flow obstruction (arrow). (B) megadolicho basilar artery.

The man had no previous psychiatric history and retained the ability to speak perfect Italian. The clinical report includes the only instance of the word “fling” that I recall seeing in a scientific journal, so I'll quote at length:

He had superficially learned French at school, used it in his 20's due to a fling with a French girl but he has not spoken it for about 30 years. In his professional life he used English as his second language. Before brain damage he never manifested a particular attachment to French culture or French cuisine. His accent is not due to dysarthria and he speaks polished and correct Italian, his mother tongue. However, he now states that French is his preferred language refusing to speak in Italian spontaneously.
. . .

JC's French is maladroit and full of inaccuracies, yet he speaks it in a fast pace with exaggerated intonation using a movie-like prosody and posing as a typical caricature of a French man. His French vocabulary is reduced and he commits several grammatical errors but he does not speak grammelot or gibberish and never inserts Italian terms in his French sentences. He uses French to communicate with everybody who is prepared to listen; he speaks French with his bewildered Italian relatives, with his hospital inmates, with the consultants; he spoke French even in front of the befuddled Committee deciding on his pension scheme. He claims that he cannot but speak in French, he believes that he is thinking in French and he longs to watch French movies (which he never watched before), buys French food, reads French magazines and seldom French books, but he writes only in Italian. He shows no irritation if people do not understand him when he speaks in French.

He performed well on picture naming and verbal fluency tests in Italian, although he first tried to name the item in French (substituting category names like ‘vegetable’ for the low frequency word ‘asparagus’). His episodic memory was poor and he could not recall autobiographical incidents from the previous few years (but could recall earlier memories). He performed well on most other cognitive tests. But he did show some psychiatric symptoms that were secondary to the brain injury.

However, he presents with some delusions of grandeur, sleep disturbances and has some compulsive behaviours: he buys unnecessarily large quantities of objects (e.g., needing two hangers he bought 70) and he makes tons of bread to his wife's chagrin. He also shows unjustified euphoria (which he labels joie de vivre): for example in the morning he opens the windows and shouts bonjour stating that it is a wonderful day. He manifests signs of social disinhibition, for example proposing to organise a singing tour for his daughter's teenage friend or offering French lessons to his neighbours. These symptoms are indicative of secondary mania (Santos, Caeiro, Ferro, & Figueira, 2011) and were drug-resistant.

This is certainly a highly usual consequence of megadolicho basilar artery, but note that the subtitle of Beschin et al.'s article is “A clinical observation not a mystery.” There is no true xenoglossy here (or anywhere else, for that matter).

Further Reading

Man Wakes Up From Coma Speaking New Language: The media’s love of xenoglossy

Foreign Language Syndrome–“There actually isn’t a legitimate foreign language syndrome...”

References

Beschin, N., de Bruin, A., & Della Sala, S. (2016). Compulsive foreign language syndrome: A clinical observation not a mystery. Cortex DOI: 10.1016/j.cortex.2016.04.020

Stengel, E. (1941). On the Aetiology of the Fugue States. British Journal of Psychiatry 87 (369): 572-599.

Thiex R, Mull M. (2006). Basilar megadolicho trunk causing obstructive hydrocephalus at the foramina of Monro. Surg Neurol. 65(2):199-201.

Jen speaks fake Italian on the IT Crowd.

Headache, Guillaume DELEBARRE (Guigui-Lille)

A recent neuroessay in the New York Times asked, Can Tylenol Help Heal a Broken Heart?

What’s crazy about the pain of a broken heart is that your body perceives it as physical pain.

No it does not. Do you feel heartbroken every time you stub your toe?

Well... I guess the social pain = physical pain isomorphism is a one way street. Anyway, the author continued:

In research published in 2010, scientists found that acetaminophen can reduce physical and neural responses associated with the pain of social rejection, whether in romantic relationships, friendships or otherwise.

The pain reliever Tylenol (acetaminophen) lessens the pain of social rejection, according to the 2010 study in Psychological Science[except when it doesn't].¹ Acetaminophen also purportedly soothes the existential angst of watching a David Lynch film, blunts your emotions, and kills your empathy.²

So if you’re hurting from heartache, try popping some Tylenol.

Do not pop Tylenol after a breakup. It can cause serious liver damage if you take too much.

But What About Advil?

A 2014 study in the journal Personal Relationships was the first to break the stranglehold of acetaminophen (Vangelisti et al., 2014). The paper made few headlines (an exception was the Daily Mail), and it was not cited by the Tylenol researchers after its publication. Yet I saw no difference in quality, and even found more to like about it compared to the Tylenol papers (all of which appeared in higher impact journals). One of the Advil authors was Dr. James Pennebaker, chair of Psychology at the University of Texas. Dr. Pennebaker is well-known for his research on text analysis and what word choice can reveal about sex, age, social class, personality, mood, and affective state.

The focus of the study by Dr. Anita Vangelisti and colleagues was on potential sex differences in the effects of a physical pain reliever on social pain. They cited evidence suggesting that women are more sensitive to physical pain, and men might be more responsive to pain relievers like ibuprofen (Walker & Carmody, 1998).

Proposed explanations for sex differences in pain and analgesia include the bullet list below (Mogil & Bailey, 2010). These could potentially influence the effects of ibuprofen (and acetaminophen) on social pain.³

Sociocultural–manly and stoic machismo
Psychological– greater negative affect and catastrophizing in women
Experiential– women may have more experience with clinical pain, which affects current pain perception
Opioid receptors– and especially their interactions with gonadal hormones
Other potential biological factors– a long list

Advil Worsened Social Pain in Men

Ibuprofen did indeed increase ratings of social pain in male participants, but decreased ratings in female participants Vangelisti et al. (2014). For more details, read on.

The participants were 138 undergraduates enrolled in communication courses (62 male and 76 female). Half took 400 mg ibuprofen (the dosage in 2 tablets), and half took placebo. In one task, they rated their feelings after being excluded from a ball-tossing video game (Cyberball), similar to the 2010 study of Dewall and colleagues. In the second task, they wrote detailed descriptions about an experience of betrayal by a close relational partner and an experience of physical pain. Participants completed the Positive and Negative Affective Schedule (PANAS) before treatment and after each of the tasks. On the PANAS, respondents rated their experience of 20 different feelings or emotions on a 7-point scale (1 = very slightly or not at all, 7 = extremely).⁴

Two additional items assessed social pain or hurt. One required participants to rate the extent to which they felt hurt; the other required them to indicate the degree to which they felt emotionally injured. An average of these two questions comprised the dependent measure of Social Pain (presumably also on a 1 to 7 scale). Another dependent measure used the Linguistic Inquiry and Word Count (LIWC) program to calculate a weighted percentage of Emotion Words and First-Person Pronouns in the written narratives, both of which are indicators of increased social pain. Neither linguistic measure reached statistical significance, so I'll focus on Social Pain ratings.

Within-subjects comparisons showed that in all cases, Social Pain ratings were higher after the tasks than before.

Placebo Group
Before        M = 1.52, SD = 0.86
Cyberball    M = 2.07, SD = 1.31
Betrayal      M = 3.12, SD = 1.62

Treatment Group
Before        M = 1.54, SD = 1.01
Cyberball     M = 1.93, SD = 1.11
Betrayal      M = 3.04, SD = 1.71

Pre-treatment ratings didn't differ between men and women, but post-treatment Cyberball and Betrayal ratings showed crossover interactions, meaning the effects were opposite in men and women. On placebo, women had higher social pain ratings than men. On Advil, women's ratings dropped but men's increased. Since women are generally lighter than men, these analyses controlled for weight effects on dosage, since everyone got 400 mg.

- click on image for a larger view -

So the women responded in the predicted way, based on past research. But the men did not. Did the subjects' expectations influence the results? The study description specifically stated it “was being conducted to examine the link between physical and emotional pain.” In contrast, the Tylenol studies were a little more vague: “advertised as a general assessment of the cognitive and emotional impacts of acetaminophen” for the study of existential angst, and “Tylenol and social cognition” for the blunted emotion experiment.

The authors proposed a social cognitive model:

Because men are comparatively likely to curb their emotional pain, it is possible that men who take a physical pain reliever will display a disinhibition effect. That is, when men take a physical pain reliever, their cognitive response may act to blunt or inhibit their tendency to suppress their emotional pain. The cognitive processes underlying such a disinhibition effect are akin to [a] reverse placebo effect.

This didn't make sense to me, but then I found a paper that manipulated expectancy for physical pain relief in a within-subject design (Butcher & Carmody, 2012). The sample size was small (10 men, 10 women), but the participants came in once a week for 4 weeks to experience all of these conditions:

Subjects told they were receiving ibuprofen and received ibuprofen (positive expectancy).
Subjects told they were receiving ibuprofen but received placebo (positive expectancy).
Subjects told they were receiving placebo but received ibuprofen (negative expectancy).
Subjects told they were receiving placebo and received placebo (negative expectancy).

The subjects were exposed to experimentally-induced pain (electrical stimulation of the earlobe) and assessed for analgesia response (change in pain tolerance). Ibuprofen dose was 800 mg (4 tablets).

Pain tolerance in women did not differ for any of the four conditions. But pain tolerance in men conformed to their positive expectations: pain tolerance increased in both the ibuprofen and the placebo conditions when told they would receive ibuprofen. There was also negative placebo effect (a true negative placebo effect), but this was not statistically significant.

What does this mean for social pain? Although the Butcher and Carmody (2012) findings need replication, Vangelisti et al.'s disinhibition model seems to be based on expectation, not on a direct relationship between physical and social pain.

Other quibbles include the between-subjects design and small or marginal effects for some of the statistical comparisons — both of which are true for the Psych Sci Tylenol studies with their overblown interpretations. For instance, one headline from APS had this fun cure: Experiencing Existential Dread? Tylenol May Do the Trick.

To their credit, Vangelisti et al. didn't oversell their results.⁵ An article in The Alcade, the University of Texas alumni magazine, asked the same question as the NY Times neuroessay —Can Ibuprofen Mend a Broken Heart?— but arrived at a more prudent answer.

So does that mean we should all start popping ibuprofen whenever our feelings are hurt? Absolutely not, says Vangelisti.“In time, we may see psychiatrists prescribing painkillers for social pain—judiciously, I hope—but right now there are too many unanswered questions that our study has raised for this to be considered a viable treatment.”

I'll leave you with this quote from Woo et al. (2014), who found that representations of physical and social pain are clearly separable in the brain.

[Our] findings demonstrate that separate representations underlie pain and rejection despite common fMRI activity at the gross anatomical level. Rather than co-opting pain circuitry, rejection involves distinct affective representations in humans.

Thanks to @thebyrdlab for linking to the Advil paper.

Footnotes

¹ In the Cyberball fMRI study of Experiment 2 (Dewall et al., 2010), the participants on placebo vs. those on drug did not differ in their social distress ratings after being excluded from the game.

² Not surprisingly, I disagree with all of these overblown interpretations. See Acetaminophen Probably Isn't an "Empathy Killer".

³ By and large, social psychology researchers don't seem particularly concerned about the mechanisms of action of these drugs. I haven't written about ibuprofen, but see Does Tylenol Exert its Analgesic Effects via the Spinal Cord?

⁴ I thought the PANAS was on a 5-point scale, but the paper said 7-point.

⁵ On the other hand, we have this unfortunate statement:

"It's possible that taking physical pain relievers provides men with more cognitive resources to express the pain they feel," said Vangelisti. "There's some evidence that, for men, the part of the brain that enables them to regulate their emotions is linked to the part of the brain that processes physical and social pain. If that's the case, taking a physical pain reliever may affect men's ability to hide or suppress their social pain."

References

Butcher, B., & Carmody, J. (2012). Sex differences in analgesic response to ibuprofen are influenced by expectancy: A randomized, crossover, balanced placebo-designed study. European Journal of Pain, 16 (7), 1005-1013. DOI: 10.1002/j.1532-2149.2011.00104.x

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 social pain: behavioral and neural evidence. Psychol Sci. 21:931-7.

Mogil JS, & Bailey AL (2010). Sex and gender differences in pain and analgesia. Progress in brain research, 186, 141-57 PMID: 21094890

VANGELISTI, A., PENNEBAKER, J., BRODY, N., & GUINN, T. (2014). Reducing social pain: Sex differences in the impact of physical pain relievers. Personal Relationships, 21 (2), 349-363 DOI: 10.1111/pere.12036

Walker JS, Carmody JJ. (1998). Experimental pain in healthy human subjects: gender differences in nociception and in response to ibuprofen. Anesth Analg. 86(6):1257-62.

Woo CW, Koban L, Kross E, Lindquist MA, Banich MT, Ruzic L, Andrews-Hanna JR, & Wager TD (2014). Separate neural representations for physical pain and social rejection. Nature Communications 5: 538.

Oh oxytocin, you cuddly hug drug, you fine upstanding moral molecule, why are you so maligned by critics? That's because you're overrated, and misunderstood by those who look to you as a beacon of empathy, trust, love, peace, and prosperity. Sure, you're all about pair bonding in monogamous prairie voles — we have no beef with rigorous animal studies — but in humans, you're downright complicated. Yes, you can be magnanimous and romantic some of the time. But you're not always a moral molecule. You can promote antisocial behaviors such as envy and schadenfreude and aggressive tendencies. And even in voles, too much of a good thing can backfire.

Four new papers on oxytocin in humans have been published this week.¹ Collectively, there's something for nearly everyone to complain about:

Intranasal oxytocin administration – assumptions about mechanism of action
Ridiculously large numbers of variables – ripe for p-hacking
Small n candidate gene studies – not replicable
Studies of candidate gene × environment interactions – also not replicable
Epigenetics – now nearly a woo word (The Trouble with Epigenetics, Part 1 and Part 2)
Sex differences – studies often overly essentialist (although in this case, for good reason)

Oxytocin and Epigenetics

Of the four, the one that has garnered the most media attention is on epigenetics and sociability (Haas et al., 2016, published in PNAS). DNA methylation in the promoter region of the oxytocin gene (OXT) was quantified as an indicator of OXT expression. Lower methylation is presumably associated with higher OXT expression, and all sorts of sociable characteristics such as “more secure attachment styles, improved ability to recognize emotional facial expressions, greater superior temporal sulcus activity during two social-cognitive functional MRI tasks, and larger fusiform gyrus gray matter volume.”

Are these findings plausible from a mechanistic standpoint? Assuming that OXT expression was higher in the sociable sorts, which in turn assumes that methylation in saliva is a good proxy for expression in brain, how did “more“ oxytocin have all these effects? And on what time scale?

The Daily Mail was predictably credulous and hyperbolic,² using terms like “breakthrough”, “a ‘chatty’ gene which makes people sociable”, and [the kicker] “new treatments for autism”. The autism reference comes from the paper itself (and from the university press release):

"Participants with greater methylation of the OXT gene were less accurate in describing the emotional states of the people they saw in pictures," [first author Brian W. Haas] said. "That's a typical characteristic associated with autism, for example."

But it's not that simple. Let's look at the relationship between emotion recognition and OXT methylation. The task was to view 10 sec video clips of human faces morphing from neutral expressions to happy, sad, fearful and angry, and to identify the emotion as soon as it was detected. This led to 10 different dependent measures: reaction time and accuracy for each of the individual expressions, and for the mean of all expressions. The (conservative) Bonferroni corrected significance level is α = .05/10 = .005 [but the authors said it should be .025]. Overall accuracy is shown below.

Not all that impressive, eh? Another scatterplot was based on self-report questionnaires. The association between an anxious and insecure attachment style and OXT methylation fared better (p=.005), but the association between OXT methylation and avoidant attachment style was not significant. Why?

Silencing a gene promotes human sociability https://t.co/cUKaATnAnv"magical" omics problem strikes again @PNASNews pic.twitter.com/yXRxJCxRzg
— Eric Topol (@EricTopol) June 20, 2016

Oxytocin and Spirituality

The next paper, on oxytocin and spirituality (Van Cappellen et al., 2016), has gained traction on Twitter. Dan Quintana has already written an inspired blog post about it (Spray and pray: Does intranasal oxytocin increase spirituality?), so you should go and check it out. Dan has published at least 7 papers on oxytocin, so his critique is more informed than mine. I'll highlight his main points and then add a few of my own.

Good news:

First, the authors should be congratulated for posting the data for the paper on Open Science Framework (OSF). It’s great to see this dataset online considering the hype surrounding oxytocin...

Here’s a few other things I liked about this paper (or a list of things that oxytocin papers often don’t do): i) Effect sizes and confidence intervals are reported, ii) the alpha for the main outcome was adjusted for multiple tests, and iii) the placebo spray was a “true” placebo that contained all the same ingredients as the oxytocin spray, except the actual oxytocin (i.e, not just saline spray). It’s much easier to taste the difference between oxytocin and saline so this is an important point.

Bad news, genetics:

The authors included an “exploratory analysis” (their words in the intro and a section of the results) of three oxytocin pathway polymorphisms (rs53576, rs6449182, and rs3796863). There are about 10–15 candidate oxytocin pathway SNPs the could be analysed so it’s not clear why these three were chosen rather than others. Sure, rs53576 has been studied a lot, but so have many other oxytocin pathway SNPs (especially rs2254298).

Bad news, religious affiliation:

...it appears that there was a main effect of condition on both spirituality scales. However, a close read of table 1 reveals that this was after correcting for religious affiliation. Now this is reasonable when you consider that someone who’s an atheist is likely to report that spiritually is “not at all” important in my life. In fact, the data bears this out as the average spiritual rating (which can range from 0 to 7) for the atheist/agnostic group was 1.97 during the experimental visit and 1.88 a week later, whereas the average rating for the religiously affiliated group was 4.8 during the first visit and 4.9 during the second visit (I was able to calculate this from their posted dataset — isn’t open data great!).

It’s plausible for someone who identifies as agnostic or atheist to report “not at all” on both occasions — and many did. In fact, when you look at the agnostics/atheist group alone, there’s a statistically significant increase in spirituality after oxytocin compared to placebo both during the lab visit and 1 week later... However, there was no significant difference when assessing the religiously affiliated group.

@sarcastic_f the apostles were just brimming with oxytocin @edyong209 @WiringTheBrain @sTeamTraen @CoyneoftheRealm
— My Cousin Amygdala (@CousinAmygdala) June 20, 2016

(or not)

Dr. Quintana concluded his post by advocating pre-registration and replication.

Oxytocin, Meditation, Positive Emotions, Negative Emotions, Oxytocin Receptor Gene (OXTR rs53576), CD38 (rs6449182 and rs3796863), Religious Affiliation, and Spirituality After Intranasal Oxytocin Administration in 83 Predominantly White Middle Aged Men

My unwieldy subheading includes only a small subset of the 161 variables in the study of Van Cappellen et al. (2016). Granted, some of these variables (e.g, the answers to individual items on questionnaires) were never examined in isolation — they were part of a composite score. Nonetheless, I think we can tick the “Ridiculously large numbers of variables” bullet point. We also have “Intranasal oxytocin administration” and “Small n candidate gene studies” (with n's below 20 in some cells). Bonus bullet point of “Between subjects design” is a personal pet peeve. I'd really like to see some within-subjects studies.

And there's a mysterious element to some of the data not included in this paper:

The data presented here are part of a larger study testing additional hypotheses not related to the present ones. For the larger study and to test a larger model, based on power calculation, a sample of 240 participants was targeted with a breakdown female-male of 125-115... Data collection ... stopped at 239 but despite recruitment effort, the sample is skewed toward females. This report focuses only on the 83 males who took part in the study... Growing evidence suggests that the effects of oxytocin are different for males and females (Feng et al., 2015) and most of the current evidence on intranasal oxytocin’s psychological effects, which support the current hypotheses, come from studies with exclusively male samples. A separate analysis of female participants, controlling for a series of additional variables related to natural variations in oxytocin is ongoing.

The larger study also included a task using Chinese pictographs, since the ability to read Chinese pictographs was an exclusionary criterion “applied to another task unrelated to the current investigation.” I'm generally not a study pre-registration evangelist, but one can really see the point here.

In Oxytocin We Doubt

I'll conclude on a pessimistic note (what else is new?). Some highly critical reviews of the oxytocin literature have appeared recently.

Evans SL, Dal Monte O, Noble P, Averbeck BB. Intranasal oxytocin effects on social cognition: a critique. Brain Res. 2014 Sep 11;1580:69-77.

Leng G, Ludwig M. Intranasal Oxytocin: Myths and Delusions. Biol Psychiatry. 2016 Feb 1;79(3):243-50.

Despite widespread reports that intranasal application of oxytocin has a variety of behavioral effects, very little of the huge amounts applied intranasally appears to reach the cerebrospinal fluid. However, peripheral concentrations are increased to supraphysiologic levels, with likely effects on diverse targets including the gastrointestinal tract, heart, and reproductive tract. The wish to believe in the effectiveness of intranasal oxytocin appears to be widespread and needs to be guarded against with scepticism and rigor. Preregistering trials, declaring primary and secondary outcomes in advance, specifying the statistical methods to be applied, and making all data openly available should minimize problems of publication bias and questionable post hoc analyses. Effects of intranasal oxytocin also need proper dose-response studies, and such studies need to include control subjects for peripheral effects, by administering oxytocin peripherally and by blocking peripheral actions with antagonists. Reports in the literature of oxytocin measurements include many that have been made with discredited methodology. Claims that peripheral measurements of oxytocin reflect central release are questionable at best.

--- there is a retort to Leng and Ludwig by Quintana and Woolley: Intranasal Oxytocin Mechanisms Can Be Better Understood, but Its Effects on Social Cognition and Behavior Are Not to Be Sniffed At.

Walum H, Waldman ID, Young LJ. Statistical and Methodological Considerations for the Interpretation of Intranasal Oxytocin Studies. Biol Psychiatry. 2016 Feb 1;79(3):251-7.

...Our conclusion is that intranasal OT studies are generally underpowered and that there is a high probability that most of the published intranasal OT findings do not represent true effects. Thus, the remarkable reports that intranasal OT influences a large number of human social behaviors should be viewed with healthy skepticism...

McCullough ME, Churchland PS, Mendez AJ. Problems with measuring peripheral oxytocin: can the data on oxytocin and human behavior be trusted?Neurosci Biobehav Rev. 2013 Sep;37(8):1485-92.

It might be time to order Liquid Trust...

Footnotes

¹ Actually, the number of articles is closer to ten, but I'll just list these four for now.

Van Cappellen P, Way BM, Isgett SF, Fredrickson BL. Effects of Oxytocin Administration on Spirituality and Emotional Responses to Meditation. Soc Cogn Affect Neurosci. 2016 Jun 17. PMID: 27317929.
Haas BW, Filkowski MM, Cochran RN, Denison L, Ishak A, Nishitani S, Smith AK. Epigenetic modification of OXT and human sociability. Proc Natl Acad Sci. 2016 Jun 20. PMID: 27325757.
Simons RL, Lei MK, Beach SR, Cutrona CE, Philibert RA. Methylation of the oxytocin receptor gene mediates the effect of adversity on negative schemas and depression. Dev Psychopathol. 2016 Jun 20:1-12. PMID: 27323309.
Gao S, Becker B, Luo L, Geng Y, Zhao W, Yin Y, Hu J, Gao Z, Gong Q, Hurlemann R, Yao D, Kendrick KM. Oxytocin, the peptide that bonds the sexes also divides them. Proc Natl Acad Sci. 2016 Jun 20. PMID: 27325780.

² Hyperbolic and inaccurate. They called methyl groups "proteins".

References

Haas BW, Filkowski MM, Cochran RN, Denison L, Ishak A, Nishitani S, Smith AK. Epigenetic modification of OXT and human sociability. Proc Natl Acad Sci. 2016 Jun 20. PMID: 27325757.

Van Cappellen P, Way BM, Isgett SF, Fredrickson BL. Effects of Oxytocin Administration on Spirituality and Emotional Responses to Meditation. Soc Cogn Affect Neurosci. 2016 Jun 17. PMID: 27317929.

Further Reading