Friday, April 11, 2014

Let's play "Guess the Developmental Cognitive Neuroscience Speaker" (soundbytes from #cns2014)


Another CNS meeting, another series of delayed blog posts from The Neurocritic. Long in the vanguard of the slow blogging movement, these conference recaps have attained the cult status of unplanned obsolescence.



Without further ado, let's begin our walk down memory lane...

The 21st Annual Cognitive Neuroscience Society Meeting was held in Boston from April 48, 2014. We'll kick off our recapping festivities with a contest of "Name that Soundbyte!" from an invited symposium on how developmental cognitive neuroscience can (and cannot) inform policy.


Invited Symposium Session 1
Sunday, April 6 3:00 - 5:00 pm, Grand Ballroom Salon A-F


The Broader Applicability of Insights from Developmental Cognitive Neuroscience

Chair: Silvia Bunge, UC Berkeley
Speakers: John D. E. Gabrieli, Margaret Sheridan, Martha J. Farah, Helen J. Neville


The burgeoning field of developmental cognitive neuroscience is yielding important insights into how the human brain develops and changes with experience. These findings are proving to be of great interest not only to other scientists, but also to practitioners and policymakers from various corners of society. What have we learned so far that warrants consideration by those in a position to shape policy and practice in education, healthcare, or the judicial system? In this symposium, leading cognitive neuroscientists will discuss the potential applications of their research.


Given the list of symposium speakers, can you name who said each of these quotes? [or close paraphrases?]  Be sure to chime in by leaving your best guesses in the comments.

(1) “I am not a neurochauvinist”

(2) “U.S. Prison Experiment”

(3) “evidence-based politics”

(4) “IMHO still premature to dictate policy based on neuro”

(5) “Here's where going ‘neuro’ earns its keep”

(6) ‘descriptive’ often considered derogatory in science

(7) SCHOOLS MATTER!

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Sunday, March 30, 2014

Contest to Reduce Implicit Racial Bias Shows Empathy and Perspective-Taking Don't Work



NCAA college basketball isn't the only hot competition involving a team from the University of Virginia.  UVa Psychology Professor Brian Nosek is one of three founders of Project Implicit, a collaborative nonprofit dedicated to the study of implicit social cognition — how unconscious thoughts and feelings can influence attitudes and behavior.

Prof Nosek is also heavily involved in the Open Science and Replication movements. Along with graduate student Calvin Lai, he led a multinational group of 22 other researchers in a competition to see who could devise the best intervention to reduce racial bias scores on a widely administered implicit test, the race IAT (Lai et al, 2014).

The Implicit Association Test (IAT) is a mainstay of social psychology research that assesses implicit (unconscious) attitudes towards outgroups (based on race, sexual orientation, body size, age, etc.), stereotypes (e.g., men are in science, women are in arts/humanities), opposing ideologies (e.g, Democrat vs. Republican), and a staggering array of other binary preferences (Classical-Hip hop IAT, Astrology-Science, Britney Spears-50 cent, Boxers-Briefs, Harry Potter-Lord of the Rings and on and on). 

Or does it... ? There have been some vocal critics of the IAT over the years who have questioned what the test actually measures. I'll return to this point later, but for now let's look at the impressive aspects of the new paper.

Performance on the Black-White IAT was compared after 17 brief interventions aimed at changing pro-White bias (and a "faking" condition) relative to a control condition of no pre-test intervention. Participants were over 20,000 non-Black individuals registered at the Project Implicit website, randomized into groups of 300-400. Most of the interventions were tested in four different studies. The contest rules allowed changes to the design between studies. The goal was to lower pro-White bias scores to the point of no preference between Blacks and Whites.

In the IAT, participants classify faces as Black or White and words as good or bad. Some blocks contain only faces or only words. The two critical conditions are shown in the figure above. The stimulus-response mappings are rotated in different blocks to either reinforce stereotypes (bottom) or go against stereotype (top). In the Stereotype condition, participants press the same key when they see White faces or “good” words. They press the other key when they see Black faces or “bad” words. Most White participants (and many African Americans) show a pro-White “preference” or bias, with faster responses when White/good and Black/bad are mapped to the same key (than vice versa).

Conversely, in the Against Stereotype condition, Black faces and positive words are mapped to one key, and White faces and negative words are mapped to the other key. In essence, this induces a response conflict similar to that seen in many classic cognitive psychology tasks such as the color-word Stroop task, e.g. BLUE (say “red”) and the Eriksen flanker task, e.g. ← ← → ← ← (press right button). Slower response times in the IAT conflict conditions has been interpreted as an implicit bias against Black people (Greenwald et al., 2009), although one could argue that executive control abilities play a role here, just as they do in the Stroop task (Siegel et al, 2012).1


The Interventions

The interventions were divided into six different descriptive categories. Although the descriptions were based on existing hypotheses in the literature, they do not imply the operation of any specific psychological mechanism. The interventions had to be brief in length (5 min or less), yield interpretable scores, and have a low attrition rate. See Appendix 1 at the end of this post for a detailed list.

(1) Engage with others’ perspectives: imagine the thoughts, feelings, and actions of Black individuals (Interventions #1–3).

(2) Exposure to counterstereotypical exemplars: assigned to fictional groups with positive Black ingroup members and/or negative White outgroup members; OR think about famous Black people and infamous White people (Interventions #4–8).

(3) Appeals to egalitarian values: activate egalitarian goals (e.g., thinking about failures to be objective or egalitarian); OR think about multicultural values (Interventions #9–13).

(4) Evaluative conditioning: strengthen counterstereotypical associations by pairing White faces with Bad words and Black faces with Good words (Interventions #14 and #15).

(5) Inducing emotion: the positive emotion of elevation (Intervention #16).

(6) Intentional strategies to overcome biases: provide strategies to override or suppress the influence of automatic biases, rather than trying to shift associations directly (Interventions #17 and #18).


To reveal my own a priori biases regarding these descriptive categories, I favor (6) Intentional strategies to overcome biases, which I have written about previously (in 2008). These were interventions #17 Using Implementation Intentions, and #18 Faking the IAT as proposed by Calvin K. Lai, the first author of the manuscript.

Results indicated that nine of the interventions were effective, and nine were ineffective. The interventions that tried to change attitudes (Appeals to egalitarian values), increase empathy or perspective-taking (Engage with others’ perspectives), or elicit an elevated sense of morality (Inducing emotion - Haidt) were completely ineffective.

I note here that the failed interventions all tried to challenge the racially biased attitudes and prejudice purportedly measured by the IAT. These interventions are below the red line in the figure below.

- click on image for a larger view -


Figure 1 (modified from Lai et al, 2014). Effectiveness of interventions on implicit racial preferences, organized from most effective to least effective. Cohen’s d = reduction in implicit preferences relative to control; White circles = the meta-analytic mean effect size; Black circles = individual study effect sizes; Lines = 95% confidence intervals around meta-analytic mean effect sizes. IAT = Implict Association Test; GNAT = go/no-go association task.


Some of the most effective interventions showed variability across studies, because the parameters were altered between studies (which was allowed). Importantly, some of the interventions included multiple manipulations. The top three, Vivid Counterstereotypic Scenario, Practicing an IAT With Counterstereotypical Exemplars, and Shifting Group Boundaries Through Competition all employed Implementation Intentions in addition to the primary intervention.

What are Implementation Intentions? [in brief, think “Black = good”]
The mechanism connects an environmental cue with the goal intention, making associations between the behavior and the cue more accessible in memory. ... The task gave participants a short tutorial on how to take the IAT and informed them about the tendency for people to exhibit an implicit preference for Whites compared with Blacks. Participants were then asked to commit themselves to an implementation intention by saying to themselves silently, “I definitely want to respond to the Black face by thinking ‘good.’” 

On its own, this manipulation was effective in reducing bias scores (p = .032, d = .19). The effect size was enhanced by allowing participants to practice the task before the instructions were given (p = .00037, d = .32). In other words, once subjects were even superficially familiar with the task, being told to think “Black = good” significantly reduced pro-white sentiment (i.e., IAT scores).

This intervention is remarkably similar to my previous anecdotal findings (n=1) for the Human or Alien? test and the Dead or Alive? test. My 2008 results are below. I showed similar effects for the Black-White test and the Women in Science test, but I couldn't find the results for those.


The Neurocritic is Human AND Alien. Coming soon: “Tips for Manipulating the IAT.”

You have completed the study.
Your Result

Your data suggest little to no automatic identification with Human compared to Alien.

If your results, provided above, indicate a stronger identity with alien relative to human, then you are probably an alien.


The Neurocritic is NEITHER Dead NOR Alive. Or both Dead AND Alive. Plus, as promised, today we'll cover “Tips for Manipulating the IAT.”

You have completed the study.
Your Result

Your data suggest little to no automatic identification with Alive compared to Dead.

Your results, summarized above, are an implicit indicator of whether you are alive or dead. Implicit measures are superior to self-report because the latter is notoriously unreliable. People may report being alive because social pressures suggest that it is more desirable to be alive. Also, people may not have introspective access to their animate-status, making such self-report untrustworthy.

Super Secret Tip for Manipulating the IAT
My “faking” strategy was simple, and relied on neither deliberate slowing of response times nor a long-standing affiliation with aliens. When SELF and ALIEN were mapped to the same key, I merely said to myself, “I'm an alien.” This strategy was transient, applied only when those stimulus-response mappings were the same, not when SELF and ALIEN were mapped to different keys. I used the same strategy for the Dead or Alive IAT. In both cases, I responded as quickly and as accurately as possible.

Here, what I'm calling “faking” is the Using Implementation Intentions instructions (and not the Faking the IAT intervention of Lai et al, 2014). Again, the top three contest winners combined this strategic feature with another manipulation, as noted by the authors:
The three most effective interventions appear to leverage multiple mechanisms to increase their impact on implicit preferences...  The most effective intervention, Vivid Counterstereotypic Scenario, involved the participant as the subject of the story, had the participant imagine his- or herself under a highly threatening life-or-death situation, exposed participants to counterstereotypical exemplars (malevolent White villain, dashing Black hero), and provided strategies to overcome bias (goal intentions to associate good with Black and bad with White) to reduce implicit preferences.

This vivid intervention is illustrated by using a TV example in Appendix 2. [Note: participants in the actual experiment read a story; they did not watch an episode of Criminal Minds.] The strategy was receiving the instruction that “the task following the story (i.e., the race IAT) was supposed to affirm the associations: White = Bad, Black = Good.”

The conclusion I draw from this impressive project is that performance on the IAT is subject to strategic control, supporting the notion that the IAT is not a pure measure of implicit attitudes. Even a brief training session is sufficient to reduce (or reverse) stereotypical preferences and associations that are supposed to be unconscious in nature (also see Hu et al., 2012; Siegel et al, 2012).



Further Reading

Open Science Framework entry on Reducing Implicit Racial Preferences: I. A Comparative Investigation of 17 Interventions

Project Implicit

"The Disturbing World of Implicit Bias..."

Human or Alien?

Human, All Too Human (AND Alien)

I'm Alive I'm Dead

Lie To Me on the Autobiographical Implicit Association Test

The Lovely Dr. ARINA K. BONES, PhD Strikes Again!


Footnote

1 Another common paradigm in cognitive psychology, semantic priming, can explain a goodly portion of the effect as well. In one study, the bias shown in IAT scores was based on statistical co-occurrence of words and concepts in the ambient culture and not on prejudiced attitudes. A discussion of those findings is beyond the scope of this post.


References

Greenwald AG, Poehlman TA, Uhlmann EL, Banaji MR. (2009). Understanding and using the Implicit Association Test: III. Meta-analysis of predictive validity. J Pers Soc Psychol. 97:17-41.

Hu X, Rosenfeld JP, Bodenhausen GV. (2012). Combating automatic autobiographical associations: the effect of instruction and training in strategically concealing information in the autobiographical implicit association test. Psychol Sci. 23:1079-85.

Lai CK, Marini M, Lehr SA, Cerruti C, Shin JE, Joy-Gaba JA, Ho AK, Teachman BA, Wojcik SP, Koleva SP, Frazier RS, Heiphetz L, Chen EE, Turner RN, Haidt J, Kesebir S, Hawkins CB, Schaefer HS, Rubichi S, Sartori G, Dial CM, Sriram N, Banaji MR, & Nosek BA (2014). Reducing Implicit Racial Preferences: I. A Comparative Investigation of 17 Interventions. Journal of Experimental Psychology. General PMID: 24661055

Siegel EF, Dougherty MR, Huber DE (2012). Manipulating the role of cognitive control while taking the implicit association test. Journal of Experimental Social Psychology 48: 1057–1068.



Appendix 1

(1) Engaging with others’ perspectives
  • Training Empathic Responding
  • Perspective Taking
  • Imagining Interracial Contact 

(2) Exposure to counterstereotypical exemplars
  • Vivid Counterstereotypic Scenario
  • Practicing an IAT With Counterstereotypical Exemplars
  • Shifting Group Boundaries Through Competition
  • Shifting Group Affiliations Under Threat
  • Highlighting the Value of a Subgroup in Competition

(3) Appeals to egalitarian values
  • Priming Feelings of Nonobjectivity
  • Considering Racial Injustice
  • Instilling a Sense of Common Humanity
  • Priming an Egalitarian Mindset
  • Priming Multiculturalism

(4) Evaluative conditioning
  • Evaluative Conditioning
  • Evaluative Conditioning With the GNAT

(5) Inducing emotion
  • Inducing Moral Elevation

(6) Intentional strategies to overcome biases
  • Using Implementation Intentions
  • Faking the IAT


Appendix 2 - Vivid Counterstereotypic Scenario
...participants read an evocative story told in second-person narrative in which a White man assaults the participant and a Black man rescues the participant ( “With sadistic pleasure, he beats you again and again. First to the body, then to the head. You fight to keep your eyes open and your hands up. The last things you remember are the faint smells of alcohol and chewing tobacco and his wicked grin”).

In the therapist's office.



Escaped and running down the hallway.



Stalked by evil white sadist.



Caught and choked by evil white sadist.



FBI Profiler Derek Morgan to the rescue.



Perp in custody at the station.



The end.

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Sunday, March 23, 2014

Hippocampal Pathology in California Sea Lions with Domoic Acid-Induced Temporal Lobe Epilepsy


In 1987, over 100 Canadians became ill after eating cultivated mussels from Prince Edward Island. Symptoms included the typical gastrointestinal issues, but serious neurological findings such as disorientation, confusion, and memory loss were also observed (Perl et al., 1990). In the worst cases, the patients developed seizures or went into coma. Three elderly people died. The cognitive changes were persistent, and had not resolved within a two year follow-up.

The toxin was identified as domoic acid, which received the well-deserved moniker of Amnesiac Shellfish Poison. Domoic acid is a potent excitatory amino acid that activates kainate and AMPA receptors, the binding sites for the ubiquitous excitatory neurotransmitter glutamate. It acts as an excitotoxin by overstimulating these receptors, causing a flood of calcium ions into the cells. Particularly vulnerable are neurons in medial temporal lobe structures such as the amygdala and the hippocampus, which is critical for memory.

Postmortem examination of four brains revealed hippocampal pathology that could account for the clinically significant anterograde amnesia seen in other (still living) patients (Teitelbaum et al., 1990). The pattern of neuronal loss was consistent with the damage observed in kainic acid animal models of epilepsy.



Fig. 3 (modified from Teitelbaum et al., 1990).  Panel A: Section of hippocampus from a patient who died 24 days after mussel-induced intoxication, showing severe loss of neurons in all fields except CA2 (arrow), and tissue collapse is evident in part of field CA1 (double arrow).  Panel B: Control Subject.


What was the source of the Amnesiac Shellfish Poison that had accumulated in the mussels?  A "red tide" of phytoplankton created a harmful algal bloom that produced domoic acid, which accumulates not only in shellfish but also in fish such as anchovies and sardines.
This is where the California sea lions make their noisy entrance...

click here to play mp3

Bonus! Live Sea Lion Web Cam at Pier 39 in San Francisco.


Domoic Acid Toxicity in California Sea Lions

The Marine Mammal Center in Sausalito, California rescues and rehabilitates sick, stranded, and malnourished marine mammals, including seals, sea lions, and cetaceans. An up-to-date list of their current patients is available here. They are the premiere institution for the diagnosis, treatment, and scientific study of domoic acid toxicity in California sea lions:
The Marine Mammal Center was the first group to definitively diagnose DA posioning in marine mammals because of a large outbreak in California sea lions in 1998. In September 2004, the Center received a grant from the Oceans and Human Health Initiative to study the long term effects of domoic acid in sea lions. This project studied the impact of DA on health, survival, and reproduction. Part of this project focused on the neurological effects of DA. Effects were evaluated using magnetic resonance imaging (MRI), cognitive behavior tests (how the animal behaves), and histopathology (tissue samples from dead animals).

Their website on the topic is highly recommended, and contains links to published papers such as Magnetic resonance imaging quality and volumes of brain structures from live and postmortem imaging of California sea lions with clinical signs of domoic acid toxicosis [PDF].

Most recently, a team of researchers from Stanford University collaborated with the Marine Mammal Center to conduct a detailed neuropathological investigation of the brains of sea lions who suffered from seizures due to domoic acid toxicity (Buckmaster et al., 2014). Unfortunately, this is not an uncommon occurrence, since the current census of pinniped patients includes five sea lions diagnosed with acute domoic acid toxicity. In the chronic state, the animals can experience recurrent seizures, leading to a failure to thrive and poor prognosis. The authors hypothesize that the animals develop temporal lobe epilepsy, which can serve as an unfortunate accidental model of temporal lobe epilepsy in humans.

The researchers examined the brains of 14 domoic acid-exposed (DA) animals and 9 control animals. Five of the affected sea lions were admitted in status epilepticus, a state of continual seizure that can cause severe brain damage and even death. The study expanded on earlier work by using stereological methods to obtain an unbiased estimate of the total number of neurons in each hippocampus (left and right hemispheres).

In control sea lions, Buckmaster and colleagues (2014) estimated that each hippocampus contains over 6 million neurons! For the comparative hippocampal anatomy aficionados, sea lions had a relatively small proportion of neurons in the dentate gyrus granule cell layer relative to other mammals (i.e., macaque monkeys, squirrel monkeys, dogs, rats, and mice), and the granule cell layer was thinner than in other species.




Importantly, the authors observed significant neuronal loss in the DA-exposed animals, with substantial variation across the hippocampal subfields (see Fig. 3). And interestingly, the damage was unilateral in most cases: the left hippocampus in four, the right hippocampus in seven, and bilaterally in only three.



Fig. 1 (modified from Buckmaster et al., 2014). Nissl-stained cell bodies in the hippocampi from (A) control and (B-D) chronic domoic acid sea lions. Note the increasing levels of neuron loss in the three chronic DA cases. All were admitted in status epilepticus with DA toxicity. In (A), lines indicate border between the hilus (h) and CA3 field. g, granule cell.


In addition, the authors compared the pattern of neuronal loss in sea lions to that observed in human patients with temporal lobe epilepsy, using tissue obtained at autopsy or after temporal lobe resection (for seizure control):
Substantial neuron loss was evident in all hippocampal subfields of patients with temporal lobe epilepsy and chronic DA sea lions compared with controls (Fig. 3B). In sea lions neuron loss was more severe in the hilus, CA3, and CA2 subfields compared with humans. In humans neuron loss was more severe in CA1. Sea lions and humans displayed similar levels of granule cell loss.


Fig. 3 (modified from Buckmaster et al., 2014). Neuron loss in hippocampal subregions. (B) Neurons per affected hippocampus for chronic DA sea lions (mean + SEM) and neuron densities reported in 11 previously published studies for patients with temporal lobe epilepsy. Symbols indicate results from individual studies. Bars indicate averages.


As we saw in the earlier cases of Amnesiac Shellfish Poisoning in Canada, the CA1 region of the hippocampus was especially vulnerable, and this is also true in cases of hypoxia or anoxia. However, it's notable that significant neuron loss was observed throughout the hippocampus.

Why the difference from sea lion CA1? The reasons are unclear. Nonetheless, when examining the brain as a whole, it is remarkable that the hippocampus shows such qualitatively similar pathology in sea lions and humans poisoned by domoic acid, and humans with temporal lobe epilepsy. The authors speculate that the misfortune of chronic DA sea lions may yield an opportunity to test new anti-seizure treatments, for the benefit of both marine and terrestrial mammals.


References

Buckmaster, P., Wen, X., Toyoda, I., Gulland, F., & Van Bonn, W. (2014). Hippocampal neuropathology of domoic acid-induced epilepsy in California sea lions. Journal of Comparative Neurology, 522 (7), 1691-1706 DOI: 10.1002/cne.23509

Perl, T., Bédard, L., Kosatsky, T., Hockin, J., Todd, E., & Remis, R. (1990). An Outbreak of Toxic Encephalopathy Caused by Eating Mussels Contaminated with Domoic Acid. New England Journal of Medicine, 322 (25), 1775-1780 DOI: 10.1056/NEJM199006213222504

Teitelbaum, J., Zatorre, R., Carpenter, S., Gendron, D., Evans, A., Gjedde, A., & Cashman, N. (1990). Neurologic Sequelae of Domoic Acid Intoxication Due to the Ingestion of Contaminated Mussels. New England Journal of Medicine, 322 (25), 1781-1787 DOI: 10.1056/NEJM199006213222505

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Friday, March 14, 2014

Brains on Film: In the Scanner (featuring Sophie Scott and the Dead Salmon)

Everyone knows the hazards of bringing metal objects into the MRI scanner room (right?). Now we have a lovely musical reminder of why this is such a bad idea...





In the Scanner is an entry in the Brains on Film contest, a Brain Awareness Week event sponsored by the UCL Institute of Cognitive Neuroscience. The film was made by Sophie Meekings, Dana Boebinger and Nadine Lavan.

Featuring Lucy's amazing voice, a spoken word introduction by Professor Sophie Scott, and a cameo appearance by none other than the Atlantic salmon — of “oh yes you better do corrections for multiple comparisons” fMRI fame (Bennett et al. 2009 - PDF).


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Wednesday, March 05, 2014

Warning about Ketamine in the American Journal of Psychiatry


The dissociative anesthetic and ravey club drug ketamine has been hailed as a possible “miracle” cure for depression. In contrast to the delayed action of standard antidepressants such as SSRIs, the uplifting effects of Special K are noticeable within an hour. “Experimental Medication Kicks Depression in Hours Instead of Weeks,” says the National Institute of Mental Health. NIMH has been bullish on ketamine for years now. Prominent researchers Duman and Aghajanian called it the “the most important discovery in half a century” in a recent Science review.

But in 2010, I pondered whether this use of ketamine was entirely positive:
Drawbacks include the possibility of ketamine-induced psychosis (Javitt, 2010), limited duration of effectiveness (aan het Rot et al., 2010), potential long-term deleterious effects such as white matter abnormalities (Liao et al., 2010), and an inability to truly blind the ketamine condition due to obvious dissociative effects in many participants.

Ketamine can also cause memory impairments, and abuse of the drug can result in severe bladder damage. There's even a model of schizophrenia based on antagonism of glutamate NMDA receptors, ketamine's main mechanism of action.

Now, in the latest issue of the American Journal of Psychiatry, Dr. Alan F. Schatzberg of Stanford University School of Medicine has a commentary entitled, A Word to the Wise About Ketamine. He first acknowledges the excitement about acute ketamine for refractory depression, then raises several cautionary notes and warns:
“This unbridled enthusiasm needs to be tempered by a more rational and guarded perspective.”

He notes that the drug is administered off-label in free-standing private psychiatry clinics without regulation by the FDA. Some leading proponents have advocated for strictly inpatient use, but that cat is already out of the bag.

Another potential issue is abuse liability.  The antidepressant effects of ketamine are short-lived (less than a week), which means that repeated infusions are required. The published literature suggests a relatively safe profile over two weeks in a hospital setting, but patients at commercial clinics are unlikely to be monitored as closely.

The commentary also suggests that “We Need To Know More About the Mechanism of Action of the Mood-Elevating Effects” but that is true of all drugs with antidepressant properties.


The Slippery Ketamine Slope

In response to the question, “Should Clinicians Prescribe Ketamine for Patients With Refractory Depression?” Dr. Schatzberg answers:
Without more data on what ketamine can do clinically, except to produce brief euphoriant effects after acute administration, and knowing it can be a drug of abuse, it is difficult to argue that patients should receive an acute trial of ketamine for refractory depression. ... The recent ketamine studies are exciting, and they open up important avenues for investigation that should be supported; however, until we know more, clinicians should be wary about embarking on a slippery ketamine slope.

However, in the midst of all this naysaying, it's important to note that Dr. Schatzberg has extensive ties to the pharmaceutical and biotech industries. He receives consulting fees from 19 different companies and has equity in 16 different companies, including one for which he is a co-founder. Ketamine of course is not under patent and is cheap to purchase. Perhaps not coincidentally, he does not receive fees from AstraZeneca, which (until recently) was developing a “low-trapping” NMDA antagonist that does not cause the hallucinogenic effects of ketamine (AZD6765, aka lanicemine).

In the past, I have suggested that short-term use for immediate relief of life-threatening symptoms (i.e. suicidal ideation) or end-of-life depression seem to be the best indications. Neuroskeptic has argued for the use of an active placebo condition (i.e, a non-dissociative comparison drug) in clinical trials, which has happened only rarely (Murrough et al., 2013), and for better assessment of dissociative behavioral effects.

At this point, the long-term ramifications of ketamine use for treatment-resistent depression remain to be seen...

In a future post I'll investigate the potential side effects in more detail.


Declaration

I have no financial conflicts to declare. But if some company wants to employ a critic for some bizarre reason, I'll take this under advisement.


Further Reading

Ketamine for Depression: Yay or Neigh?

Chronic Ketamine for Depression: An Unethical Case Study?

While I Was Away... (more on ketamine for depression)

Update on Ketamine in Palliative Care Settings


Reference

Schatzberg AF (2014). A word to the wise about ketamine. The American journal of psychiatry, 171 (3), 262-4 PMID: 24585328





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Saturday, February 22, 2014

"Love at first sight is a myth," say Chicago researchers


Social Neuroscience power couple, John T. Cacciopo and Stephanie Cacciopo


This, my friends, is a belated Valentine's Day tale that went oh so wrong...


On Feb 14, Scientific American ran a piece about When Scientists Are Mad about Each Other. The cutesy narrative on the Cacciopos described a wonderful story of love at first sight:
He was studying loneliness and isolation. She was studying love and desire. When they found themselves together, they gravitated toward her end of the continuum of social connection.

John Cacioppo was living in Chicago and Stephanie Ortigue in Geneva when they met—in Shanghai. ... On the last night of the conference, they happened to be seated next to one another at an official dinner, and soon became absorbed in conversation. “She was wonderful and brilliant and funny and I was completely taken by her,” Cacioppo says.

They both felt the chemistry but had to return to their respective homes the next day. Before parting ways they walked out of the restaurant together and noticed a beautiful moon hanging over the city. He snapped a picture of it. “A couple weeks later, she e-mailed me and asked if I could send her the picture,” Cacioppo says—a request his wife now confesses was just an excuse to strike up another conversation.

Within weeks they arranged to meet again, and from there their love unfurled. ... Within eight months they were engaged, and a season later they had married.

Their romantic story and collaborative work has been covered by a number of professional and popular media outlets, including the press office at the University of Chicago. The newsroom issued a press release on February 13, 2014 to coincide with Valentine's Day:
Researchers find brain’s ‘sweet spot’ for love in neurological patient

A region deep inside the brain controls how quickly people make decisions about love, according to new research at the University of Chicago.

The finding, made in an examination of a 48-year-old man who suffered a stroke, provides the first causal clinical evidence that an area of the brain called the anterior insula “plays an instrumental role in love,” said UChicago neuroscientist Stephanie Cacioppo, lead author of the study.

The study (Cacioppo et al., 2013) showed no such thing (in my opinion), and I'll return that in a moment. But for now I'll point out the Cacioppo spin didn't translate so well to other reports about this neurological patient. According to the Fox News affiliate in Little Rock, AK:
Love at first sight does not exist, claim researchers in the Current Trends in Neurology journal.

A stroke patient had a damaged anterior insula -- which is the part of the brain which controls how quickly we fall for someone.

They found that he could make decisions about lust normally but needed longer to think about love.

The researchers say this finding "makes it possible to disentangle love from other biological drives".

The Chicago researchers never said that love at first sight is a myth. But that didn't stop the British tabloid Metro from running that headline, while the Times of India declared:
'Love at first sight' doesn’t exist!
Feb 18, 2014, 04.52 PM

A new study suggests that love at first sight is a myth and it does not exist.

According to the study, the speed at which we fall for someone is controlled by a region in the brain called the anterior insula, Metro.co.uk reported.

All this curt tabloid fodder contradicts the meet-cute trope of the Cacciopo's own relationship. But their study itself is also quite problematic. It doesn't support the authors' contention, in my view, and here's why.


The Martin Lindstrom School of Anterior Insula Studies

Remember this classic op-ed piece in the New York Times?
You Love Your iPhone. Literally.

By MARTIN LINDSTROM
Published: September 30, 2011


WITH Apple widely expected to release its iPhone 5 on Tuesday, Apple addicts across the world are getting ready for their latest fix.

But should we really characterize the intense consumer devotion to the iPhone as an addiction? A recent experiment that I carried out using neuroimaging technology suggests that drug-related terms like “addiction” and “fix” aren’t as scientifically accurate as a word we use to describe our most cherished personal relationships. That word is “love.”
. . .

...most striking of all was the flurry of activation in the insular cortex of the brain, which is associated with feelings of love and compassion. The subjects’ brains responded to the sound of their phones as they would respond to the presence or proximity of a girlfriend, boyfriend or family member.

Here Lindstrom committed the logical fallacy of reverse inference – one cannot directly infer the participants' cognitive or emotional state from the observed pattern of brain activity in neuroimaging experiments. 1 Fortunately, Russ Poldrack and Tal Yarkoni (and I) wrote posts about the debacle: NYT Editorial + fMRI = complete crap and the New York Times blows it big time on brain imaging and Neuromarketing means never having to say you're peer reviewed. We all corrected the completely erroneous assumption that activation of insular cortex = love.

As Dr. Poldrack said:
In Tal Yarkoni’s recent paper in Nature Methods [PDF], we found that the anterior insula was one of the most highly activated part of the brain, showing activation in nearly 1/3 of all imaging studies!

Here's where the Cacciopos and their anterior insulae come in...


The Common Neural Bases Between Sexual Desire and Love

That was the title of a review article that conducted a statistical meta-analysis of the neuroimaging literature on "love" compared to "lust" (Cacioppo et al., 2012). The emphasis was on the similarity of brain regions activated by purported experimental elicitors of these complex behavioral and cognitive states (e.g., "look at a picture of your spouse" vs. close friend, or "watch porn" vs. non-porn). However, they did report a "gradient" of differential activation from the anterior "love" insula to the posterior "lust" insula, as shown below.



Fig. 1 (modified from Cacioppo et al., 2012). Brain networks related to sexual desire (blue) vs. love (red). (B) Lateral view of regions uniquely activated by desire based on the quantitative multilevel kernel density analysis. (C) Regions uniquely activated by love.


In their more recent paper, Cacioppo et al. (2013) wanted to move beyond correlational data by testing a neurological patient with damage in the anterior insula. This is generally a good strategy to evaluate whether your highly vaunted theory based on fMRI data can hold up to causal manipulations, or in this case an accident of nature. If a person with anterior insula damage cannot feel love, then you'd say that region is necessary for feelings of love. If their ability to love is unaffected, then you'd say the anterior insula is not very important.

We can go even further and ask if that patient with damage to anterior insula – but sparing of posterior insula – can still feel lust but not love. In that case, you'd say there's a dissociation between love and lust in the anterior vs. posterior insula. 2 

But that's not what the study was about!! Instead, it was about a speeded response task: look at pictures and quickly decide whether the person evokes feelings of love (or desire, in separate blocks). From the outset, I'll say that reaction times (RTs) in this task really have nothing to do with love, even as it was conceived in the fMRI experiments (i.e., "look at a picture of your spouse" and even "look at a picture of your child" - !!)

The participant in the study was a 48 year old heterosexual man who had a stroke affecting a fairly large portion of the right insula [I think], which is good for the investigators because "lust" seems to "localize" to the left posterior insula in their schematic above. We don't know a whole lot about this man (like, how long ago was his stroke?), other than that "At the moment of evaluation, the patient showed no symptoms and his neurological exam was normal." We'll just have to trust them on that...

Oh, and he was cognitively normal on some brief screening tests, not depressed or anxious, and fine in two social cognition tasks (including empathy for pain, a task where other persons with anterior insular lesions show deficits).

On to the task. The patient and 7 age- and sex-matched controls viewed 40 pictures in blocks of 20. In two of the blocks, the participants decided whether the sexily dressed girl/young woman (aged 18-30) in the photo was "relevant to sexual desire" (yes/no) or "relevant to love" (yes/no). Each image was viewed twice. Only the RTs on "yes" responses were evaluated, for some unknown reason, so we don't know if the patient was faster/slower than controls to reject a photo.




The patient behaved similarly to controls in the "lust" task. It took him just under a second, 926 milliseconds (ms), to respond "yes" when he desired the sexy young girl in the picture, compared to 959 ms for controls [remember, these guys are 48 and the girls are as young as 18], which did not differ. The patient said "yes" to lust 58% of the time vs. 61% for controls. The authors write (PDF):
The anamnesis indicated that the patient was unaware of any differences in his feelings of love or desire, whereas behavior testing revealed a selective deficit for love (but not sexual desire).

In the "love" task, the patient said "yes" to love 35% of the time vs. 43% for controls (which again did not differ). For RT, the patient took 1279 ms to say "yes" to love vs. 1020 ms for controls. And this constitutes his selective deficit for love!! It took him 259 ms longer to decide that a stranger in a photo in a laboratory task was "relevant to love." And we don't know how long it took him to say "no." And he reported no subjective change in his feelings of love, and no significant others or family or friends were queried about this.

The patient could have been slower to make that decision for any number of reasons that have nothing to do with “playing an instrumental role in love.” I won't belabor the point, but this particular region of the brain is implicated in many different functions.

With all due respect to the authors, I don't understand how this paper was published in its current form.3 

Might as well do fMRI and neuropsychological studies of Celebrity "F#@k, Marry, Kill"...






Footnotes

1 See papers by Aguirre (2003) and Poldrack (2006) for detailed explanations.

2 To complete the package with a double dissociation, a posterior insula lesion that affects lust but not love would confirm the hypothesis.

3 Current Trends in Neurology isn't exactly a stellar journal... it's published by Research Trends of India (not the prestigious Cell Press Trends series), and noted as "questionable" by scholarly publishing watchdog Jeffrey Beall. The paper is not listed in PubMed, nor can it be found at the journal website. A Google Scholar search only turns up a PDF at the authors' own labs.


References

Cacioppo S, Bianchi-Demicheli F, Frum C, Pfaus JG, & Lewis JW (2012). The common neural bases between sexual desire and love: a multilevel kernel density fMRI analysis. The journal of sexual medicine, 9 (4), 1048-54 PMID: 22353205

Cacioppo S, Couto B, Bolmont M ... Cacciopo JT (2013). Selective decision-making deficit in love following damage to the anterior insula Current Trends in Neurology, 7, 15-19 PDF


Dedication: For my wife.

> I love you
>
> Now and always
>
> Across space and time

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Sunday, February 09, 2014

I Wanna Hold Your Hand (after 23 sessions of Emotionally Focused Therapy)


Can neuroscience illuminate the nature of human relationships? Or does it primarily serve as a prop to sell self-help books? The neurorelationship cottage industry touts the importance of brain research for understanding romance and commitment. But any knowledge of the brain is completely unnecessary for issuing take-home messages like tips on maintaining a successful marriage.

In an analogous fashion, we can ask whether successful psychotherapy depends on having detailed knowledge of the mechanisms of “neuroplasticity” (a vague and clichéd term). Obviously not (or else everyone's been doing it wrong). Of course the brain changes after 12 sessions of psychotherapy, just as it changes after watching 12 episodes of Dexter. The important question is whether knowing the pattern of neural changes (via fMRI) can inform how treatment is administered. Or whether pre-treatment neuroimaging can predict which therapy will be the most effective.

However, neuroimaging studies of psychotherapy that have absolutely no control conditions are of limited usefulness. We don't know what sort of changes would have happened over an equivalent amount of time with no intervention. More importantly, we don't know whether the specific therapy under consideration is better than another form of psychotherapy, or better than going bowling once a week.

Enter Love Sense: The Revolutionary New Science of Romantic Relationships, a new book by Dr. Sue Johnson, the clinical psychologist who developed Emotionally Focused Therapy (EFT).1 The book is reviewed by Dr. Helen Fisher in the New York Times:

Love in the Time of Neuroscience

By HELEN FISHER  FEB. 7, 2014

In “The Devil’s Dictionary,” Ambrose Bierce defined love as “a temporary insanity curable by marriage.” Enter Sue Johnson, a clinical psychologist and couples therapist who says that relationships are a basic human need and that “a stable, loving relationship is the absolute cornerstone of human happiness and general well-being.” To repair ailing partnerships, she has developed a new approach in marriage counseling called Emotionally Focused Therapy, or EFT, which she introduces in her new book, “Love Sense.”
...

Johnson believes EFT can help couples break out of patterns, “interrupting and dismantling these destructive sequences and then actively constructing a more emotionally open and receptive way of interacting.” She aims to transform relationships “using the megawatt power of the wired-in longing for contact and care that defines our species,” and offers various exercises to restore trust.

Most interesting to me was Johnson’s brain-scanning study. Before EFT therapy, unhappily married women participating in the study reported considerable pain from an electric shock to the ankle as they held their husbands’ hands. After 20 sessions of EFT, however, these now more securely attached women judged their pain as only “uncomfortable” and their brain scans showed no alarm response. Secure attachment appears to change brain function and reduce pain.

Initial questions:
  • Is there a “wired-in longing for contact and care that defines our species”? {my needy cat seems to long for contact and care}
  • What's with that hand-holding ankle shock brain-scanning study? {did EFT really eliminate the “alarm response” in these women?}
 
Then Fisher continues:
But Johnson too often focuses on attachment to the exclusion of other “megawatt” brain systems. Remarkably, she lumps romantic love with attachment, saying “adult romantic love is an attachment bond, just like the one between mother and child.” In reality, romantic love is associated with a constellation of thoughts and motivations that are strikingly different from those of attachment. My research bears out that humankind evolved distinct but interrelated brain systems for mating and reproduction: the sex drive (to seek a range of partners); feelings of romantic love (to focus one’s mating energy on a single partner); and feelings of attachment (to drive our forebears to form a pair-bond to rear their young together). Each brain system is associated with different neurochemicals; each is a powerful drive that still plays a continuing role in partnership stability.

More questions:
  • Are there distinct (but interrelated) brain systems for the sex drive, romantic love, and feelings of attachment? {I actually find this to be plausible}
  • Is each brain system associated with different neurochemicals? {i.e. testosterone, dopamine, and oxytocin, respectively. I find this to be less plausible, or at least a bit simplistic.}

It's time to correct the misperceptions and overinterpretations that have arisen from this research!!

This is a job for...





Since there are a number of issues to tackle here – too many for a single post – I'll concentrate on only one of them here.


I Wanna Hold Your Hand

In 2006, Dr. James Coan and colleagues published a neuroimaging paper suggesting that the brains of happily married women showed an attenuation of activity related to emotion and threat when they held the hands of their husbands (Coan et al., 2006). Threat was induced experimentally by presenting a stimulus which occasionally signaled that a mild electric shock would be delivered to the ankle (20% of the time). Holding the hand of a male stranger also attenuated the hemodynamic response in some of these regions, relative to a no hand-holding control condition.2

Backing up a bit, the participants in the study were 16 heterosexual couples who rated their marital satisfaction as at least 40 on the Satisfaction subscale of the 50 point Dyadic Adjustment Scale (DAS). Total scores on the DAS were 126 for husbands (on a 151 point scale) and 127 for wives.3

The experimental design is illustrated below. The red X indicated a 20% chance of shock.

Figure adapted from a 2011 presentation by Coan (PDF), part of which can be viewed here.


At the end of each block, the women rated their subjective levels of unpleasantness and arousal on a 5 point scale. The results of the hand-holding manipulation were a bit weak. Unpleasantness ratings in the husband-hand condition were indeed significantly lower than no-hand (p=.001), but only marginally so compared to the stranger-hand condition (p=.05, with p<.05 being the usual cutoff for significance). The arousal ratings for husband-hand vs. no-hand (p=.07) and stranger-hand vs. no-hand (p=.08) were not officially significant either.

This raises a question I considered in 2006: why were the wives the only ones who were scanned?
...what about married women holding their mothers' hands? married men holding their wives' hands? unmarried women holding their partners' hands? single women holding the hands of their best friends? Perhaps the authors started with the relationship that they most expected to yield significant results...

The subjective effects of spousal-handholding were not enormous in women, which might explain why we've never seen data from husbands (i.e., perhaps there were no effects on self-report and/or neural activity). The highly-touted correlations between the wife's relationship quality rating and attenuation of threat-related brain signals weren't especially impressive either: −.59, p = .02 for the left superior frontal gyrus, −.47, p = .07 (not significant) for the right anterior insula, and −.46, p = .08 (not significant) for the hypothalamus. These numbers represent the magnitude of reduction in threat-related activity when holding the husband's hand, and were interpreted to suggest that the attenuations in pain (insula) and stress (hypothalamus) were related to the strength of attachment.4


Emotionally Focused Therapy

This finally brings us to the recent paper by Johnson et al. (2013). They followed the imaging protocol of Coan et al. in a set of 35 married couples who were screened for relationship dissatisfaction and scanned both before and after 23 sessions of EFT couples counseling (range of 13 to 35 sessions over 3.25 to 8.75 months). On average, the couples were white Canadians 44-45 years of age, married for 17 years. In contrast to the happy couples described above (DAS scores of 127), these couples reported moderate levels of relationship distress, with DAS scores of 80-97. For various understandable reasons, only 23 couples completed pre- and post-EFT fMRI scans. Again, only the wives were scanned.

Still, retaining 23 couples over 6 months of treatment is no mean feat. However, I will again note that there is no control condition in this experiment, so we can't know whether any changes are specifically due to the treatment of interest.

According to Johnson et al. (2013), EFT is "a manualized treatment that conceptualizes relationship distress as reflecting emotional disconnection and unmet attachment needs [18]."
Session and therapy length varied depending on the couples' presenting concerns and their progression through EFT-defined therapeutic change events [18], [28]. Specifically, when a couple was deemed according to EFT guidelines to have achieved 1) “softening” – a state of vulnerability and sharing of attachment related needs between the partners [37] – and 2) “consolidation” – where the therapist works with the couple to review treatment gains – treatment was terminated.

I am not qualified to comment on EFT and will not discuss it further, beyond saying that post-therapy DAS scores were significantly increased (pre-EFT mean=81 and post-EFT mean=96) but still, on average, in the moderately distressed range. Unpleasantness and arousal ratings in the husband-hand fMRI condition were lower after EFT.

The fMRI results after EFT were.... complicated, as shown below, and involve what appears to be post-hoc reasoning in relation to initial marital strife. Percent signal change was assessed for all voxels in the ROIs that were reported by Coan et al., which is a good and unbiased method for analyzing an independent dataset.



Fig. 2 (Johnson et al., 2013). Point estimates of percent signal change graphed as a function of EFT (pre vs. post) by handholding (alone, stranger, partner) and DAS score. Point estimates were computed separately for individuals high (+1SD) and low (−1SD) in DAS. Point estimates reflect average percent signal change (threat – safe) from all voxels activated in the original Coan et al. handholding study.


But the results are a little hard to interpret for the wives with high DAS scores, who nonetheless still experienced relationship distress. The intervention had no effect on their global threat-related brain response when holding their husbands' hands. In contrast, those with lower DAS scores showed a post-EFT increase in the threat response in the no-hand condition, a large reduction for stranger-hand, and a very large reduction for husband-hand.

Next the authors moved towards analyzing specific ROIs. I'll skip the husband vs. alone comparisons because these are less relevant. Well, except I'll quote this bizarre finding (which isn't terribly relevant, just hard to explain):
Interestingly, participants with higher DAS scores were generally less active in the substantia nigra/red nucleus when holding hands with their partners relative to when alone, independent of EFT, F(1,49.5)=6.6, p=.01.

OK then. What about the husband vs. stranger comparisons? There were a number of brain areas that showed pre- to post-therapy decreases that did not differ for husband-hand vs. stranger-hand.5 These regions included the right insula, which was related to relationship quality in the Coan et al. (2006) study. The two regions with positive findings (i.e., threat-related reductions in husband-hand and increases in stranger-hand) are right dorsolateral prefrontal cortex (dlPFC) and left supplementary motor area (SMA). No relationships to DAS score were reported.


Fig. 5 (Johnson et al., 2013). Percent signal change (±SE) graphed as a function of EFT (pre vs. post) by handholding (stranger vs. partner) interaction effects. Row A represents activity in the supplementary motor cortex (SMG) [sic]. Row B represents activity in the right dlPFC.


What have we learned from this study, and how does it inform the practice of EFT? If we take it at face value, the one consistent finding between the two experiments is that the threat response in right dlPFC was attenuated when holding the husband's hand, relative to holding a stranger's hand. If this neural region serves to downregulate negative emotional responses expressed elsewhere (as described below), there were no downstream regions in need of downregulation:
The dlPFC in particular supports explicit, cognitive, or “reappraisal” based self-control strategies active during unpleasant emotional states [54].  ...  The relative post-EFT inactivity of the dlPFC implies further that a secure connection with an attachment figure does not help individuals to maintain equilibrium by boosting self-regulatory capabilities per se but by reducing the perception and significance of threats, thus obviating the need for self-regulation to occur [13]

Having some kind of autonomic measure of threat perception (e.g., skin conductance or heart rate) would be useful in verifying this hypothesis. The authors don't interpret their other major finding, a similar effect in the left SMA (a motor control region).

The final question remains unanswered: how does this study inform the practice of EFT? The authors state:
Ultimately, our handholding paradigm has provided a unique opportunity to test some of the proposed mechanisms of social support in general, and EFT in particular, all at the level of brain function, in vivo.  

But not all of their predictions were supported. In particular, to explain the changes in neural threat processing observed in the no-hand condition, they resorted to an alternate model of therapeutic change:
We predicted that EFT would not affect neural threat responding during the alone condition.  ... [But] threat-related activity during the alone condition actually increased as a function of EFT in regions such as the dACC and portions of the PFC. Increased reactivity in these regions suggests a possible cost to increasing one's dependence upon social resources: that it becomes more difficult to tolerate being alone.
...

This is not what we observed. Although positivity ratings did not change, subjective arousal actually decreased. This suggests an alternative hypothesis: that EFT either trained or motivated clients to be more effective self-regulators even when alone.  ...  Although EFT focuses strongly on interpersonal attachments and interdependence, doing so may also increase self-regulatory motivation as clients come to value fostering effective relationships in part through self-regulatory effort.

I'm not sure that I understand this formulation, or that a dissociation between behavioral self-report and dACC activity warrants a reinterpretation of EFT's therapeutic effects. Ultimately, I don't feel like a BS-fighting superhero either, because it's not clear whether Magneto has effectively corrected the misperceptions and overinterpretations that have arisen from this fMRI research.


Footnotes

1 Not to be confused with Emotional Freedom Techniques, or “tapping”, a rather ridiculous practice that purports to manipulate the body's energy field.

2 The specific neuroimaging results were a bit less straightforward and easily interpreted than this. Regions of interest (ROIs) were defined by determining which areas were activated by the red X threat compared to the safe signal in the no-hand condition. This threat response was attenuated in the husband-hand vs. no-hand condition in the ventral anterior cingulate cortex (vACC), left caudate, superior colliculus, posterior cingulate, left supramarginal gyrus, and right postcentral gyrus. The threat response was also specifically attenuated in husband-hand vs. stranger-hand only in right dorsolateral prefrontal cortex, considered a “cognitive control” area. Finally, the stranger-hand vs. no-hand comparison revealed attenuation in the same bold blue regions above.

3 However, the correlation between husbands' and wives' DAS scores was not significant. Hmm... Would knowledge of this finding create any discord?

4 I won't get into how those single functions were assigned to these two complex and diverse brain regions.

5 Johnson et al. (2013): “In the vmPFC, left NAcc, left pallidum, right insula, right pallidum, and right planum polare, main effects of EFT revealed general decreases from pre- to post- therapy in threat activation, regardless of whose hand was held.”


References

Coan JA, Schaefer HS, & Davidson RJ (2006). Lending a hand: social regulation of the neural response to threat. Psychological science, 17 (12), 1032-9 PMID: 17201784

Johnson SM, Moser MB, Beckes L, Smith A, Dalgleish T, Halchuk R, Hasselmo K, Greenman PS, Merali Z, & Coan JA (2013). Soothing the threatened brain: leveraging contact comfort with emotionally focused therapy. PloS one, 8 (11) PMID: 24278126

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