Thursday, April 17, 2014

Post-Publication Peer Review, Systemic Changes to Biomedical Research, NIH R01A7s, and Social Media



My, that title sure is a mouthful, isn’t it? That's because in the span of a few short days, we’ve seen the following:

(1) An invited review in Neuron on the role of blogs, Twitter, Facebook, and online forums such as PubPeer, PubMed Commons, and journal comments in shaping discussions about published research papers.

(2) A commentary in PNAS about the sad structural state of biomedical research in the U.S. and  suggestions for change.

(3) A MAJOR revision in how NIH (National Institutes of Health) reviews research grants.

These communiques intersect because of how rapidly we can discuss them, who is allowed to comment, and where the debate takes place. Let me take these in turn.


The Vacuum Shouts Back: Postpublication Peer Review on Social Media

(1) An invited review in Neuron covered the role of blogs, Twitter, Facebook, and online forums such as PubPeer, PubMed Commons, and journal comments (like at PLOS ONE) in shaping discussions about published research papers (by Dr. Zen Faulkes):
Postpublication peer review through traditional scientific publishing is like kabuki theater: a slow, rehearsed drama in which the viewer must recognize the subtle profundities of performers wearing deliberately ambiguous masks.

Postpublication peer review on social media is like the mosh pit at a punk rock show. It’s fast, uncoordinated, a lot less subtle, more in your face, and involves a few more risks.

I thank Dr. Faulkes (“Dr. Zen”) for mentioning this blog and its cousin, The Neurocomplimenter.  I started the latter in response to overt dismissals of neuroscience as providing anything useful to our understanding of human cognition (and to emphasize the importance of studying brain function, more broadly). I see it as “a new project designed to counter gratuitous anti-neuroscience sentiment. It’s part of my campaign to combat pop neurobashing profiteers.”

Lately, the compliments have been sparse (perhaps due to my pessimistic nature) but I will try to highlight the positives anon. Meanwhile, the critical element soldiers on. Dr. Zen nailed my reason for starting an anonymous blog right on the head: professional peer review is anonymous, so why should bloggers identify themselves? Many do, of course, and some researchers sign their reviews.
Regardless, there are strong traditions for using both anonymity and pseudonyms in science (Neuroskeptic, 2013), not the least of which is journal peer review itself. It is a little audacious for authors and editors to decry the negative effects of “anonymous bloggers” when essentially every journal practices anonymous peer review. Bloggers are often easier to identify than journal reviewers. We still don’t know who reviewed Wolfe-Simon et al. (2011)) for Science. But we know Rosie Redfield critiqued it on her blog (http://rrresearch.fieldofscience.com/2010/12/arsenic-associated-bacteria-nasas.html), which ultimately led to a paper that failed to replicate key claims of the original paper (Reaves et al., 2012).

The voodoo correlations neuroimaging brouhaha is another major example of post-publication peer review (that went a little pre-publication due to a preprint going public), much to the dismay of the journal editor and some of the implicated researchers (see The Voodoo of Peer Review).

Dr. Zen also made the important distinction between completely anonymous commenters and those who identify as a pseudonym, a point that I often fail to make, e.g. Anonymous Peer Review Means Never Having to Say You're Sorry: “The Neurocritic is happy to provide a new form of anonymous peer review, free of charge.”


Rescuing US biomedical research from its systemic flaws

(2) A commentary in PNAS relayed the sad structural state of biomedical research in the U.S. and made [some unrealistic, some potentially helpful] suggestions for change (by four distinguished scientists in positions of power):
There is a no more worrisome consequence of the hypercompetitive culture of biomedical science than the pall it is casting on early careers of graduate students, postdoctoral fellows, and young investigators.

The commentary discusses the unsustainable growth of the biomedical research enterprise and the overly competitive yet conservative culture it has spawned. This win-at-all costs mentality squelches creativity and collaboration, and concentrates resources in the hands of fewer and fewer investigators. The average age for landing one’s first tenure-track position has risen to 37. And some estimates project that fewer than 8% of new PhDs will get tenure, with the figure an abysmal 0.45% according to one report.

The “post-doc apocalypse”1 has been widely discussed on social media (and in the popular press) for some time now. Potential solutions have been expressed by researchers at all levels, but these voices have been scattered. Those of us who are not in certain informal social circles may overlook a site of discussion somewhere, but who has time to search for it.

On the other hand, specific responses to the Alberts et al. PNAS article have already appeared on PubPeer (which allows anonymity) and PubMed Commons (which does not). Professor Dorothy Bishop made some trenchant points on the three major solutions proposed by the authors. You can read these at PubMed Commons and click on links to blog posts, where she expands on the topics of academic workload, grant review, and evaluation.

Here's my worthless $0.02 on the matter, from a position of no power and no influence: I agree with Prof. Bishop that the “Predictable and Stable Funding of Science” solution is a pipe dream...
We encourage Congressional appropriators and the executive branch to consider adding a 5-y projected fiscal plan to the current budgetary process. This plan would be updated each year, at the same time that annual appropriation bills are written.

Ha ha ha ha ha! Have they forgotten the Great Budget Sequestration of 2013 already? Getting the political parties to agree (or factions within parties) seems impossible to me. Even if all four authors win plum positions in Congress or the White House, good luck with that.

Perhaps more plausible are recommendations for downsizing the future workforce to reduce the glut of under- and unemployed junior scientists. However, they have to persuade graduate programs to admit fewer students and ban principal investigators from funding students through research grants (rather than through training grants). Some funding sources/agencies already forbid PIs from paying student stipends, and Alberts et al. propose that NIH should move towards this model.

They also suggest “Broadening the career paths for young scientists” so they're not looked down upon as failures if they don't become a clone of their advisor at MIT. This would also require changing the minds of Bob Graybeards everywhere. Good luck with that.

Another modest proposal is to force universities to pay their faculty. Here, however, they have to convince Chancellors and Deans of medical schools to forgo the “perverse incentives” of “soft money” positions, where the institution benefits from the indirect costs awarded to the university in conjunction with salary money paid by NIH. This would do away with a whole army of productive researchers. What a great idea.

Perhaps these unemployed “soft money” faculty could apply for the proposed Staff Scientist positions, displacing all the post-docs who are supposed to be in line for them. What a great idea. Good luck with that.

To be fair, let's see if the proposed Staff Scientist position might be a good idea. Post-post-docs could move into higher paying jobs that would better prepare them to run their own labs. This is because they will actually run their supervisor's lab, at much lower pay and with no prestige:
We believe that staff scientists can and should play increasingly important roles in the biomedical workforce. Within individual laboratories, they can oversee the day-to-day work of the laboratory, taking on some of the administrative burdens that now tend to fall on the shoulders of the laboratory head; orient and train new members of the laboratory; manage large equipment and common facilities; and perform scientific projects independently or in collaboration with other members of the group. Within institutions, they can serve as leaders and technical experts in core laboratories serving multiple investigators and even multiple institutions.

Or here's an idea: there could actually be a place in the system for individuals who may not want to run their own lab! These people could conduct their own independent research and help with the grant application process, if so inclined. We'd call them Staff Scientists. We'd hire different people to take on the administrative burdens and call them Lab Managers. Still others could be hired as “technical experts in core laboratories serving multiple investigators and even multiple institutions.” We'd call them Technical Experts.

But this would be prohibitively expensive. Back to cheap graduate student labor...

The most important point is that I can lobby all I want for the Snarky Policy Consultant position, since this is my blog.


NIH and AHRQ Announce Updated Policy for Application Submission

(3) A MAJOR, MAJOR revision in how the NIH reviews research grants was released today (April 17, 2014). At first I thought it was an April Fool's joke (and that I must have been dreaming for the last 16 days, which would explain a lot of things).
Effective immediately … following an unsuccessful resubmission (A1) application, applicants may submit the same idea as a new (A0) application for the next appropriate due date. The NIH and AHRQ will not assess the similarity of the science in the new (A0) application to any previously reviewed submission when accepting an application for review.

In essence, this does away with the “two strikes” rule – which meant that rejected proposals were barred from being submitted again sans a complete overhaul.

Within minutes of this announcement, Drug Monkey had 159 tweets and a blog post on this new policy, which would allow investigators to submit multiple revisions of basically the same grant (hence the R01 A7, a grant funded on the eighth try). But it wouldn't really be considered the same grant, so the numbers only go up to A1 (one amendment), thereby avoiding the stigma of A7. Thank you, NIH, that's very considerate.

And here we are again on social media, providing immediate feedback and discussion of important issues that impact the biomedical research enterprise. Can I get a full-time job doing that? We'd call it Blogger-in-Residence.


Footnote

1 I refuse to use the neologism because of what Google will turn up. And this is nothing new; it's been brewing since the early 90s: “From the early 1990s, every labor economist who has studied the pipeline for the biomedical workforce has proclaimed it to be broken.”

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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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