JeanKing Dr. Jean A. King [webpage] is Vice-Chair of Research and Professor in the Department of Psychiatry at the University of Massachusetts Medical School [PubMed; CV]. She completed her PhD in 1988 at NYU in Neurophysiology and conducted postdoctoral training at Emory. Dr. King’s research record is diverse but can be characterized as focusing on neuroendocrine systems, stress, aggression, fear and substance abuse. Her work has also focused on advancing noninvasive imaging techniques in animal models using magnetic resonance imaging, in addition to the papers she has credit on three patents for neuroimaging advances. Professor King is the Director of the Center for Comparative Neuroimaging within the UMass Medical School. A recent paper from her laboratory (open access) applies imaging techniques to investigate white matter structural integrity in the brains of nicotine addicted human subjects that are associated with measures of physical dependence.

Over the years Dr. King’s work has been funded by the National Science Foundation and the National Institutes of Health (a RePORTER search illustrates her NIH funding history as a Principal Investigator).

As you would expect for a scientist of this caliber, her expertise has been sought by an array of journals to provide peer review of manuscripts and by the NIH to serve on many grant review panels. I can confirm that Professor King is an excellent and insightful reviewer of grant applications with a persuasive and often humorous demeanor. Her comments were invariable informative, particularly for noob-ish grant reviewers (ahem). Similarly, Dr. King has supervised numerous trainees, participated on many service committees for her University, for the NIH and for multiple academic societies or entities. She has additional service in nonacademic settings. In this record there is a strong addition of service on issues important to women in science and in careers, generally.

I thank you, Professor Jean A King, for your long commitment to advancing our understanding of the brain and of affective disorder.

__

Disclaimer: I am professionally acquainted with Dr. King.

picture borrowed from http://www.umassmed.edu/Content.aspx?id=96786

Series Note: The Diversity in Science Blog Carnival was created by D.N. Lee of the Urban Science Adventures! blog. In early 2009 she issued a call for a new blog carnival celebrating diversity in science and hosted the inaugural edition. The Diversity in Science Carnival #2 was hosted at Thus Spake Zuska under the theme Women Achievers in STEM – Past and Present. Prior entries from me have focused on Laura O’Dell, Carl Hart, Chana Akins, Percy Julian, Jean Lud Cadet,  and Yasmin Hurd.

An email from current president of the Society for Neuroscience announced the intent of the society to launch a new Open Access journal. They are seeking an Editor in Chief, so if you know any likely candidates nominate them.

The Society for Neuroscience Council has appointed a Search Committee to recommend candidates to serve as editors-in-chief for two Society-published journals:

The Editor-in-Chief of The Journal of Neuroscience, to be appointed for a 5-year term beginning Jan. 1, 2015, after a period of transition with the current editor; and
The first Editor-in-Chief of a new online, open access neuroscience journal, expected to launch in late 2014, and temporarily referred to herein as “New Journal.” Please see the announcement here for more information about New Journal. This 5-year appointment will commence in the spring of 2014, to allow the new editor to be involved in decisions connected with the start-up of New Journal and the organizing of an initial editorial board.

The members of the Search Committee are: Moses Chao, Chair; Holly Cline; Barry Everitt; David Fitzpatrick; and Eve Marder.

The list of evaluation criteria may help you to think about who you should nominate.

In evaluating candidates for the editor-in-chief positions, the Search Committee will consider the following criteria:

  • previous editorial experience

  • adequate time flexibility to take on the responsibilities of editor-in-chief

  • a distinguished record of research in neuroscience

  • familiarity with online submission, peer review and manuscript tracking systems

  • ideas about novel approaches and receptivity to innovation during a time of great change in the scientific publishing field

  • service to and leadership in the neuroscience community (e.g., SfN committees)

  • evidence of good management skills and the ability to lead colleagues on an editorial board

  • for New Journal: the capacity to proactively engage on a start-up venture, and to innovate and lead in the creation of a high quality open access neuroscience journal, and guide it on a path to success

  • for The Journal of Neuroscience: the capacity to build on an established record of success, while continuing to evolve a leading journal in the field and take it to the next level

Interesting next step for the SfN. Obviously reflects some thinking that they may be left behind (even further, see diminishing reputation after the launch of Nature Neuroscience and Neuron) in the glorious New World Order of Open Access publication. Might just be a recognition that Open Access fees for a new journal when all the infrastructure is already there is going to be a cash cow for the Society from the beginning.

What I will be fascinated to see is where they pitch the New Journal* in terms of impact. Are they just trying to match JNeuro? Will they deliberately go a little lower down the feeding chain to avoid undercutting the flagship journal?

__
*my suggestion of Penfield must have been too esoteric a reference…..

BRAIN Initiative

May 7, 2013

I just watched part of a live stream [current link] of some meeting to brainstorm about what the $100M BRAIN Initiative should be.

What at a disaster.

Bunch of reinforcement that this is all about a bunch of senior dudes (mostly male dewds too) in neuron-recording neuroscience who used to make out like bandits from NIMH support. Now that we’ve undergone a long slide in funding levels and Insel’s push to translational-ize the NIMH portfolio has gained the upper hand…these folks are struggling to get grants. JUST. LIKE. THE. REST. OF. US.

and they can’t come up with anything amazing by themselves so they need $100M cash money to build some new recording tools to….you guessed it, record some more neurons.

Outside of the regular grant process because they find it hard to compete these days. JUST. LIKE. THE. REST. OF. US.

I have a proposal. Let’s throw down, what, maybe $1M to record symposia and meetings of these people for the next year. Maybe have a few more of these summits. And after all that, if they’ve come up with some thing that is ACTUALLY NEW AND INTERESTING then and only then do we give them the $99M.

UPDATE: Permalink

Failure to Replicate

March 20, 2013

I should have put that in quotes because it actually appears in the title of this new paper published in Neuropsychopharmacology:

Hart AB, de Wit H, Palmer AA. Candidate gene studies of a promising intermediate phenotype: failure to replicate. Neuropsychopharmacology. 2013 Apr;38(5):802-16. doi: 10.1038/npp.2012.245. Epub 2012 Dec 3. [PubMed]

ResearchBlogging.orgfrom the Abstract alone you can get a sense

We previously conducted a series of 12 candidate gene analyses of acute subjective and physiological responses to amphetamine in 99-162 healthy human volunteers (ADORA2A, SLC6A3, BDNF, SLC6A4, CSNK1E, SLC6A2, DRD2, FAAH, COMT, OPRM1). Here, we report our attempt to replicate these findings in over 200 additional participants ascertained using identical methodology. We were unable to replicate any of our previous findings.

The team, with de Wit’s lab expert on the human phenotyping and drug-response side and Palmer’s lab expert on the genetics, has been after genetic differences that mediate differential response to amphetamine for some time. There’s a human end and a mouse end to the overall program which has been fairly prolific.

In terms of human results, they have previously reported effects as varied as:
-association of an adenosine receptor gene polymorphism with degree of anxiety in response to amphetamine
-association of a dopamine transporter gene promotor polymorphism with feeling the drug effect and diastolic blood pressure
-association of casein-kinase I epsilon gene polymophisms with feeling the drug effect
-association with fatty acid amide hydrolase (FAAH) with Arousal and Fatigue responses to amphetamine
-association of mu 1 opioid receptor gene polymorphisms with Amphetamine scale subjective report in response to amphetamine

There were a dozen in total and for the most part the replication attempt with a new group of subjects failed to confirm the prior observation. The Discussion is almost plaintive at the start:

This study is striking because we were attempting to replicate apparently robust findings related to well-studied candidate genes. We used a relatively large number of new participants for the replication, and their data were collected and analyzed using identical procedures. Thus, our study did not suffer from the heterogeneity in phenotyping procedures implicated in previous failures to replicate other candidate gene studies (Ho et al, 2010; Mathieson et al, 2012). The failure of our associations to replicate suggests that most or all of our original results were false positives.

The authors then go on to discuss a number of obvious issues that may have led to the prior “false positives”.

-variation in the ethnic makeup of various samples- one reanalysis using ancestry as covariate didn’t change their prior results.

-power in Genome-Wide association studies is low because effect sizes / contribution to variance by rare alleles is small. they point out that candidate gene studies continue to report large effect sizes that are probably very unlikely in the broad scheme of things…and therefore comparatively likely to be false positives.

-multiple comparisons. They point out that not even all of their prior papers applied multiple comparisons corrections against the inflation of alpha (the false positive rate, in essence) and certainly they did no such thing for the 12 findings that were reported in a number of independent publications. As they note, the adjusted p value for the “322 primary tests performed in this study” (i.e., the same number included in the several papers which they were trying to replicate) would be 0.00015.

-publication bias. This discussion covers the usual (ignoring all the negative outcomes) but the interesting thing is the confession on something many of us (yes me) do that isn’t really addressed in the formal correction procedures for multiple comparisons.

Similarly, we sometimes considered several alternative methods for calculating phenotypes (eg, peak change score summarization vs area under the curve, which tend to be highly but incompletely correlated). It seems very likely that the candidate gene literature frequently reflects this sort of publication bias, which represents a special case of uncorrected multiple testing.

This is a fascinating read. The authors make no bones about the fact that they’ve found that no less than 12 papers that they have published were the result of false positives. Not wrong…not fraudulent. Let us be clear. We must assume they were published with peer review, analysis techniques and samples sizes that were (and are?) standard for the field.

But they are not true.

The authors offer up solutions of larger sample sizes, better corrections for multiple comparisons and a need for replication. Of these, the last one seems the best and most likely solution. Like it or not, research funding is limited and there will always be a sliding scale. At first we have pilot experiments or even anecdotal observations to put us on the track. We do one study, limited by the available resources. Positive outcomes justify throwing more resources at the question. Interesting findings can stimulate other labs to join the party. Over time, the essential features of the original observation or finding are either confirmed or consigned to the bin of “likely false alarm”.

This is how science progresses. So while we can use experiences like this to define what is a target sample size and scope for a real experiment, I’m not sure that we can ever overcome the problems of publication bias and cherry picking results from amongst multiple analyses of a dataset. At first, anyway. The way to overcome it is for the lab or field to hold a result in mind as tentatively true and then proceed to replicate it in different ways.

__
UPDATE: I originally forgot to put in my standard disclaimer that I’m professionally acquainted with one or more of the authors of this work.

Hart, A., de Wit, H., & Palmer, A. (2012). Candidate Gene Studies of a Promising Intermediate Phenotype: Failure to Replicate Neuropsychopharmacology, 38 (5), 802-816 DOI: 10.1038/npp.2012.245

Go Team!!!!!

February 3, 2013

I’ve decided I am rooting for neuronal survival during the NFL SuperBowl today.

Go #teamneuron!

Hard on the heels of something I just learned about at a recent conference, the NIMH issued a Press Release for a new clinical trial they funded.

A drug that works through the same brain mechanism as the fast-acting antidepressant ketamine briefly improved treatment-resistant patients’ depression symptoms in minutes, with minimal untoward side effects, in a clinical trial conducted by the National Institutes of Health. The experimental agent, called AZD6765, acts through the brain’s glutamate chemical messenger system.

Interesting. The background is that prior studies* have shown that the dissociative anesthetic ketamine is capable of the rapid (within hours) amelioration of depressive symptoms. Yes, ketamine. The recreational drug known as Special K and the veterinary anesthetic they’ve used on your pet cat or dog. Same ketamine that is approved for human use in pediatric anesthesia, emergency medicine in some cases and for tricky clinical situations.

The same ketamine that has been widely used for decades in humans and nonhuman animals. It has established efficacy, mechanism of action and a huge therapeutic index. A big distance between effective doses and the dose that will kill you. Whether effect is recreational, medical or veterinary. Meaning it is safe.

So why are the studies (cited below*) of effect in depression so exciting? Because traditional drug therapy for depression takes weeks to have effect. Weeks of daily dosing. Selective Serotonin Reuptake Inhibitors (SSRIs) like Prozac are broadly familiar to most of my Readers, I would assume. Efficacy with these front-line meds takes up to three weeks to see effect on depressive symptoms. Trouble is, some cases of depression are acutely suicidal–they may just kill themselves before any SSRI has a chance to make them feel better. And hell, who wants to wait three weeks if another med could make you feel better by tomorrow? Prior to the ketamine work, the only other thing that seemed to have such a rapid effect was ECT. Yeah, ElectroConvulsive Therapy. Which has come a loooooong way from the One Flew Over the Cuckoo’s Nest era….but still. A single ketamine dosing seems quite preferable.

So…..on to the me-too drug development! Woot!
Zarate CA Jr, Mathews D, Ibrahim L, Chaves JF, Marquardt C, Ukoh I, Jolkovsky L, Brutsche NE, Smith MA, Luckenbaugh DA. A Randomized Trial of a Low-Trapping Nonselective N-Methyl-D-Aspartate Channel Blocker in Major Depression. Biol Psychiatry. 2012 Nov 30. pii: S0006-3223(12)00941-9. doi: 10.1016/j.biopsych.2012.10.019. [Epub ahead of print][Publisher, PubMed]

This AZD6765 compound is, as you might deduce from the letters, property of AstraZeneca Pharmaceuticals and indeed one of the authors lists this as his affiliation. The rest of the folks are from the NIMH intramural program which, presumably, provided the majority of the funding for the study.

The conclusions appear to be that this novel compounds, with a similar mechanism of action as ketamine worked but less well. From the Presser:

About 32 percent of 22 treatment-resistant depressed patients infused with ASD6765 showed a clinically meaningful antidepressant response at 80 minutes after infusion that lasted for about half an hour – with residual antidepressant effects lasting two days for some. By contrast, 52 percent of patients receiving ketamine show a comparable response, with effects still detectable at seven days. So a single infusion of ketamine produces more robust and sustained improvement, but most patients continue to experience some symptoms with both drugs.

However, depression rating scores were significantly better among patients who received AZD6765 than in those who received placebos. The researchers deemed this noteworthy, since, on average, these patients had failed to improve in seven past antidepressant trials, and nearly half failed to respond to electroconvulsive therapy (ECT).

So this is good. Anything that shows promise as a rapid-alleviator of depression is good by my lights.

But why is NIMH spending taxpayer dollars to develop me-too drugs? Look, I recognize that drugs within a class of pharmacological mechanism, like the SSRIs, may be differentially effective for different patients. And it is a good thing if we have more options to tailor medication to the individual patient. ADHD is another situation where an array of monoamine transporter inhibitors, including methylphenidate and amphetamine, are used with success and failure. One drug works for one patient, another works for a different patient….and they might describe the other medication as even worse than not being treated. So…great.

But make no mistake. The central feature driving me-too drug development is profit. Drug companies decide they can take a big enough slice of the market away from the market-leader to make it worth their while. Perhaps they had development in parallel and had sunk enough cost in by the time their competitor gained FDA approval that there was no turning back. Whatever. Point being that they are in it for the money and not for some noble cause of serving that subset of patients that do not gain relief from their competitor’s drug.

Over the past few years the side-chatter about the ketamine effect on depression has frequently been a lament about the lack of financial motive for companies to push forward with ketamine. Push forward with specific clinical trials to gain on-label approval for the indication of depression. Push forward with marketing campaigns. Push forward with physician education and stroking like they do with their proprietary stuff.

The Zarate paper took a stab at claiming the reason for developing something else was an attempt to avoid the adverse effects of ketamine. The dissociative type effects can be unpleasant and recovery doesn’t look fun. So there’s some toehold there to claim one is motivated to find a “perfect” drug which somehow produces the therapeutic effect with nothing else. Color me skeptical, given what I know about existing NMDA channel blockers like ketamine (and PCP, did I mention that? Yeah, angel dust might work for depression….).

So I smell profit motive in this effort.

What I don’t understand is why NIMH is involved with this. Why not just pursue the evidence body for ketamine?
___
*References pulled out of the paper
R.M. Berman, A. Cappiello, A. Anand, D.A. Oren, G.R. Heninger, D.S. Charney et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry, 47 (2000), pp. 351–354

N. Diazgranados, L. Ibrahim, N.E. Brutsche, A. Newberg, P. Kronstein, S. Khalife et al. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry, 67 (2010), pp. 793–802

C.A. Zarate Jr, N.E. Brutsche, L. Ibrahim, J. Franco-Chaves, N. Diazgranados, A. Cravchik et al. Replication of ketamine’s antidepressant efficacy in bipolar depression: A randomized controlled add-on trial Biol Psychiatry, 71 (2012), pp. 939–946

G.W. Valentine, G.F. Mason, R. Gomez, M. Fasula, J. Watzl, B. Pittman et al. The antidepressant effect of ketamine is not associated with changes in occipital amino acid neurotransmitter content as measured by [(1)H]-MRS Psychiatry Res, 191 (2011), pp. 122–127

M. aan het Rot, K.A. Collins, J.W. Murrough, A.M. Perez, D.L. Reich, D.S. Charney et al. Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression Biol Psychiatry, 67 (2010), pp. 139–145

There are two new pharmacological investigations on the substituted cathinone drugs that have been discussed here on occasion.

Each of

Baumann MH, Partilla JS, Lehner KR, Thorndike EB, Hoffman AF, Holy M, Rothman RB, Goldberg SR, Lupica CR, Sitte HH, Brandt SD, Tella SR, Cozzi NV, Schindler CW.Powerful Cocaine-Like Actions of 3,4-Methylenedioxypyrovalerone (MDPV), a Principal Constituent of Psychoactive ‘Bath Salts’ Products. Neuropsychopharmacology. 2012 Oct 17. doi: 10.1038/npp.2012.204.

and

Simmler LD, Buser TA, Donzelli M, Schramm Y, Dieu LH, Huwyler J, Chaboz S, Hoener MC, Liechti ME.Pharmacological characterization of designer cathinones in vitro. Br J Pharmacol. 2012 Aug 17. doi: 10.1111/j.1476-5381.2012.02145.x.

report very similar findings for MDPV, the cathinone that appears most frequently in US newspaper reports.

As a very general rule, the amphetamine class stimulants do a couple of things to enhance the neuron-to-neuron chemical communication that occurs in the brain. The most common and significant effects tend to involve the transporter mechanisms that remove dopamine, norepinephrine and / or serotonin from the synapse, the gap between two neurons. These transporter molecules are an integral part of terminating a signalling event which has been caused by the release of one of these three monoamines from one of the neurons in question. Interfere with the operation of these transporters and a drug can potentiate the magnitude or duration of a given signalling event (i.e., release of one of the dopamine (DA), norepinephrine (NE) or serotonin neurotransmitters).

The amphetamine class stimulants have these properties. As does cocaine. As do therapeutic drugs such as methylphenidate (Ritalin) and Prozac. The term selective serotonin re-uptake inhibitor, SSRI, for Prozac-class antidepressant drugs refers to the transporter, obviously, and also indicates a key thing with the term “selective”. Drugs which have the ability to interact with one of the monoamine transporters tend to interact with the other ones as well. Substantial differences in effect can be associated with differences in the relative ability a specific molecule has to attach to the DAT versus the NET versus the SERotonin transporter (SERT). As one clear example, methamphetamine and MDMA differ in their relative ability to inhibit the SERT….this property of MDMA is associated with many of it’s stimulant-atypical properties relative to other amphetamine-class drugs.

The new studies both show that MDPV blocks all three transporters with much more potent effects at the DAT and NET relative to SERT. As Baumann and colleagues note, MDPV is 50 and 10 times more potent than cocaine (not an amphetamine, we’ll come to this) at DAT and NET respectively. Simmler and colleagues similarly indicate that MDPV is much more potent at DAT than cocaine or methamphetamine which did not qualitatively differ from each other.

So to this point, MDPV looks like a high-potency traditional stimulant. Most effective at the DAT, fairly effective at the NET and with less ability to block the SERT.

Cocaine and the amphetamines diverge at this point because the amphetamines act as a substrate at the transporters. Instead of only interfering and blocking them from doing anything, the amphetamines actually substitute for the neurotransmitter in question and are taken up into the cell. In so doing, they also cause an exchange to happen whereby the transporter moves some neurotransmitter from inside the cell back into the synapse. This transporter mediated efflux contributes to any “regular” release of neurotransmitter mediated through the merging of intracellular sacs (called vesicles) with the cell membrane.

The two papers agree in finding that MDPV has no ability to cause transporter-mediated efflux of dopamine and is therefore best categorized neuropharmacologically as a “pure” blocker (like cocaine) rather than an amphetamine-like transporter substrate.

The Simmler paper adds an in vitro model of blood/brain barrier penetration…in very simple terms the degree to which a molecule is fat-liking versus water-liking can alter the speed at which it can cross cell membranes and get into the brain. This paper used an in vitro preparation of human capillary endothelial cells (that form the blood-brain barrier) to show that MDPV is likely to cross the blood-brain barrier very rapidly, consistent with high lipophilicity predicted from its structure.

The upshot of the two papers is that MDPV shows pharmacological properties consistent with classical stimulants. It shows relatively high selectivity for DAT over SERT and high potency relative to drugs such as methamphetamine or cocaine. In vivo neurochemistry in the Baumann paper confirm that MDPV has potent effects on dopamine levels in the nucleus accumbens, a hallmark of drugs (beyond the stimulants even) which have substantial risk for compulsive use. The only somewhat discordant note for the structure-activity nerds is that MDPV looks so much like the rest of the amphetamines and cathinones that it will be interesting to discover why it doesn’t act as a transporter substrate (Simmler et al included a number of other cathinones and showed that many of them do act as transporter substrates.)

Together these papers suggest that MDPV has high abuse liability with a use pattern characterized by frequent re-dosing much like one sees with cocaine. This is consistent with many self-reports that are emerging from people who use MDPV and therefore, despite the relatively brief time on the “market”, we can predict a cocaine-like dependence problem to emerge for MDPV in the near future.