Archive for the 'Neuroscience' category

Sometimes the good guys win

Sep 30 2014 Published by under Neuroscience, NIH

I've mentioned a time or two that I think the DREADD approach is infinitely more useful than optogenetics for anything that matters.

So congrats to the team for this new award.

DREADD2.0: AN ENHANCED CHEMOGENETIC TOOLKIT

DESCRIPTION (provided by applicant): The Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative has the ambitious goal of elucidating how neuronal ensembles interactively encode higher brain processes. To accomplish this goal, new and improved methods for both recording and manipulating neuronal activity will be needed. In this application, we focus on technologies for manipulating neuronal activity. The major significance of this application is that we will provide an enhanced chemogenetic toolbox that allows non-invasive, multiplexed spatiotemporal control of neuronal activity in domains ranging from single synapses to ensembles of neurons. To achieve this, we will provide: Chemical actuators with improved pharmacokinetics and pharmacodyamics suited for use with current DREADDs in eukaryotes ranging from Drosophila to primates (Specific Aim #1) Photo-caged CNO and other chemical actuators to provide millisecond-scale control (Specific Aim #1) Novel DREADDs and 'split-DREADDs' targeted to distinct neuronal pathways to enable multiplexed interrogation of neuronal circuits (Specific Aims #2 and 3) Chemogenetic platforms with minimized desensitization and down-regulation (Specific Aim #3)

I am excited to see where this leads.

More awards under The BRAIN Initiative.

18 responses so far

Hard truths for supposed neuroscientists

This is the truest and best thing I have read on the internet today.

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Guest Post: Gender Sensitivity in Neuroscience is a Work in Progress

This is a guest post from someone who wishes to remain anonymous.

 


 

This week, the Society for Neuroscience opened its website allowing attendees to book their hotels for their annual meeting. The timing was couldn’t have been worse for the Vanderbilt neuroscience community given that on Monday, a former graduate student of the program leveled a disturbing series of accusations against neuroscientist Aurelio Galli. At least 10 of the 60+ alleged events of harassment occurred at SfN meetings. The year before the defendant claims she was subject to harassment, The Society for Neuroscience named Vanderbilt their ‘Neuroscience Training Program of the Year’.

 

In a 20 million dollar harassment suit filled in Nashville, sordid details were laid out of alcohol fueled harassment both in the lab and at the Society for Neuroscience’s annual meetings in 2012 and 2013. The student, a recovering alcoholic, alleges she was subjected to unwelcome and embarrassing commentary from Galli about her perceived lesbianism, her sex life and her looks both in lab as well as in front of male professors.

 

Vanderbilt fired back saying they had investigated the claims and would vigorously defend themselves.  The medical center director and the chancellor were named as defendants, as were Mark Wallace, the head of the Vanderbilt Brain Institute and National Academy member and Chair of the Department of Molecular Biology and Physiology, Roger Cone. Wallace and Cone were included for their failure to act on the student’s claims and protect her career.

 

For those outside the field, the neuroscience community seems to be holding down opposite poles in gender and racial equality. The leadership of both the Journal of Neuroscience and the Society are enviably gender balanced in the last decade. SfN was one of the first national societies to initiate meaningful career-long mentorship for women and minorities. Thanks in part to this commitment, women constitute 50% of most neuroscience graduate training programs. The national attrition of women from academic science is also evident in Vanderbilt’s neuroscience program which has an all male leadership and > 30% of its training faculty as women. The vast majority of these female faculty members are assistant professors.

 

Sending a female graduate student from a heavily male influenced neuroscience graduate program to SfN would present many sources of potential conflict. The first SfN meeting the student claims she was harassed at was in New Orleans, a city proud of its tradition of asking women to show their breasts for beads.

 

The female graduate student alleges that at SfN, her PI required her to attend a cocktail party on a boat where senior male scientists “became intoxicated and were allowed to make romantic and sexual advances on the students”. <I’ll insert my editorial opinion that news does not surprise me especially in light of the report this week from Kate Clancy that the majority of women in her survey of field scientists say they have been harassed with more than 20% reporting that they have been assaulted.>

 

Why would anyone attend boat party or any other kind of party where alcohol is flowing freely and fun is a much more clear objective than science?   For many trainees, this is often the only chance they have to spend time talking to well-published PIs. Presumably, at a party like this, senior investigators would be amenable to laid back conversations with trainees providing a rare chance to judge the character of potential future mentors.

 

These parties are the products of the bygone era of much larger gatherings held a decade or more ago by men who were SfN officers and investigators. Hosts had ample institutional ‘slush’ funds and open bar was the norm. The fabled parties hosted by former Emory Psychiatry chairman Charlie Nemeroff were more or less the height of partying for many members.

 

While at Emory, Nemeroff managed to get millions in personal wealth by consulting for drug companies while also studying those drugs using funding for his lab from NIMH. This income presumably enabled him to host these lavish events. Nemeroff’s parties would often devolve into factions that went skinny-dipping, participated in drinking contests and unwelcome ass grabbing, and yes, accomplished some important networking.

 

From the Venderbuilt lawsuit, “networking” was the reported benefit Galli touted as a reason for the trainee to attend the boat party. Indeed, Galli trained at Emory from 1993-1995 while Nemeroff was there, so these kinds of parties probably did help him advance his career. The expectation that a female recovering alcoholic would likewise benefit underscores a clear cultural clash that needs to be addressed by both the Vanderbilt community and the Society for Neuroscience.

30 responses so far

A chance to support research on Parkinson's Disease

Apr 23 2014 Published by under CrowdFund, LinkLove, Neuroscience, Public Health

The scientist known as @parklifensci (Parklife blog) on the Internet will be walking in the Parkinson's Unity Walk. The donation page says:

Why I'm walking:
Every walker and donor makes a difference by taking the Walk one step closer to finding the cause and cure for Parkinson’s. By joining together with thousands of others, we'll be empowering those who are living with the disease, and honoring those who lived with Parkinson’s.

Who I’m walking for:
Over 1 million people in the United States have Parkinson’s. 60,000 people are newly diagnosed every year – one person, every nine minutes. Walking and raising funds and awareness for research is my chance to help.

Why I'm supporting the Parkinson’s Unity Walk:
100% of donations go to research. The Parkinson’s Unity Walk is the largest grassroots event in the U.S., raising funds and awareness for research.

Ways to support my fundraising efforts:
There's strength in numbers so please join me. Donate, register to walk, and fundraise.

I encourage you to donate if you can or join the walk if you are nearby.

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Faces of Neuroscience: Jean A. King, Ph.D.

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.

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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.

One response so far

The Society for Neuroscience is launching a new Open Access journal

Jan 15 2014 Published by under Neuroscience, Open Access, Society for Neuroscience

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?

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

13 responses so far

BRAIN Initiative

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

35 responses so far

Failure to Replicate

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.

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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

19 responses so far

Go Team!!!!!

Feb 03 2013 Published by under Neuroscience, Psychology, Public Health

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

Go #teamneuron!

5 responses so far

Should NIMH be funding Me-Too drug development?

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?
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*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

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