Saturday, March 28, 2015

Follow #CNS2015

Whether or not you're in sunny San Francisco for the start of Cognitive Neuroscience Society Meeting today, you can follow Nick Wan's list of conference attendees on Twitter: @nickwan/#CNS2015. There's also the #CNS2015 hashtag, and the official @CogNeuroNews account.

Nick will also be blogging from the conference at True Brain. You may see a post or two from The Neurocritic, but I'm usually not very prompt about it. Please comment if you'll be blogging too.

Two of the program highlights are today:

Keynote Address, Anjan Chatterjee:
“The neuroscience of aesthetics and art”

2015 Distinguished Career Contributions Awardee, Marta Kutas:
“45 years of Cognitive Electrophysiology: neither just psychology nor just the brain but the visible electrical interface between the twain”

Here are the CNS interviews with Dr. Chatterjee and Dr. Kutas.

Enjoy the meeting!

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Monday, March 16, 2015

Update on the BROADEN Trial of DBS for Treatment-Resistant Depression

Website for the BROADEN™ study, which was terminated

In these days of irrational exuberance about neural circuit models, it's wise to remember the limitations of current deep brain stimulation (DBS) methods to treat psychiatric disorders. If you recall (from Dec. 2013), Neurotech Business Report revealed that "St. Jude Medical failed a futility analysis of its BROADEN trial of DBS for treatment of depression..."

A recent comment on my old post about the BROADEN Trial1 had an even more pessimistic revelation: there was only a 17.2% chance of a successful study outcome:
Regarding Anonymous' comment on January 30, 2015 11:01 AM, as follows in part:
"Second, the information that it failed FDA approval or halted by the FDA is prima facie a blatant lie and demonstratively false. St Jude, the company, withdrew the trial."

Much of this confusion could be cleared up if the study sponsors practiced more transparency.
A bit of research reveals that St. Judes' BROADEN study was discontinued after the results of a futility analysis predicted the probability of a successful study outcome to be no greater than 17.2%. (According to a letter from St. Jude)

Medtronic hasn't fared any better. Like the BROADEN study, Medtronics' VC DBS study was discontinued owing to inefficacy based on futility Analysis.

If the FDA allowed St. Jude to save face with its shareholders and withdraw the trial rather than have the FDA take official action, that's asserting semantics over substance.

If you would like to read more about the shortcomings of these major studies, please read (at least):
Deep Brain Stimulation for Treatment-resistant Depression: Systematic Review of Clinical Outcomes,
Takashi Morishita & Sarah M. Fayad &
Masa-aki Higuchi & Kelsey A. Nestor & Kelly D. Foote
The American Society for Experimental NeuroTherapeutics, Inc. 2014
DOI 10.1007/s13311-014-0282-1

The Anonymous Commenter kindly linked to a review article (Morishita et al., 2014), which indeed stated:
A multicenter, prospective, randomized trial of SCC DBS for severe, medically refractory MDD (the BROADEN study), sponsored by St. Jude Medical, was recently discontinued after the results of a futility analysis (designed to test the probability of success of the study after 75 patients reached the 6-month postoperative follow-up) statistically predicted the probability of a successful study outcome to be no greater than 17.2 % (letter from St. Jude Medical Clinical Study Management).

I (and others) had been looking far and wide for an update on the BROADEN Trial, whether in or published by the sponsors. Instead, the authors of an outside review article (who seem to be involved in DBS for movement disorders and not depression) had access to a letter from St. Jude Medical Clinical Studies.

Another large randomized controlled trial that targeted different brain structures (ventral capsule/ventral striatum, VC/VS) also failed a futility analysis (Morishita et al., 2014):
Despite the very encouraging outcomes reported in the open-label studies described above, a recent multicenter, prospective, randomized trial of VC/VS DBS for MDD sponsored by Medtronic failed to show significant improvement in the stimulation group compared with a sham stimulation group 16 weeks after implantation of the device. This study was discontinued owing to perceived futility, and while investigators remain hopeful that modifications of inclusion criteria and technique might ultimately result in demonstrable clinical benefit in some cohort of severely debilitated, medically refractory patients with MDD, no studies investigating the efficacy of VC/VS DBS for MDD are currently open.
In this case, however, the results were published (Dougherty et al., 2014):
There was no significant difference in response rates between the active (3 of 15 subjects; 20%) and control (2 of 14 subjects; 14.3%) treatment arms and no significant difference between change in Montgomery-Åsberg Depression Rating Scale scores as a continuous measure upon completion of the 16-week controlled phase of the trial. The response rates at 12, 18, and 24 months during the open-label continuation phase were 20%, 26.7%, and 23.3%, respectively.

Additional studies (with different stimulation parameters, better target localization, more stringent subject selection criteria) are needed, one would say. Self-reported outcomes from the patients themselves range from “...the side effects caused by the device were, at times, worse than the depression itself” to “I feel like I have a second chance at life.”

So where do we go now?? Here's a tip: all the forward-looking investors are into magnetic nanoparticles these days (see Magnetic 'rust' controls brain activity)...

UPDATE to the update (March 22 2015): The Vancouver Sun reported (on 3/17/2015) that the sponsor ended the trial:
A procedure that treats depression by using electrodes implanted deep in the brain won’t be available to the public soon, says the researcher who pioneered the procedure more than a decade ago with a team at the University of Toronto.

Neurologist Dr. Helen Mayberg, now at Emory University in Atlanta, said in Vancouver Tuesday that 80 per cent of her recent patients find sustained relief from severe depression after fine wires are surgically implanted to deliver electrical current to a specific part of the brain.

But a medical equipment maker halted its tests to commercialize the discovery six months after implanting devices in 125 recruits in 2013.

Data from that work has not yet been released by St. Jude Medical Inc. based in St. Paul, Minn., although a spokesman for the company said Tuesday that it will be made public. The patients still have the implanted devices and the study was not stopped for safety reasons.


1 BROADEN is an tortured acronym for BROdmann Area 25 DEep brain Neuromodulation. The target was subgenual cingulate cortex (aka BA 25). The trial was either halted by the FDA or withdrawn by the sponsor.


Dougherty DD, Rezai AR, Carpenter LL, Howland RH, Bhati MT, O'Reardon JP, Eskandar EN, Baltuch GH, Machado AD, Kondziolka D, Cusin C, Evans KC, Price LH, Jacobs K, Pandya M, Denko T, Tyrka AR, Brelje T, Deckersbach T, Kubu C, Malone DA Jr. (2014). A Randomized Sham-Controlled Trial of Deep Brain Stimulation of the Ventral Capsule/Ventral Striatum for Chronic Treatment-Resistant Depression. Biol Psychiatry Dec 13. [Epub ahead of print].

Morishita, T., Fayad, S., Higuchi, M., Nestor, K., & Foote, K. (2014). Deep Brain Stimulation for Treatment-resistant Depression: Systematic Review of Clinical Outcomes. Neurotherapeutics, 11 (3), 475-484. DOI: 10.1007/s13311-014-0282-1

DBS for MDD targets as of November 2013
(Image credit: P. HUEY/SCIENCE)

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Monday, March 09, 2015

Daylight Savings Time and "The Dress"

Could one's chronotype (degree of "morningness" vs. "eveningness") be related to your membership on Team white/gold vs. Team blue/black?

Dreaded by night owls everywhere, Daylight Savings Time forces us to get up an hour earlier. Yes, [my time to blog and] I have been living under a rock, but this evil event and an old tweet by Vaughan Bell piqued my interest in melanopsin and intrinsically photosensitive retinal ganglion cells.

I thought this was a brilliant idea, perhaps differences in melanopsin genes could contribute to differences in brightness perception. More about that in a moment.

{Everyone already knows about #thedress from Tumblr and Buzzfeed and Twitter obviously}

In the initial BuzzFeed poll, 75% saw it as white and gold, rather than the actual colors of blue and black. Facebook's more systematic research estimated this number was only 58% (and influenced by probably exposure to articles that used Photoshop). Facebook also reported differences by sex (males more b/b), age (youngsters more b/b), and interface (more b/b on computer vs. iPhone and Android).

Dr. Cedar Riener wrote two informative posts about why people might perceive the colors differently, but Dr. Bell was not satisfied with this and other explanations. Wired consulted two experts in color vision:
“Our visual system is supposed to throw away information about the illuminant and extract information about the actual reflectance,” says Jay Neitz, a neuroscientist at the University of Washington. “But I’ve studied individual differences in color vision for 30 years, and this is one of the biggest individual differences I’ve ever seen.”
“What’s happening here is your visual system is looking at this thing, and you’re trying to discount the chromatic bias of the daylight axis,” says Bevil Conway, a neuroscientist who studies color and vision at Wellesley College. “So people either discount the blue side, in which case they end up seeing white and gold, or discount the gold side, in which case they end up with blue and black.”

Finally, Dr. Conway threw out the chronotype card:
So when context varies, so will people’s visual perception. “Most people will see the blue on the white background as blue,” Conway says. “But on the black background some might see it as white.” He even speculated, perhaps jokingly, that the white-gold prejudice favors the idea of seeing the dress under strong daylight. “I bet night owls are more likely to see it as blue-black,” Conway says.

Melanopsin and Intrinsically Photosensitive Retinal Ganglion Cells

Rods and cones are the primary photoreceptors in the retina that convert light into electrical signals. The role of the third type of photoreceptor is very different. Intrinsically photosensitive retinal ganglion cells (ipRGCs) sense light without vision and:
  • ...contribute to the regulation of pupil size and other behavioral responses to ambient lighting conditions...
  • ...contribute to photic regulation of, and acute photic suppression of, release of the hormone melatonin...

Recent research suggests that ipRGCs may play more of a role in visual perception than was originally believed. As Vaughan said, melanopsin (the photopigment in ipRGCs) is involved in brightness discrimination and is most sensitive to blue light. Brown et al. (2012) found that melanopsin knockout mice showed a change in spectral sensitivity that affected brightness discrimination; the KO mice needed higher green radiance to perform the task as well as the control mice.

The figure below shows the spectra of human cone cells most sensitive to Short (S), Medium (M), and Long (L) wavelengths.

Spectral sensitivities of human cone cells, S, M, and L types. X-axis is in nm.

The peak spectral sensitivity for melanopsin photoreceptors is in the blue range. How do you isolate the role of melanopsin in humans?  Brown et al. (2012) used metamers, which are...
...light stimuli that appear indistinguishable to cones (and therefore have the same color and photopic luminance) despite having different spectral power distributions.  ... to maximize the melanopic excitation achievable with the metamer approach, we aimed to circumvent rod-based responses by working at background light levels sufficiently bright to saturate rods.

They verified their approach in mice, then used a four LED system to generate stimuli that diffed in presumed melanopsin excitation, but not S, M, or L cone excitation. All six of the human participants perceived greater brightness as melanopsin excitation increased (see Fig. 3E below). Also notice the individual differences in test radiance with the fixed 11% melanopic excitation (on the right of the graph).

Modified from Fig. 3E (Brown et al. (2012). Across six subjects, there was a strong correlation between the test radiance at equal brightness and the melanopic excitation of the reference stimulus (p < 0.001).1

Maybe Team white/gold and Team blue/black differ on this dimension? And while we're at it, is variation in melanopsin related to circadian rhythms, chronotype, even seasonal affective disorder (SAD)? 2 There is some evidence in favor of the circadian connections. Variants of the melanopsin (Opn4) gene might be related to chronotype and to SAD, which is much more common in women. Another Opn4 polymorphism may be related to pupillary light responses, which would affect light and dark adaptation. These genetic findings should be interpreted with caution, however, until replicated in larger populations.

Could This Device Hold the Key to “The Dress”?

ADDENDUM (March 10 2015): NO, according to Dr. Geoffry K. Aguirre of U. Penn.: Speaking as a guy with a 56-primary version of This Device to study melanopsin, I think the answer to your question is 'no'…” His PNAS paper, Opponent melanopsin and S-cone signals in the human pupillary light response, is freely available.3

A recent method developed by Cao, Nicandro and Barrionuevo (2015) increases the precision of isolating ipRGC function in humans. The four-primary photostimulator used by Brown et al. (2012) assumed that the rod cells were saturated at the light levels they used. However, Cao et al. (2015) warn that “a four-primary method is not sufficient when rods are functioning together with melanopsin and cones.” So they:
...introduced a new LED-based five-primary photostimulating method that can independently control the excitation of melanopsin-containing ipRGC, rod and cone photoreceptors at constant background photoreceptor excitation levels.

Fig. 2 (Cao et al., 2015). The optical layout and picture of the five-primary photostimulator.

Their Journal of Vision article is freely available, so you can read all about the methods and experimental results there (i.e., I'm not even going to try to summarize them here).

So the question remains: beyond the many perceptual influences that everyone has already discussed at length (e.g., color constancy, Bayesian priors, context, chromatic bias, etc.), could variation in ipRGC responses influence how you see “The Dress”?


1Fig 3E (continued). The effect was unrelated to any impact of melanopsin on pupil size. Subjects were asked to judge the relative brightness of three metameric stimuli (melanopic contrast −11%, 0%, and +11%) with respect to test stimuli whose spectral composition was invariant (and equivalent to the melanopsin 0% stimulus) but whose radiance changed between trials.

2 This would test Conway's quip that night owls are more likely to see the dress as blue and black.

3 Aguirre also said that a contribution from melanopsin (to the dress effect) was doubtful, at least from any phasic effect: “It's a slow signal with poor spatial resolution and subtle perceptual effects.” It remains to be seen whether any bias towards discarding blue vs. yellow illuminant information is affected by chronotype.

Interesting result from Spitschan, Jain, Brainard, & Aguirre 2014):
The opposition of the S cones is revealed in a seemingly paradoxical dilation of the pupil to greater S-cone photon capture. This surprising result is explained by the neurophysiological properties of ipRGCs found in animal studies.


Brown, T., Tsujimura, S., Allen, A., Wynne, J., Bedford, R., Vickery, G., Vugler, A., & Lucas, R. (2012). Melanopsin-Based Brightness Discrimination in Mice and Humans. Current Biology, 22 (12), 1134-1141 DOI: 10.1016/j.cub.2012.04.039

Cao, D., Nicandro, N., & Barrionuevo, P. (2015). A five-primary photostimulator suitable for studying intrinsically photosensitive retinal ganglion cell functions in humans. Journal of Vision, 15 (1), 27-27 DOI: 10.1167/15.1.27

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