Wednesday, April 15, 2015

Trends in Cognitive, Computational, and Systems Neuroscience 2015

What are the Hot Topics in cognitive neuroscience? We could ask these people, or we could take a more populist approach by looking at conference abstracts. I consulted the program for the recent Cognitive Neuroscience Society meeting (CNS 2015) and made a word cloud using Wordle.1 For comparison, we'll examine the program for the most recent Computational and Systems Neuroscience meeting (Cosyne 2015).

CNS is all about memory, people, and cognitive processing.

Cosyne is about neurons, models, and neural activity.

Read more »

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Monday, April 06, 2015

Cognitive Neuroscience 2015: State of the Union

What can we do to solve the mind/body problem once and for all? How do we cure devastating brain diseases like Alzheimer's, Parkinson's, schizophrenia, and depression? I am steadfast in following the course of my 500 year plan that may eventually solve these pressing issues, to the benefit of all Americans!

There's nothing like attending a conference in the midst of a serious family illness to make one take stock of what's important. My mind/brain has been elsewhere lately, along with my body in a different location. My blogging output has declined while I live in this alternate reality. But aside from the disunion caused by depersonalization/derealization, what is my view of the state of Cognitive Neuroscience in 2015?

But first, let's examine what we're trying to unify. Studies of mind and studies of brain?  Cognition and neuroscience?  Let's start with “neuroscience”.

Wikipedia says:
Neuroscience is the scientific study of the nervous system. Traditionally, neuroscience has been seen as a branch of biology. ... The term neurobiology is usually used interchangeably with the term neuroscience, although the former refers specifically to the biology of the nervous system, whereas the latter refers to the entire science of the nervous system. 

This reminds me of a recent post by Neuroskeptic, who asked: Is Neuroscience Based On Biology? On the face of it, this seemed like an absurd question to me, because the brain is a biological organ and of course we must know its biology to understand how it works. But what he really meant was, Is Cognitive Science Based On Biology? I say this because he adopted a functionalist view and used the brain-as-computer metaphor:
Could it be that brains are only accidentally made of cells, just as computers are only accidentally made of semiconductors? If so, neuroscience would not be founded on biology but on something else, something analogous to the mathematical logic that underpins computer science. What could this be?

See John Searle on Beer Cans & Meat Machines (1984):
This view [the brain is just a digital computer and the mind is just a computer program] has the consequence that there’s nothing essentially biological about the human mind. The brain just happens to be one of an indefinitely large number of different kinds of hardware computers that could sustain the programs which make up human intelligence. ... So, for example, if you made a computer out of old beer cans powered by windmills, if it had the right program. It would have to have a mind.

The infamous argument-by-beer-cans. In the end, Neuroskeptic admitted he's not sure he subscribes to this view. But the post sparked an interesting discussion. There were a number of good comments, e.g. Jayarava said: “Neuro-science absolutely needs to be neuron-science, to focus on brains made of cells because that's what we need to understand in the first place.” Indeed, some neuroscientists don't consider “cognitive neuroscience” to be “neuroscience” at all, because the measured units are higher (i.e., less reductionist) than single neurons.1

A comment by Adam Calhoun gets to the heart of the matter, making a sharp point about the disunity of neuroscience:
Although we use the term 'neuroscience' as though it refers to one coherent discipline, the problem here is that it does not. If you were to pick a neuroscientist at random and ask: "what does your field study?" you will not get the same answer two times in a row.

Neural development? Molecular pathways? Cognition? Visual processing? Are these the same field? Or different fields that have been given the same name?

One of the selling points of neuroscience is its interdisciplinary nature, but it's really hard to talk to each other if we don't speak the same language (or work in the same field). Some graduate programs dwell in an idealized world where students can become knowledgeable in molecular, cellular, developmental, systems, and cognitive neuroscience in one year. The reality is that professors in some subfields couldn't pass the exams given in another subfield. And why would they possibly want to do this, given they're way too busy writing grants.

Sometimes I think cognitive neuroscience is on a completely different planet from the other branches, estranged from even its closest cousin, behavioral neuroscience.2 It's even further away these days from systems neuroscience3 which used to be dominated by the glamour of single unit recordings in monkeys, but now is all about manipulating circuits with opto- and chemogenetics.

But as the Systems/Circuits techniques get more and more advanced (and invasive and mechanistic), the gulf between animal and human studies grows larger and the prospects for clinical translation fade.  [Until the neuroengineers come in and save the day.]

I'll end on a more optimistic note, with a quote from a man who wished to bridge the gap between Aplysia californica and Sigmund Freud.


1 And often not even a direct measure of neural activity at all (e.g. the hemodynamic response in fMRI). The rare exceptions to this are studies in patients with epilepsy, which have revealed the existence of Marilyn Monroe neurons and Halle Berry neurons and (my personal favorite) the rare multimodal Robert Plant neuron in the medial temporal lobe.

2 Though if you look at the mission of the journal called Behavioral Neuroscience, its scope has broadened to include just about anything:
We seek empirical papers reporting novel results that provide insight into the mechanisms by which nervous systems produce and are affected by behavior. Experimental subjects may include human and non-human animals and may address any phase of the lifespan, from early development to senescence.

Studies employing brain-imaging techniques in normal and pathological human populations are encouraged, as are studies using non-traditional species (including invertebrates) and employing comparative analyses. Studies using computational approaches to understand behavior and cognition are particularly encouraged.

In addition to behavior, it is expected that some aspect of nervous system function will be manipulated or observed, ranging across molecular, cellular, neuroanatomical, neuroendocrinological, neuropharmacological, and neurophysiological levels of analysis. Behavioral studies are welcome so long as their implications for our understanding of the nervous system are clearly described in the paper.

3 Actually, systems neuroscience is mostly about engineering and computational modelling these days.

Some Final Definitions (for the record)

The Society for Neuroscience (SfN) explanation of what neuroscientists do:
Neuroscientists specialize in the study of the brain and the nervous system. They are inspired to try to decipher the brain’s command of all its diverse functions. Over the years, the neuroscience field has made enormous progress. Scientists continue to strive for a deeper understanding of how the brain’s 100 billion nerve cells [NOTE: the number is only 86 billion] are born, grow, and connect. They study how these cells organize themselves into effective, functional circuits that usually remain in working order for life.

The SfN mission:
SfN advances the understanding of the brain and the nervous system by bringing together scientists of diverse backgrounds, facilitating the integration of research directed at all levels of biological organization, and encouraging translational research and the application of new scientific knowledge to develop improved disease treatments and cures. 

The CNS mission:
The Cognitive Neuroscience Society (CNS) is committed to the development of mind and brain research aimed at investigating the psychological, computational, and neuroscientific bases of cognition.

The term cognitive neuroscience has now been with us for almost three decades, and identifies an interdisciplinary approach to understanding the nature of thought.

And according to Wikipedia:
Cognitive neuroscience is an academic field concerned with the scientific study of biological substrates underlying cognition,[1] with a specific focus on the neural substrates of mental processes. It addresses the questions of how psychological/cognitive functions are produced by neural circuits in the brain. Cognitive neuroscience is a branch of both psychology and neuroscience, overlapping with disciplines such as physiological psychology, cognitive psychology and neuropsychology.[2] Cognitive neuroscience relies upon theories in cognitive science coupled with evidence from neuropsychology and computational modeling.[2]

Barack Obama, Jan. 24, 2012:
“…We should all want a smarter, more effective government. And while we may not be able to bridge our biggest philosophical differences this year, we can make real progress. With or without this Congress, I will keep taking actions that help the economy grow. But I can do a whole lot more with your help. Because when we act together, there is nothing the United States of America can’t achieve.”

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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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Thursday, February 19, 2015

One Brain Network for All Mental Illness

What do schizophrenia, bipolar disorder, major depression, addiction, obsessive compulsive disorder, and anxiety have in common? A loss of gray matter in the dorsal anterior cingulate cortex (dACC) and bilateral anterior insula, according to a recent review of the structural neuroimaging literature (Goodkind et al., 2015). These two brain regions are important for executive functions, the top-down cognitive processes that allow us to maintain goals and flexibly alter our behavior in response to changing circumstances. The authors modestly concluded they had identified a “Common Neurobiological Substrate for Mental Illness.”

One problem with this view is that the specific pattern of deficits in executive functions, and their severity, differ across these diverse psychiatric disorders. For instance, students with anxiety perform worse than controls in verbal selection tasks, while those with depression actually perform better (Snyder et al., 2014). Another problem is that gray matter volume in the dorsolateral prefrontal cortex, a key region for working memory (a core impairment in schizophrenia and to a lesser extent, in major depression and non-psychotic bipolar disorder), was oddly unaffected in the meta-analysis.

The NIMH RDoC movement (Research Domain Criteria) aims to explain the biological basis of psychiatric symptoms that cut across traditional DSM diagnostic categories. But I think some of the recent research that uses this framework may carry the approach too far (Goodkind et al., 2015):
Our findings ... provide an organizing model that emphasizes the import of shared endophenotypes across psychopathology, which is not currently an explicit component of psychiatric nosology. This transdiagnostic perspective is consistent...with newer dimensional models such as the NIMH’s RDoC Project.

However, not even the Director of NIMH believes this is true:
"The idea that these disorders share some common brain architecture and that some functions could be abnormal across so many of them is intriguing," said Thomas Insel, MD...


"I wouldn't have expected these results. I've been working under the assumption that we can use neuroimaging to help classify the different forms of mental illness," Insel said. "This makes it harder."

Anterior Cingulate and Anterior Insula and Everyone We Know

The dACC and anterior insula are ubiquitously activated 1 in human neuroimaging studies (leading Micah Allen to dub it the ‘everything’ network), and comprise either a salience network or task-set network (or even two separate cingulo-opercular systems) in resting state functional connectivity studies. But the changes reported in the newly published work were structural in nature. They were based on a meta-analysis of 193 voxel-based morphometry (VBM) studies that quantified gray matter volume across the entire brain in psychiatric patient groups, and compared this to controls.

Goodkind et al., (2015) included a handy flow chart for how they selected the papers for their review.

I could be wrong, but it looks like 34 papers were excluded because they found no differences between patients and controls. This would of course bias the results towards greater differences between patients and controls. And we don't know which of the six psychiatric diagnoses were included in the excluded batch. Was there an over-representation of null results in OCD? Anxiety? Depression?

What Does VBM Measure, Anyway?

Typically, VBM measures gray matter volume, which in the cortex is determined by surface area (which can vary due to differences in folding patterns) and by thickness (Kanai & Rees, 2011). These can be differentially related to some ability or characteristic. For example, Song et al. (2015) found that having a larger surface area in early visual cortex (V1 and V2) was correlated with better performance in a perceptual discrimination task, while larger cortical thickness was actually correlated with worse performance. Other investigators warn that volume really isn't the best measure of structural differences between patients and controls, and that cortical thickness is better (Ehrlich et al., 2012):
Cortical thickness is assumed to reflect the arrangement and density of neuronal and glial cells, synaptic spines, as well as passing axons. Postmortem studies in patients with schizophrenia showed reduced neuronal size and a decrease in interneuronal neuropil, dendritic trees, cortical afferents, and synaptic spines, while no reduction in the number of neurons or signs of gliosis could be demonstrated.
This leads us to the huge gap between dysfunction in cortical and subcortical microcircuits and gross changes in gray matter volume.

Psychiatric Disorders Are Circuit Disorders

This motto tells us that mental illnesses are disorder of neural circuits, in line with the funding priorities of NIMH and the BRAIN Initiative. But structural MRI studies tell us nothing about the types of neurons that are affected. Or how their size, shape, and synaptic connections might be altered. Basically, volume loss in dACC and anterior insula could be caused by any number of reasons, and by different mechanisms across the disorders under consideration. Goodkind et al., (2015) state:
Our connection of executive functioning to integrity of a well-established brain network that is perturbed across a broad range of psychiatric diagnoses helps ground a transdiagnostic understanding of mental illness in a context suggestive of common neural mechanisms for disease etiology and/or expression.

But actually, we might find a reduction in the density of von Economo neurons in the dACC of individuals with early-onset schizophrenia (Brüne et al., 2010), but not in persons with other disorders. Or a reduction in the density of GAD67 mRNA-expressing neurons in ACC cortical layer 5 in schizophrenia, but not in bipolar disorder. On the other hand, we could see something like an alteration in the synapses onto parvalbumin inhibitory interneurons (due to stress) that cuts across multiple diagnoses.

And it's not always the case that bigger is better: smaller cortical volumes can also be associated with better performance (Kanai & Rees, 2011).

As Kanai and Rees (2011) noted in their review:
...a direct link between microstructures and macrostructures has not been established in the human brain. A histological study directly compared whether histopathological measurements of resected temporal lobe tissue correlated with grey matter density as used in typical VBM studies. However, none of the histological measures — including neuronal density — showed a clear relationship with the grey matter volume. 

So where do we go from here? Bridging the technological gulf between exceptionally invasive methods (like optogenetics and chemogenetics in animals) and non-invasive ones (TMS, MRI in humans) is a minor funding priority of the BRAIN Initiative. Another more manageable strategy for the present would be a comprehensive review of imaging, genetic, and post-mortem neuroanatomical studies of brains from people who lived with schizophrenia, bipolar disorder, major depression, addiction, obsessive compulsive disorder, and anxiety. This has been done most extensively (perhaps) for schizophrenia (e.g., Meyer-Lindenberg, 2010; Arnsten, 2011). Certain types of electrophysiological studies in primate prefrontal cortex may provide another bridge, although this has been disputed.

Goodkind and colleagues have indeed uncovered some “biological commonalities that may have been underappreciated in prior work,” but it's also clear there are “some fairly obvious distinctions between schizophrenia and bipolar disorder” at a clinical level (to give one example). In the rush to cut up psychiatric nosology along the RDoC dotted lines, let's not forget the limitations of current methods that are designed to do the carving.

Further Reading

Other comprehensive reviews:

Large-scale brain networks and psychopathology: a unifying triple network model

Does the salience network play a cardinal role in psychosis? An emerging hypothesis of insular dysfunction

Salience processing and insular cortical function and dysfunction

Critiques of phrenology-like VBM studies:

Now Is That Gratitude?

Should Policy Makers and Financial Institutions Have Access to Billions of Brain Scans?

Anthropomorphic Neuroscience Driven by Researchers with Large TPJs

Liberals Are Conflicted and Conservatives Are Afraid

Great discussion of a failure to replicate VBM studies (at Neuroskeptic):

Failed Replications: A Reality Check for Neuroscience?


1 To quote Russ Poldrack:
In Tal Yarkoni's recent paper in Nature Methods, 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!
2 Links to recent J Neurosci articles via @prerana123 and @MyCousinAmygdala.


Brüne M, Schöbel A, Karau R, Benali A, Faustmann PM, Juckel G, Petrasch-Parwez E. (2010). Von Economo neuron density in the anterior cingulate cortex is reduced inearly onset schizophrenia. Acta Neuropathol. 119(6):771-8.

Ehrlich S, Brauns S, Yendiki A, Ho BC, Calhoun V, Schulz SC, Gollub RL, Sponheim SR. (2012). Associations of cortical thickness and cognition in patients with schizophrenia and healthy controls. Schizophr Bull. 38(5):1050-62.

Goodkind, M., Eickhoff, S., Oathes, D., Jiang, Y., Chang, A., Jones-Hagata, L., Ortega, B., Zaiko, Y., Roach, E., Korgaonkar, M., Grieve, S., Galatzer-Levy, I., Fox, P., & Etkin, A. (2015). Identification of a Common Neurobiological Substrate for Mental Illness. JAMA Psychiatry DOI: 10.1001/jamapsychiatry.2014.2206

Kanai, R., & Rees, G. (2011). The structural basis of inter-individual differences in human behaviour and cognition. Nature Reviews Neuroscience, 12 (4), 231-242. DOI: 10.1038/nrn3000

Song C, Schwarzkopf DS, Kanai R, Rees G. (2015). Neural population tuning links visualcortical anatomy to human visual perception. Neuron 85(3):641-56.

Snyder HR, Kaiser RH, Whisman MA, Turner AE, Guild RM, Munakata Y. (2014). Opposite effects of anxiety and depressive symptoms on executive function: the case of selecting among competing options. Cogn Emot. 28(5):893-902.

Fig. 3 (Meyer-Lindenberg, 2010). Schematic summary of putative alterations in dorsolateral prefrontal cortex circuitry in schizophrenia.

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Saturday, January 31, 2015

Against Initiatives: "don't be taken in by the boondoggle"

 ...or should I say braindoggle...

I've been reading The Future of the Brain, a collection of Essays by the World's Leading Neuroscientists edited by Gary Marcus and Jeremy Freeman. Amidst the chapters on jaw-dropping technical developments, Big Factory Science, and Grand Neuroscience Initiatives, one stood out for its contrarian stance (and personally reflective tone). Here's Professor Leah Krubitzer, who heads the Laboratory of Evolutionary Biology at University of California, Davis:

“From a personal rather than scientific standpoint, the final important thing I've learned is don't be taken in by the boondoggle, don't get caught up in technology, and be very suspicious of "initiatives." Science should be driven by questions that are generated by inquiry and in-depth analysis rather than top-down initiatives that dictate scientific directions. I have also learned to be suspicious of labels declaring this the "decade of" anything: The brain, The mind, Consciousness. There should be no time limit on discovery. Does anyone really believe we will solve these complex, nonlinear phenomena in ten years or even one hundred? Tightly bound temporal mandates can undermine the important, incremental, and seemingly small discoveries scientists make every day doing critical, basic, nonmandated research. These basic scientific discoveries have always been the foundation for clinical translation. By all means funding big questions and developing innovative techniques is worthwhile, but scientists and the science should dictate the process.”

...although it should be said that a bunch of scientists did at least contribute to the final direction taken by the BRAIN Initiative (Brain Research through Advancing Innovative NeurotechnologiesSM)...

An AS @ UVA Project
by Meagan Hess
May 2004

Top image: vintage spoof Monopoly game issued during the 1936 US presidential campaign.

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