The story of the early Italian neuroscientist Dr Angelo Mosso and his ‘human circulation balance’ is an old one – I remember reading about it as a student, in the introductory bit of a textbook on fMRI – but until now, the exact details were murky.

In the new paper, Italian neuroscientists Sandrone and colleagues report that they’ve unearthed Mosso’s original manuscripts from an archive in Milan.

Mosso worked in the late 19th century, an era that was – in retrospect – right at the dawn of modern neuroscience. A major question at that time was the relationship between brain function and blood flow.

His early work included studies of the blood pressure in the brains of individuals with skull defects. His most ambitious project, however, was his balance – or as he sometimes called it, according to his daughter, his ‘metal cradle’ or ‘machine to weigh the soul’.

Here’s his own 1884 drawing of the contraption:

It was in essence just a large balance. A volunteer lay on a table, their head on one side of the scale’s pivot and their feet on the other. It was carefully adjusted so that the two sides were perfectly balanced.

The theory was that if mental activity caused increased brain blood flow, it ought to increase the weight of the head relative to the rest of the body, so that side of the balance would fall.

Mosso claimed that this, indeed, occurred – starting to read a newspaper caused the brain to get weightier, while a difficult book of philosophy was even more effective, presumably because it required more mental effort to understand.

Matters were rather complex, however, because Mosso had realized that in order to obtain valid results, it was necessary to correct for things such as head movement, breathing, and pulse. These physiological artifacts still cause endless problems for neuroscientists to this day.

To measure and eliminate these sources of noise, Mosso build his balance to include a series of sphygmographs – pressure monitors (complex machines in their own right) – to record blood-flow in the hand, the foot, and also chest movements during breathing. The whole thing was connected to a pen that made a trace on a sheet of paper stuck to a rotating, clockwork drum – thus plotting the data as a graph.

But did it really work? It’s plausible, but Sandrone et al are noncommittal:

Overall, despite Mosso’s keen awareness of the number of artifacts that might arise from this procedure, together with his extensive efforts to quantify possible confounding variables, it is not clear whether the ‘Mosso method’ could realistically and sensibly discriminate between the signal (real brain blood flow changes) and the noise.

While it’s certainly true that local brain activity does alter local blood flow (this is the basis of fMRI and other modern neuroimaging methods), it’s hard to say whether this would affect the overall weight of the head. Even if it did, the effect might be too small to detect with any technology available in Mosso’s time.

Either way, it was an amazing endeavor. The public at the time were sold on the idea – so much so, that they sound almost 21st century in their hopes…

On 1 December 1908, a French newspaper reported that numerous people ‘were passionate about the experiments of Professor Angelo Mosso’ and enthusiastically believed that this device ‘would soon fully explain the physiology of the human brain’ and lead to new treatments for neurological and mental illnesses.

Plus ça change…?

Sandrone S, Bacigaluppi M, Galloni MR, Cappa SF, Moro A, Catani M, Filippi M, Monti MM, Perani D, & Martino G (2013). Weighing brain activity with the balance: Angelo Mosso’s original manuscripts come to light. Brain PMID: 23687118

A new paper in the journal European Neurology reports on a remarkable case of perceptual distortion that’ll please any connoisseur of neurogothic:

A 48-year-old woman woke up one morning without knowing where she was. She recognized her husband and finally realized that she was at home, but reported that she felt that all surroundings appeared ‘strange’ to her. She did not report any changes in the shape of furniture, rooms and people, but complained that voices and noises were ‘dinosaurs shouts’, or were made by ‘prehistorical beasts’…

After arriving at the hospital, she continued to complain that the surrounding sounds were made by dinosaurs, even adding that these were of the meat-eating type. She was not confused, she knew that she was in the hospital, and she reported the exact date.

A second case, this time a 61 year old male, reported seeing:

body distortion above the waist (especially the face) in people that he knew previously, not in people that he saw for the first time. He described Afro-style hair, sunken eyes, large ears, elongated eyebrows, saw-like teeth, discolored fingers and no nails. He reported that these perceptions were not real and were-not frightening…

MRI scans revealed that both patients had suffered strokes damaging the dorsomedial nucleus of the thalamus. The strange experiences stopped within a few days, and both of the patients made a good recovery.

The authors of the paper, neurologists Montserrat Delgado and Julien Bogousslavsky, say that these ‘monstrous’ perceptual alterations are a newly described syndrome. They’re not like classic hallucinations, in which sights and sounds appear ‘out of nowhere’. Nor are they the same as pareidolias, in which a random pattern or background is mistaken for a familiar thing.

Rather, these patients experienced distorted perceptions, in which familiar things appeared fantastic and unreal. The authors dub this distorteidolia.

Delgado MG, & Bogousslavsky J (2013). ‘Distorteidolias’ – Fantastic Perceptive Distortion. A New, Pure Dorsomedial Thalamic Syndrome. European neurology, 70 (1), 6-9 PMID: 23652461

Over at Scientific American, Samuel McNerney writes about the dangers of learning about common human cognitive biases. The problem is that it’s easy to find out about, say, confirmation bias, and think “Well, it affects other people, but now I know about it, I am immune to it” – and then proceed exactly as you did before, suffering the bias but now with misplaced confidence in your abilities.

I fear that a similar thing is at work in science, in the form of the Limitations Section.

It’s become fashionable for scientific papers to end with a few paragraphs about “the limitations of the work”. Why is this a problem?

Well, just as a morally confused Catholic might prefer to confess his sins regularly rather than change his sinful ways, the Limitations Section can serve as a kind of ritual cleansing which makes poor scientific practice seem acceptable. There’s a sense, usually unspoken, but I have heard it said, that “We acknowledge this limitation, so don’t criticize it.”

Worse still, if papers are getting published despite the fact that even the authors admit to a certain limitation, it would be easy to conclude that the limitation isn’t all that bad – so why should anyone bother fixing it?

Still, at least acknowledged limitations provide the reader with something to go on. Worse are the trivial ‘problems’ that often fill the Limitations Section, taking up room that ought to be spent addressing the real flaws. This kind of thing is actively misleading. To say that a handful of minor issues are the limitations is tantamount to saying there are no major ones.

When you think about it, it’s strange that scientists are expected to be their own critics in this way. Surely the flaws are for the reader to judge? Or the peer reviewers?

In fact, the reviewers are often the ones who write the Limitations Section, but I think this is often a way of passing the buck. When reviewing a manuscript, one sometimes feels that something about the study is flawed, not spectacularly so but seriously, and that in an ideal world it would prevent the paper from being published.

But rather than bite the bullet and reject the paper, you may feel – well, being realistic, everyone’s in the same boat, who hasn’t cut corners, and we’ve all got to earn a living… etc… – so you recommend the paper is accepted, but in order to avoid feeling like a walkover, you make the authors include your concerns as Limitations.

You act as the confessor for their scientific sins, in other words.

The BBC today has an interesting article by Mark Brown of British mental health magazine One in Four: Do famous role models help or hinder?

The context is that in Britain, charities and other advocates for people with mental illness have become fond of pointing to famous people, past and present, who suffered from a psychiatric disorder.

The hope is that highlighting these ‘role models’ will fight stigma and provide hope. Winston Churchill and Steven Fry are especially popular in this regard.

But, as Brown argues, these well-intentioned campaigns may not be so helpful -

“Look,” they say. “Here is a person who has achieved so much. Do not lose heart, you too can overcome your disability if you follow their example.”

…but where the inspirational figure is selected for us, and the gap between their life and ours is too great, the effect is not one of encouragement but of disillusionment – especially if their story is told in terms of personal qualities like bravery or persistence.

Knowing that a famous person has the same impairment as you can be reassuring, but only in the vague way that hearing of a successful distant relative is reassuring.

Most of us will never scale Everest, compete for our country at sports or have a showbiz career. This doesn’t mean we’ve failed.

I agree. “He’s got it, and so do you, so you can be like him” is perilously close to “He’s got it, and so do you, so you should be like him – what’s your excuse?”

That said, I think some of these celebrity examples are useful, not as generic inspirations for ‘the mentally ill’ but as concrete answers to particular attitudes. Against the simplistic view that there’s a single ‘stigma of mental illness’, I think there are many different stigmas and they have to be tackled separately.

In the case of depression, the core stigma is that depression is a weakness, a moral failing. That depressed people are soft, weak, pitiable. This attitude is specific to depression – not even bipolar disorder is seen in the same way, let alone the other diagnoses. They have their own stigmas. Depression’s is weakness.

Now this is why Churchill is a good counterexample. Not just because he’s famous or ‘great’, but because he was famously tough. He faced down Hitler. He was blood, sweat and tears. In the most famous photos of him (and they are famous, out of all his photos, because they correspond to the mental image) he is almost unsmiling – but never despairing. Just resolute.

That he experienced depression undermines the myths surrounding that condition, in a way that an entertainer or other generic celebrity wouldn’t.

But there are many beautiful ways of visualizing the brain’s connections, as neuroscientists Daniel Margulies and colleagues of Leipzig discuss in a colourful paper showcasing these techniques.

Here, for example, are two ways of showing the brain’s white matter tracts, as studied with diffusion tensor imaging (DTI):

Another striking image is this one, a representation of the brain’s functional connectivity – the degree to which activation in each part of the brain is correlated with activity in every other part.

The functional connectome is inherently difficult to visualize in 2D (or even 3D), but in this ingenious display, the brain’s surface is shown covered with hundreds of little brains, each one a colour-coded map of the connectivity from that particular point:

The Margulies paper is about more than just pretty pictures, though. The authors also discuss the scientific questions and theoretical tensions that surround the choice of one visualization over another:

Scientific figure and illustrations are – to paraphrase Tufte – where seeing turns into showing. The capacity of these images to influence our interpretation of data and to direct the questions of the scientific community make visualizations worthy of careful consideration during their production…

If we present a figure that clarifies the scientific content, but does so by creating a distortion of brain space, is that bad practice? What if the caption and methods explicitly stated that the contents of the figure were not to be taken literally? To what degree should a visualization be allowed to stand alone?

In my view, the study of connections has been dominated by images, more than any other branch of neuroscience. It’s rarely easy to say where ‘method’ or ‘analysis’ ends and ‘visualization’ begins.

This is not a bad thing – connectivity is spatial, by definition, and to understand space is to visualize it. But it does mean that in the connectome, there is always a danger of valuing aesthetics over accuracy, beauty above brains.

Margulies DS, Böttger J, Watanabe A, & Gorgolewski KJ (2013). Visualizing the Human Connectome. NeuroImage PMID: 23660027

In a short blog post last week, Thomas Insel, director of the National Institute of Mental Health (NIMH), announced that the organization would be “re-orienting its research away from DSM categories“.

After criticizing the fact that

Unlike our definitions of lymphoma or AIDS, the DSM diagnoses are based on a consensus about clusters of clinical symptoms, not any objective laboratory measure… Patients with mental disorders deserve better.

Insel went on:

NIMH has launched the Research Domain Criteria (RDoC) project to transform diagnosis by incorporating genetics, imaging, cognitive science, and other levels of information to lay the foundation for a new classification system…

This comes just weeks before the final publication of the latest edition of the American Psychiatric Association’s (APA) DSM – the notorious DSM-5.

In response to this, the APA released a statement saying, in essence, “Come back when you’ve actually done it; until then, we’ll carry on.”

What does this mean?

Well, you don’t need me to tell you. There’s been a lot written about this, some that’s good, much that’s not. A rule of thumb – if it mentions “paradigms” it’s probably the latter. For informed commentary, start out here, here and here.

In this post, rather than get into the details, I’d like to propose an analogy for NIMH’s move.

Some people have likened this to a ‘revolution’. In a previous draft of this post I toyed with the idea of a ‘civil war’ or a ‘coup’. But none of those really fit.

Rather I think that this ought to be seen as a Reformation, as in Protestant. Hey, we’re almost at the 500 year anniversary of the ‘post’ that started the last one.

We have an old, hegemonic institution, once revered but increasingly regarded as sclerotic – the DSM system / Catholic Church. This institution is, in theory, the one true embodiment of an idea – biological psychiatry / Christianity. But along comes a critic who believe in the idea, perhaps more fervently than ever, but want to reform the institution that they believe has failed its mission – Thomas Insel / Martin Luther.

Note that in this model, the DSM is the Church, not the Bible. Although a lot of people call it ‘The Bible of Psychiatry’, this ascribes to the DSM too creative a role. All the DSM does is codify and elaborate on a much older set of ideas. You can find the roots of most DSM diagnoses in psychiatry textbooks from decades before it was written. The DSM is more like the Catechism of psychiatry. The RDoC is a rival one.

This is why it’s wrong to see this as a paradigm shift. The NIMH proposals don’t mean a revolution in either research or treatment. Although researchers applying for NIMH grants will have to adapt the language of their pitches, framing it in terms of domains rather than disorders, I suspect that what they do with the money will be much the same.

Catholics and Protestants make much of their differences but to the rest of the world, they’re all Christians.

Suppose neuroscientists faced absolutely no financial or ethical constraints. What would that allow us to do? What kind of hitherto-intractable questions would we be able to answer?

Well, the money would certainly let us make our studies larger and more elaborate, while the lack of ethics would allow us to do the kind of research currently performed on animals, on humans (I did say a complete lack of ethics.)

But those kinds of improvements are all essentially quantitative – bigger samples, better species.

I wonder, would there be a qualitatively different neuroscience in such a neuro-dystopia?

Gabrielle Carlson of Stony Brook Children’s Hospital offers her thoughts in a brief paper: The Dramatic Rise in Neuroleptic Use In Children: Why Do We Do It and What Does It Buy Us?

Carlson is a specialist in ‘pediatric bipolar disorder’, which is a controversial topic at best, but I think this is still a thought-provoking piece:

The 10-bed children’s psychiatric inpatient unit at Stony Brook University Hospital, which opened in late 1986, treats children between the ages of 5 and 12…

The inpatient unit has experienced the same dramatic increase in use of neuroleptic medication as seen elsewhere, from 15.2% of patients receiving conventional antipsychotics in the 1988-1993 sample, to 68.5% use of atypical antipsychotics more recently (2002-2004, 2010-2011).

So the introduction of the newer, ‘atypical’ antipsychotics probably contributed to the rise, but there were other factors:

Simultaneously, however, the mean length of inpatient stay dropped from 10 weeks to 5 weeks. The rate of rehospitalization increased from 17% to 42%. Rates of children needing isolation have increased… Fewer children now return home to a biological parent.

It’s just not like it used to be:

Residents used to have a rotation of 3 months, meaning that they got to know and treat their patients; their rotations are now 1 month. Primary nurses used to spend time with the children; now they are shackled to their computers doing electronic medical records.

When children are admitted now, the first words out of the mouths of the managed care gatekeepers seems to be, “what drug are you going to start?” regardless of the six drugs the child was taking at admission…

She concludes that doctors turn to these drugs thanks to insufficient provision for other treatments:

Atypical antipsychotics clearly have important adverse effects. The question is whether society (and insurance companies) want to support the alternatives.

Carlson GA (2013). The dramatic rise in neuroleptic use in children: why do we do it and what does it buy us? Theories from inpatient data 1988-2010. Journal of child and adolescent psychopharmacology, 23 (3), 144-7 PMID: 23607407

To me, this paper marked the start of a new era of ‘critical’ (in the proper sense of thoughtful discussion and reflection) neuroscience, with fMRI researchers becoming more aware that fundamental statistics are as important as ever, despite the amazing technical advances and novel techniques of the 1990s and 2000s.

Now London neuroscientist James Kilner has reminded us that the ‘voodoo problem’ applies not only to fMRI but also to EEG and MEG, methods for measuring brain electro-magnetic activity: Bias in a common EEG and MEG statistical analysis and how to avoid it

The problem, in essence, is about selecting values out of a random population. If you apply a selection criteria to lots of random variables, and pick out only the highest (or lowest) values, then any statistical tests you run on those picked values will probably be biased because they’re selected. It sounds simple, but in a complex data analysis, it’s surprising how easy it is to select and test without realizing it.

In the case of EEG and MEG, the recorded data consists of anywhere from 20 to 250 sensors or electrodes placed around the head. It’s not clear however which sensors are most ‘interesting’ in any given experiment.

A common practice is to focus on the electrode at which the largest electrical or magnetic response (ERP) is seen to a given stimulus, but Kilner shows that this is dangerous unless care is taken to make the selection criteria independent of the subsequent analysis. Selection itself is fine, but ‘double dipping’ or ‘circular’ testing of the same things that were used as selection criteria (e.g. testing the size of the ERP at the electrode where that ERP is largest) is problematic.

Kilner, J. (2013). Bias in a common EEG and MEG statistical analysis and how to avoid it Clinical Neurophysiology DOI: 10.1016/j.clinph.2013.03.024

Neurorant’s criticism is anonymous, unscholarly, snarky, and not published in a peer reviewed journal… but it also has some bad points:

Pre-registration of studies is meant to stop unconstrained post-hoc analyses that end up finding differences that are actually just noise in the data.

That’s one of the motivations; but equally important, it will facilitate the publication of negative findings. Indeed, there seems to be a common misconception that registration is essentially about prevention, a kind of scientific contraceptive intended to eliminate bad results from the gene pool.

Pre-registration will act to discourage exploratory science… In fMRI, for example, the really interesting developments almost all use existing data… i.e. working on defining and understanding functional brain networks using data that has not been acquired for the purpose (e.g., generic resting state data). There’s no way to pre-register for this kind of research.

Let’s consider the example of the 1000 Connectomes Project, (1000C) an existing dataset of the kind in question. Anyone can download this, and analyze it. Should those analyses be preregistered?

My answer is: they already are. Or rather, they’re not, and everyone knows it, so everything’s above board, which is exactly how exploratory analyses would be under a registration regime. We all know that any 1000C finding might be a picked cherry from a rich fruit basket.

The trouble with the current system is that planned and exploratory analyses are confused. All registration does, at its core, is make the distinction clear.

Incidentally, I’m strongly in favor of fMRI data sharing.

It will slow science down for two reasons: i) there will end up being several rounds of review of the pre-registration phase so these will have to be written carefully, slowly. (If there isn’t any review of pre-registration then the whole thing can’t work).

This is another common misconception.

Registration doesn’t need to be linked to any kind of review. In clinical trial registration, the model for the whole thing, there isn’t any. You just submit. Likewise, anyone could just register their non-clinical work today, unilaterally. Jona Sassenhagen has, along with various others e.g. the Bem replication experiments.

No-one formally reviewed those notices of registration. The judge is the reader of the eventual results, who can compare them to the registered protocol and decide if they think the final cherries were subject to picking, or whether (most likely negative) results are going unreported.

That said, I believe that uniting preregistration and peer review (as implemented e.g. like this) would be a great idea, and that it could actually save time overall. This, however, is registration plus reform of peer-reviewed publishing. Plain vanilla registration is a lot simpler.

ii) In fast moving fields, there will be analysis and theoretically developments throughout the planning/data acquisition phase that will mean that if you’re taking pre-registration seriously, you have to re-register and collect more data, not just repurpose what you have. This may also involve people collecting even more boring FMRI datasets that all show the same thing (this already happens by the way), which swallows precious research resources.

I think the concern here is that registration will mean that if people have some data (or are halfway through collecting it) and want to try a new, unregistered analysis on it, they’d have to register and run a wasteful new study, rather than just repurposing the existing data. If that’s the worry, then it’s largely groundless. The authors in this case could do it, and publish it, as an exploratory analysis… which after all is what it is.

It’s true that if registration were combined with peer review, our hypothetical researchers might have to convince the reviewers (and the journal) to let them bundle the new analysis into the same paper as the registered stuff. But if it doesn’t get allowed, they could just publish it elsewhere. Whether or not to allow a large “Secondary Results” section of a paper is a matter for the journal; it’s a publishing decision.

Neurorant’s third point is that like an AAA credit rating, preregistration could be exploited by fraudsters. Well, I’m sure that will happen – unfortunately, fraudsters exploit systems. It’s what they do. They’re doing it currently. I’m not aware of an increase in fraud in US clinical trials after they were all made preregistered by law, although that would be interesting to investigate.

Finally (and I detect a mischievous grin peering from between these lines)

I don’t think dodgy results in some papers have that big an effect, or not enough to lead to any drastic, restrictive countermeasures. In fact, it’s possible that having dodgy papers is good for science as a whole, maybe it’s like stochastic resonance in motor systems, a bit of noise may help the field.

Well, fair enough. Maybe it depends on the field of science you inhabit; some are worse-hit than others. But ultimately, I think this is a question of how you feel about science today:

Personally, I’m not smiling.