Sunday, November 29, 2015

Carving Up Brain Disorders

Neurology and Psychiatry are two distinct specialties within medicine, both of which treat disorders of the brain. It's completely uncontroversial to say that neurologists treat patients with brain disorders like Alzheimer's disease and Parkinson's disease. These two diseases produce distinct patterns of neurodegeneration that are visible on brain scans. For example, Parkinson's disease (PD) is a movement disorder caused by the loss of dopamine neurons in the midbrain.

Fig. 3 (modified from Goldstein et al., 2007). Brain PET scans superimposed on MRI scans. Note decreased dopamine signal in the putamen and substantia nigra (S.N.) bilaterally in the patient.

It's also uncontroversial to say that drugs like L-DOPA and invasive neurosurgical interventions like deep brain stimulation (DBS) are used to treat PD.

On the other hand, some people will balk when you say that psychiatric illnesses like bipolar disorder and depression are brain disorders, and that drugs and DBS (in severe intractable cases) may be used to treat them. You can't always point to clear cut differences in the MRI or PET scans of psychiatric patients, as you can with PD (which is a particularly obvious example).

The diagnostic methods used in neurology and psychiatry are quite different as well. The standard neurological exam assesses sensory and motor responses (e.g., reflexes) and basic mental status. PD has sharply defined motor symptoms including tremor, rigidity, impaired balance, and slowness of movement. There are definitely cases where the symptoms of PD should be attributed to another disease (most notably Lewy body dementia)1, and other examples where neurological diagnosis is not immediately possible. But by and large, no one questions the existence of a brain disorder.

Things are different in psychiatry. Diagnosis is not based on a physical exam. Psychiatrists and psychologists give clinical interviews based on the Diagnostic and Statistical Manual (DSM-5), a handbook of mental disorders defined by a panel of experts with opinions that are not universally accepted. The update from DSM-IV to DSM-5 was highly controversial (and widely discussed).

The causes of mental disorders are not only biological, but often include important social and interpersonal factors. And their manifestations can vary across cultures.

Shortly before the release of DSM-5, the former director of NIMH (Dr. Tom Insel) famously dissed the new manual:
The strength of each of the editions of DSM has been “reliability” – each edition has ensured that clinicians use the same terms in the same ways. The weakness is its lack of validity. Unlike our definitions of ischemic heart disease, lymphoma, or AIDS, the DSM diagnoses are based on a consensus about clusters of clinical symptoms, not any objective laboratory measure.

In other words, where are the clinical tests for psychiatric disorders?

For years, NIMH has been working on an alternate classification scheme, the Research Domain Criteria (RDoC) project, which treats mental illnesses as brain disorders that should be studied according to domains of functioning (e.g., negative valence). Dimensional constructs such as acute threat (“fear”) are key, rather than categorical DSM diagnosis. RDoC has been widely discussed on this blog and elsewhere it's the best thing since sliced bread, it's necessary but very oversold, or it's ill-advised.

What does this have to do with neurology, you might ask? In 2007, Insel called for the merger of neurology and psychiatry:
Just as research during the Decade of the Brain (1990-2000) forged the bridge between the mind and the brain, research in the current decade is helping us to understand mental illnesses as brain disorders. As a result, the distinction between disorders of neurology (e.g., Parkinson's and Alzheimer's diseases) and disorders of psychiatry (e.g., schizophrenia and depression) may turn out to be increasingly subtle. That is, the former may result from focal lesions in the brain, whereas the latter arise from abnormal activity in specific brain circuits in the absence of a detectable lesion. As we become more adept at detecting lesions that lead to abnormal function, it is even possible that the distinction between neurological and psychiatric disorders will vanish, leading to a combined discipline of clinical neuroscience.

Actually, Insel's view dates back to 2005 (Insel & Quirion, 2005)....2
Future training might begin with two post-graduate years of clinical neuroscience shared by the disciplines we now call neurology and psychiatry, followed by two or three years of specialty training in one of several sub-disciplines (ranging from peripheral neuropathies to public sector and transcultural psychiatry). This model recognizes that the clinical neurosciences have matured sufficiently to resemble internal medicine, with core training required prior to specializing.

...and was expressed earlier by Dr. Joseph P. Martin, Dean of Harvard Medical School (Martin, 2002):
Neurology and psychiatry have, for much of the past century, been separated by an artificial wall created by the divergence of their philosophical approaches and research and treatment methods. Scientific advances in recent decades have made it clear that this separation is arbitrary and counterproductive. .... Further progress in understanding brain diseases and behavior demands fuller collaboration and integration of these fields. Leaders in academic medicine and science must work to break down the barriers between disciplines.

Contemporary leaders and observers of academic medicine are not all equally ecstatic about this prospect, however. Taylor et al. (2015) are enthusiastic advocates of a move beyond “Neural Cubism”, to increased integration of neurology and psychiatry. Dr. Sheldon Benjamin agrees that greater cross-discipline training is needed, but wants the two fields to remain separate. But Dr. Jose de Leon thinks the psychiatry/neurology integration is a big mistake that revives early 20th century debates (see table below, in the footnotes).3

I think a distinction can (and should) be made between the research agenda of neuroscience and the current practice of psychiatry. Neuroscientists who work on such questions assume that mental illnesses are brain disorders and act accordingly, by studying the brain. They study animal models and brain slices and genes and humans with implanted or attached electrodes and humans in scanners. And they study the holy grail of neural circuits using DREDDs and optogenetics. This doesn't invalidate the existence of social, cultural, and interpersonal factors that affect the development and manifestation of mental illnesses. As an non-clinician, I have less to say about medical practice. I'm not grandiose enough to claim that neuroscience research (or RDoC, for that matter) will transform the practice of psychiatry (or neurology) in the near future. [Though you might think differently if you read Public Health Relevance Statements or articles in high profile journals.]

Basic researchers may not even think about the distinction between neurology and psychiatry. Is the abnormal deposition of amyloid-β peptide in Alzheimer's disease (AD) an appropriate target for treatment? Are metabotropic glutamate receptors an appropriate target in schizophrenia? These are similar questions, despite the fact that one disease is neurological and the other psychiatric. There are defined behavioral endpoints that mark treatment-related improvements in either case. It's very useful to measure a change in amyloid burden4 using florbetapir PET imaging in AD [there's nothing similar in schizophrenia], but the most important measure is cognitive improvement (or a flattening of cognitive decline).

Does Location Matter?

In response to the pro-merger cavalcade, a recent meta-analysis asked whether the entire category of neurological disorders affects different brain regions than the entire category of psychiatric disorders (Crossley et al., 2015). The answer was why yes, the two categories affect different brain areas, and for this reason neurology and psychiatry should remain separate.

I thought this was an odd question to begin with, with an even odder conclusion. It's not surprising that disorders of movement, for example, involve different brain regions than disorders of mood or disorders of thought. From my perspective, it's more interesting to look at where the two categories overlap, with an eye to specific comparisons (not global lumping). For instance, are compulsive and repetitive behaviors in OCD associated with alterations in some of the subcortical circuits implicated in movement disorders? Why yes.

But let's take a closer look at the technical details of the study.

Read more »

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Sunday, November 22, 2015

Happiness Is a Large Precuneus

What is happiness, and how do we find it? There are 93,290 books on happiness at Happiness is Life's Most Important Skill, an Advantage and a Project and a Hypothesis that we can Stumble On and Hard-Wire in 21 Days.

The Pursuit of Happiness is an Unalienable Right granted to all human beings, but it also generates billions of dollars for the self-help industry.

And now the search for happiness is over! Scientists have determined that happiness is located in a small region of your right medial parietal lobe. Positive psychology gurus will have to adapt to the changing landscape or lose their market edge. “My seven practical, actionable principles are guaranteed to increase the size of your precuneus or your money back.”

The structural neural substrate of subjective happiness is the precuneus.

A new paper has reported that happiness is related to the volume of gray matter in a 222.8 mm3 cluster of the right precuneus (Sato et al., 2015). What does this mean? Taking the finding at face value, there was a correlation (not a causal relationship) between precuneus gray matter volume and scores on the Japanese version of the Subjective Happiness Scale.1

Fig. 1 (modified from Sato et al., 2015).  Left: Statistical parametric map (p < 0.001, peak-level uncorrected for display purposes). The blue cross indicates the location of the peak voxelRight: Scatter plot of the adjusted gray matter volume as a function of the subjective happiness score at the peak voxel. [NOTE: Haven't we agreed to not show regression lines through scatter plots based on the single voxel where the effect is the largest??]

The search for happiness: Using MRI to find where happiness happens,” said one deceptive headline. Should we accept the claim that one small region of the brain is entirely responsible for generating and maintaining this complex and desirable state of being?

NO. Of course not. And the experimental subjects were not actively involved in any sort of task at all. The study used a static measure of gray matter volume in four brain Regions of Interest (ROIs): left anterior cingulate gyrus, left posterior cingulate gyrus, right precuneus, and left amygdala. These ROIs were based on an fMRI activation study in 26 German men (mean age 33 yrs) who underwent a mood induction procedure (Habel et al., 2005). The German participants viewed pictures of faces with happy expressions and were told to “Look at each face and use it to help you to feel happy.” The brain activity elicited by happy faces was compared to activity elicited by a non-emotional control condition. Eight regions were reported in their Table 1.

Table 1 (modified from Habel et al., 2005).

Only four of those regions were selected as ROIs by Sato et al. (2015). One of these was a tiny 12 voxel region in the paracentral lobule, which was called precuneus by Sato et al. (2015).

Image: John A Beal, PhD. Dept. of Cellular Biology & Anatomy, Louisiana State University Health Sciences Center Shreveport.

Before you say I'm being overly pedantic, we can agree that the selected coordinates are at the border of the precuneus and the paracentral lobule. The more interesting fact is that the sadness induction of Habel et al. (2005) implicated a very large region of the posterior precuneus and surrounding regions (1562 voxels). An area over 100 times larger than the Happy Precuneus.

Oops. But the precuneus contains multitudes, so maybe it's not so tragic. The precuneus is potentially involved in very lofty functions like consciousness and self-awareness and the recollection of  autobiographical memories. It's also a functional core of the default-mode network (Utevsky et al., 2014), which is active during daydreaming and mind wandering and unconstrained thinking.

But it seems a bit problematic to use hand picked ROIs from a study of transient and mild “happy” states (in a population of German males) to predict a stable trait of subjective happiness in a culturally distinct group of younger Japanese college students (26 women, 25 men).

Cross-Cultural Notions of Happiness

Isn't “happiness” a social construct (largely defined by Western thought) that varies across cultures?

Should we expect “the neural correlates of happiness” (or well-being) to be the same in Japanese and Chinese and British college students? In the Chinese study, life satisfaction was positively correlated with gray matter volume in the right parahippocampal gyrus but negatively correlated with gray matter volume in the left precuneus... So the participants with the largest precuneus volumes in that study had the lowest well-being.

What does a bigger (or smaller) size even mean for actual neural processing? Does a larger gray matter volume in the precuneus allow for a higher computational capacity that can generate greater happiness?? We have absolutely no idea: “...there is no clear evidence of correlation between GM volume measured by VBM and any histological measure, including neuronal density” (Gilaie-Dotan et al., 2014).

Sato et al. (2015) concluded that their results have important practical implications: Are you happy? We don't have to take your word for it any more!
In terms of public policy, subjective happiness is thought to be a better indicator of happiness than economic success. However, the subjective measures of happiness have inherent limitations, such as the imprecise nature of comparing data across different cultures and the difficulties associated with the applications of these measures to specific populations, including the intellectually disabled. Our results show that structural neuroimaging may serve as a complementary objective measure of subjective happiness.

Finally, they issued the self-help throw down: “...our results suggest that psychological training that effectively increases gray matter volume in the precuneus may enhance subjective happiness.”

Resting-state functional connectivity of the default mode network associated with happiness is so last month...

adapted from Luo et al. (2015)

Further Reading

Are You Conscious of Your Precuneus?

Be nice to your Precuneus – it might be your real self…

Your Precuneus May Be the Root of Happiness and Satisfaction

The Precuneus and Recovery From a Minimally Conscious State


1 The Subjective Happiness Scale is a 4-item measure of global subjective happiness (Lyubomirsky & Lepper, 1999).


Habel, U., Klein, M., Kellermann, T., Shah, N., & Schneider, F. (2005). Same or different? Neural correlates of happy and sad mood in healthy males NeuroImage, 26 (1), 206-214 DOI: 10.1016/j.neuroimage.2005.01.014

Sato, W., Kochiyama, T., Uono, S., Kubota, Y., Sawada, R., Yoshimura, S., & Toichi, M. (2015). The structural neural substrate of subjective happiness Scientific Reports, 5 DOI: 10.1038/srep16891

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Monday, November 16, 2015

The Neuroscience of Social Media: An Unofficial History

There's a new article in Trends in Cognitive Sciences about how neuroscientists can incorporate social media into their research on the neural correlates of social cognition (Meshi et al., 2015). The authors outlined the sorts of social behaviors that can be studied via participants' use of Twitter, Facebook, Instagram, etc.: (1) broadcasting information; (2) receiving feedback; (3) observing others' broadcasts; (4) providing feedback; (5) comparing self to others.

Meshi, Tamir, and Heekeren / Trends in Cognitive Sciences (2015)

More broadly, these activities tap into processes and constructs like emotional state, personality, social conformity, and how people manage their self-presentation and social connections. You know, things that exist IRL (this is an important point to keep in mind for later).

The neural systems that mediate these phenomena, as studied by social cognitive neuroscience types, are the Mentalizing Network (in blue below), the Self-Referential Network (red), and the Reward Network (green).

Fig. 2 (Meshi et al., 2015). Proposed Brain Networks Involved in Social Media Use.  (i) mentalizing network: dorsomedial prefrontal cortex (DMPFC), temporoparietal junction (TPJ), anterior temporal lobe (ATL), inferior frontal gyrus (IFG), posterior cingulate cortex/precuneus (PCC). (ii) self-referential network: medial prefrontal cortex (MPFC) and PCC. (iii) reward network: ventromedial prefrontal cortex (VMPFC), ventral striatum (VS), ventral tegmental area (VTA). 

The article's publication was announced on social media:

I anticipated this day in 2009, when I wrote several satirical articles about the neurology of Twitter.  I proposed that someone should do a study to examine the neural correlates of Twitter use:
It was bound to happen. Some neuroimaging lab will conduct an actual fMRI experiment to examine the so-called "Neural Correlates of Twitter" -- so why not write a preemptive blog post to report on the predicted results from such a study, before anyone can publish the actual findings?

Here are the conditions I proposed, and the predicted results (a portion of the original post is reproduced below).

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Tuesday, November 10, 2015

Obesity Is Not Like Being "Addicted to Food"

Credit: Image courtesy of Aalto University

Is it possible to be “addicted” to food, much like an addiction to substances (e.g., alcohol, cocaine, opiates) or behaviors (gambling, shopping, Facebook)? An extensive and growing literature uses this terminology in the context of the “obesity epidemic”, and looks for the root genetic and neurobiological causes (Carlier et al., 2015; Volkow & Bailer, 2015).

Fig. 1 (Meule, 2015). Number of scientific publications on food addiction (1990-2014). Web of Science search term “food addiction”.

Figure 1 might lead you to believe that the term “food addiction” was invented in the late 2000s by NIDA. But this term is not new at all, as Adrian Meule (2015) explained in his historical overview, Back by Popular Demand: A Narrative Review on the History of Food Addiction Research. Dr. Theron G. Randolph wrote about food addiction in 1956 (he also wrote about food allergies).

Fig. 2 (Meule, 2015). History of food addiction research.

Thus, the concept of food addiction predates the documented rise in obesity in the US, which really took off in the late 80s to late 90s (as shown below).1

Prevalence of Obesity in the United States, 1960-2012

1960-62 1971-74 1976-80 1988-89 1999-2000
12.80% 14.10% 14.50% 22.50% 30.50%

2007-08 2011-12

33.80% 34.90%

Sources: Flegal et al. 1998, 2002, 2010; Ogden et al. 2014

One problem with the “food addiction” construct is that you can live without alcohol and gambling, but you'll die if you don't eat. Complete abstinence is not an option.2

Another problem is that most obese people simply don't show signs of addiction (Hebebrand, 2015):
...irrespective of whether scientific evidence will justify use of the term food and/or eating addiction, most obese individuals have neither a food nor an eating addiction.3 Obesity frequently develops slowly over many years; only a slight energy surplus is required to in the longer term develop overweight. Genetic, neuroendocrine, physiological and environmental research has taught us that obesity is a complex disorder with many risk factors, each of which have small individual effects and interact in a complex manner. The notion of addiction as a major cause of obesity potentially entails endless and fruitless debates, when it is clearly not relevant to the great majority of cases of overweight and obesity.

Still not convinced? Surely, differences in the brains' of obese individuals point to an addiction. The dopamine system is altered, right, so this must mean they're addicted to food? Well think again, because the evidence for this is inconsistent (Volkow et al., 2013; Ziauddeen & Fletcher, 2013).

An important new paper by a Finnish research group has shown that D2 dopamine receptor binding in obese women is not different from that in lean participants (Karlsson et al., 2015). Conversely, μ-opioid receptor (MOR) binding is reduced, consistent with lowered hedonic processing. After the women had bariatric surgery (resulting in mean weight loss of 26.1 kg, or 57.5 lbs), MOR returned to control values, while the unaltered D2 receptors stayed the same.

In the study, 16 obese women (mean BMI=40.4, age 42.8) had PET scans before and six months after undergoing the standard Gastric Bypass procedure (Roux-en-Y Gastric Bypass) or the Sleeve Gastrectomy. A comparison group of non-obese women (BMI=22.7, age 44.9) was also scanned. The radiotracer [11C]carfentanil measured MOR availability and [11C]raclopride measured D2R availability in two separate sessions. The opioid and dopamine systems are famous for their roles in neural circuits for “liking” (pleasurable consumption) and “wanting” (incentive/motivation), respectively (Castro & Berridge, 2014).

The pre-operative PET scans in the obese women showed that MOR binding was significantly lower in a number of reward-related regions, including ventral striatum, dorsal caudate, putamen, insula, amygdala, thalamus, orbitofrontal cortex and posterior cingulate cortex. Six months after surgery, there was an overall 23% increase in MOR availability, which was no longer different from controls.

Fig. 1 (modified from Karlsson et al., 2015). Top: μ-opioid receptors are reduced in obese participants pre-operatively (middle), but after bariatrc surgery (right) they recover to control levels (left). Bottom: D2 receptors are unaffected in the obese participants.

Karlsson et al. (2015) suggest that:
The MOR system promotes hedonic [pleasurable] aspects of feeding, and this can make obese individuals susceptible to overeating in order to gain the desired hedonic response from food consumption, which may further promote pathological eating. We propose that at the initial stages of weight gain, excessive eating may cause perpetual overstimulation of the MOR system, leading to subsequent MOR downregulation.  ...  However, bariatric surgery-induced weight loss and decreased food intake may reverse this process.

The unchanging striatal dopamine D2 receptor densities in the obese participants are in stark contrast to what is seen in individuals who are addicted to stimulant drugs, such as cocaine and methamphetamine (Volkow et al., 2001). Drugs of abuse are consistently associated with decreases in D2 receptors.

Fig. 1 (modified from Volkow et al., 2001). Ratio of the Distribution Volume of [11C]Raclopride in the Striatum (Normalized to the Distribution Volume in the Cerebellum) in a Non-Drug-Abusing Comparison Subject and a Methamphetamine Abuser.

So the next time you see a stupid ass headline like, “Cheese really is crack. Study reveals cheese is as addictive as drugs”, you'll know the writer is on crack.

Further Reading - The Scicurious Collection on Obesity

Overeating and Obesity: Should we really call it food addiction?

No, cheese is not just like crack

Dopamine and Obesity: The D2 Receptor

Dopamine and Obesity: The Food Addiction?

Cheesecake-eating rats and food addiction, a commentary


1 Not surprisingly, papers on the so-called obesity epidemic lagged behind the late 80s-mid 90s rise in prevalence.

- click on image for a larger view -
Number of papers on "obesity epidemic" in PubMed (1996-2015)

2 Notice in Fig. 2 that anorexia is considered the opposite: an addiction to starving.

3 Binge eating disorder (BED) might be another story, and I'll refer you to an informative post by Scicurious for discussion of that issue. You do not have to be obese (or even overweight) to have BED.


Carlier N, Marshe VS, Cmorejova J, Davis C, Müller DJ. (2015). Genetic Similarities between Compulsive Overeating and Addiction Phenotypes: A Case for "Food Addiction"? Curr Psychiatry Rep. 17(12):96.

Castro, D., & Berridge, K. (2014). Advances in the neurobiological bases for food ‘liking’ versus ‘wanting’ Physiology & Behavior, 136, 22-30 DOI: 10.1016/j.physbeh.2014.05.022

Karlsson, H., Tuulari, J., Tuominen, L., Hirvonen, J., Honka, H., Parkkola, R., Helin, S., Salminen, P., Nuutila, P., & Nummenmaa, L. (2015). Weight loss after bariatric surgery normalizes brain opioid receptors in morbid obesity Molecular Psychiatry DOI: 10.1038/mp.2015.153

Meule A (2015). Back by Popular Demand: A Narrative Review on the History of Food Addiction Research. The Yale journal of biology and medicine, 88 (3), 295-302 PMID: 26339213

Volkow ND, Baler RD. (2015). NOW vs LATER brain circuits: implications for obesity and addiction. Trends Neurosci. 38(6):345-52.

Volkow ND, Wang GJ, Tomasi D, Baler RD. (2013). Obesity and addiction: neurobiological overlaps. Obes Rev. 14(1):2-18.

Ziauddeen H, Fletcher PC. (2013). Is food addiction a valid and useful concept? Obes Rev. 14(1):19-28.

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Saturday, October 31, 2015

Buried Alive! The Immersive Experience

Ryan Reynolds in Buried (2010)

The pathological fear of being buried alive is called taphophobia.1  This seems like a perfectly rational fear to me, especially if one is claustrophobic and enjoys horror movies and Edgar Allan Poe short stories. Within a modern medical context, however, it simply not possible that a person will be buried while still alive.

But this wasn't always the case. In the 19th century, true stories of premature burial were common, appearing in newspapers and medical journals of the day. Tebb and Vollum (1896) published a 400 page tome (Premature burial and how it may be prevented: with special reference to trance, catalepsy, and other forms of suspended animation) that was full of such examples:

The British Medical Journal, December 8, 1877,
p. 819, inserts the following : —


"A correspondent at Naples states that the Appeal Court has had before it a case not likely to inspire confidence in the minds of those who look forward with horror to the possibility of being buried alive. It appeared from the evidence that some time ago a woman was interred with all the usual formalities, it being believed that she was dead, while she was only in a trance. Some days afterwards, the grave in which she had been placed being opened for the reception of another body, it was found that the clothes which covered the unfortunate woman were torn to pieces, and that she had even broken her limbs in attempting to extricate herself from the living tomb. The Court, after hearing the case, sentenced the doctor who had signed the certificate of decease, and the mayor who had authorised the interment, each to three months' imprisonment for involuntary manslaughter."

To avoid this fate worse than death, contraptions known as “safety coffins” were popular, with air tubes, bells, flags, and/or burning lamps (Dossey, 2007). Some taphophobes went to great lengths to outline specific instructions for handling their corpse, to prevent such an ante-mortem horror from happening to them. Some might even say these directives were a form of “overkill”...

From the Lancet, August 20, 1864, p. 219.


"Amongst the papers left by the great Meyerbeer, were some which showed that he had a profound dread of premature interment. He directed, it is stated, that his body should be left for ten days undisturbed, with the face uncovered, and watched night and day. Bells were to be fastened to his feet. And at the end of the second day veins were to be opened in the arm and leg. This is the gossip of the capital in which he died. The first impression is that such a fear is morbid. No doubt fewer precautions would suffice, but now and again cases occur which seem to warrant such a feeling, and to show that want of caution may lead to premature interment in cases unknown. An instance is mentioned by the Ost. Deutsche Post of Vienna. A few days since, runs the story, in the establishment of the Brothers of Charity in that capital, the bell of the dead-room was heard to ring violently, and on one of the attendants proceeding to the place to ascertain the cause, he was surprised at seeing one of the supposed dead men pulling the bell-rope. He was removed immediately to another room, and hopes are entertained of his recovery."

Here's a particularly gruesome one:

From the Daily Telegraph, January 18, 1889.

"A gendarme was buried alive the other day in a village near Grenoble. The man had become intoxicated on potato brandy, and fell into a profound sleep. After twenty hours passed in slumber, his friends considered him to be dead, particularly as his body assumed the usual rigidity of a corpse. When the sexton, however, was lowering the remains of the ill-fated gendarme into the grave, he heard moans and knocks proceeding from the interior of the 'four-boards.' He immediately bored holes in the sides of the coffin, to let in air, and then knocked off the lid. The gendarme had, however, ceased to live, having horribly mutilated his head in his frantic but futile efforts to burst his coffin open."

Doesn't that sound like fun? Wouldn't you like to experience this yourself? Now you can!

Taphobos, an immersive coffin experience (by James Brown)

How does it work?

The game uses a real life coffin, an Oculus Rift, a PC and some microphones. One player gets in the coffin with the Rift on, together with a headset + microphone. The other player plays on a PC again with mic + headset, this player will play a first person game where they must work with the buried player to uncover where the coffin is and rescue the trapped player before their oxygen runs out. This is all powered by the Unity engine.

But why?? (Brown, 2015):

This work is intended to explore “uncomfortable experiences and interactions” as part of academic research in the Human Computer Interaction field (HCI) from an MSc by Research in Computer Science student, James Brown. The player inside the coffin will experience various emotions as they are put in and then try to get out of the confined space. Claustrophobia as well as the fear of being buried alive “taphophobia” may well affect players of the game and they must cope with these emotions as they play.

Further Reading

Buried Alive! (October 31, 2011)


1 Also spelled taphephobia. From the Greek taphos, or grave.


Brown J. (2015). Taphobos: An Immersive Coffin Experience. British HCI 2015, July 13-17, 2015, Lincoln, United Kingdom.

Dossey L. (2007). The undead: botched burials, safety coffins, and the fear of the grave. Explore (NY). 3:347-54.

Tebb W, Vollum EP. (1896). Premature burial and how it may be prevented: with special reference to trance, catalepsy, and other forms of suspended animation. SWAN SONNENSCHEIN & CO., LIM.: London.  {}

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Thursday, October 29, 2015

Ophidianthropy: The Delusion of Being Transformed into a Snake

Scene from Sssssss (1973).

When Dr. Stoner needs a new research assistant for his herpetological research, he recruits David Blake from the local college.  Oh, and he turns him into a snake for sh*ts and giggles.”

Movie Review by Jason Grey

Horror movies where people turn into snakes are relatively common (30 by one count), but clinical reports of delusional transmogrification into snakes are quite rare. This is in contrast to clinical lycanthropy, the delusion of turning into a wolf.

What follows are two frightening tales of unresolved mental illness, minimal followup, and oversharing (plus mistaking an April Fool's joke for a real finding).

THERE ARE NO ACTUAL PICTURES OF SNAKES in this post [an important note for snake phobics].

The first case of ophidianthropy was described by Kattimani et al. (2010):
A 24 year young girl presented to us with complaints that she had died 15 days before and that in her stead she had been turned into a live snake. At times she would try to bite others claiming that she was a snake. ... We showed her photos of snakes and when she was made to face the large mirror she failed to identify herself as her real human self and described herself as snake. She described having snake skin covering her and that her entire body was that of snake except for her spirit inside.  ...  She was distressed that others did not understand or share her conviction. She felt hopeless that nothing could make her turn into real self. She made suicidal gestures and attempted to hang herself twice on the ward...

The initial diagnosis was severe depressive disorder with psychotic features. A series of drug trials was unsuccessful (Prozac and four different antipsychotics), and a course of 10 ECT sessions had no lasting effect on her delusions. The authors couldn't decide whether the patient should be formally diagnosed with schizophrenia or a more general psychotic illness. Her most recent treatment regime (escitalopram plus quetiapine) was also a failure because the snake delusion persisted.

“Our next plan is to employ supportive psychotherapy in combination with pharmacotherapy,” said the authors (but we never find out what happened to her). Not a positive outcome...

Scene from Sssssss (1973).

Ophidiantrophy with paranoid schizophrenia, cannabis use, bestiality, and history of epilepsy

The second case is even more bizarre, with a laundry list of delusions and syndromes (Mondal, 2014):
A 23 year old, married, Hindu male, with past history of  ... seizures..., personal history of non pathological consumption of bhang and alcohol for the last nine years and one incident of illicit sexual intercourse with a buffalo at the age of 18 years presented ... with the chief complains of muttering, fearfulness, wandering tendency ... and hearing of voices inaudible to others for the last one month. ... he sat cross legged with hands folded in a typical posture resembling the hood of a snake. ... The patient said that he inhaled the breath of a snake passing by him following which he changed into a snake. Though he had a human figure, he could feel himself poisonous inside and to have grown a fang on the lower set of his teeth. He also had the urge to bite others but somehow controlled the desire. He said that he was not comfortable with humans then but would be happy on seeing a snake, identifying it belonging to his species. ... He says that he was converted back to a human being by the help of a parrot, which took away his snake fangs by inhaling his breath and by a cat who ate up his snake flesh once when he was lying on the ground. ...  the patient also had thought alienation phenomena in the form of thought blocking, thought withdrawal and thought broadcasting, delusion of persecution, delusion of reference, delusion of infidelity [Othello syndrome], the Fregoli delusion, bizarre delusion, nihilistic delusion [Cotard's syndrome], somatic passivity, somatic hallucinations, made act [?], third person auditory hallucinations, derealization and depersonalisation. He was diagnosed as a case of paranoid schizophrenia as per ICD 10.


He was was given the antipsychotic haloperidol while being treated as an inpatient for 10 days. Some of his symptoms improved but others did not. “Long term follow up is not available.”

The discussion of this case is a bit... terrifying:
Lycanthropy encompasses two aspects, the first one consisting of primary lupine delusions and associated behavioural deviations termed as lycomania, and the second aspect being a psychosomatic problem called as lycosomatization (Kydd et al., 1991).
Kydd, O.U., Major, A., Minor, C (1991). A really neat, squeaky-clean isolation and characterization of two lycanthropogens from nearly subhuman populations of Homo sapiens. J. Ultratough Molec. Biochem. 101: 3521-3532.  [this is obviously a fake citation]
Endogenous lycanthropogens responsible for lycomania are lupinone and buldogone which differ by only one carbon atom in their ring structure; their plasma level having a lunar periodicity with peak level during the week of full moon. Lycosomatization likely depends on the simultaneous secretion of suprathreshold levels of both lupinone and the peptide lycanthrokinin, a second mediator, reported to be secreted by the pineal gland, that “initiates and maintains the lycanthropic process” (Davis et al., 1992). Thus, secretion of lupinone without lycanthrokinin results in only lycomania. In our patient these molecular changes were not investigated.

oh my god, the paper by Davis et al. on the Psychopharmacology of Lycanthropy (and "endogenous lycanthropogens") was published in the April 1, 1992 issue of the Canadian Medical Association Journal. There is no such thing as lupinone and buldogone.

Fig. 1 (Davis et al., 1992): Structural formulas of endogenous lycanthropogens.

I know the authors are non-native English speakers, but where was the peer review for the Asian Journal of Psychiatry??  We might as well return to the review for Sssssss, which was more thorough.

   David Blake -
Our hapless victim.  David is a college student who gets recruited by Dr. Stoner to help out at his farm, and be his latest test subject.  He's a nice guy, and there really is not much to say about him, as he's pretty bland until he starts growing scales.

   Dr. Carl Stoner - The villain of our piece.  He's a snake researcher looking for new grant money, and a new test subject.  He actually means well enough, and is looking to advance humanity, but in classic horror movie fashion, he plays God and things go too far.

   Kristine Stoner - The doctor's daughter, who is also interested in snakes.  Especially David's.  She's smart, and kind, and again a bit of a blank slate beyond those traits.  Loyal to a fault with her father.

   Dr. Daniels - A minor character, but Stoner's chief rival, and the man who holds the purse strings.  The two doctors have an antagonistic relationship, but there seems to be an undercurrent of past friendship as well, overshadowed by Daniels' position.  Or I'm reading too much into things.

Sssssss has a score of 13% on Rotten Tomatoes. We don't have a similar rating system for journal articles, but there's always PubMed Commons and PubPeer...

Further Reading

People Who Change into Snakes in Movies - from California Herps

Snake me up before you go-go: An unusual case of ophidianthropy - by Dr Mark Griffiths

Psychopharmacology of Lycanthropy

Werewolves of London, Ontario


Davis WM, Wellwuff HG, Garew L, Kydd OU. (1992). Psychopharmacology of lycanthropy. CMAJ Apr 1;146(7):1191-7.

Kattimani S, Menon V, Srivastava MK, Mukharjee A. (2010). Ophidianthropy: the case of a woman who ‘Turned into  a Snake’. Psychiatry On-Line.

Mondal, G., Nizamie, S., Mukherjee, N., Tikka, S., & Jaiswal, B. (2014). The ‘snake’ man: Ophidianthropy in a case of schizophrenia, along with literature review, Asian Journal of Psychiatry, 12, 148-149 DOI: 10.1016/j.ajp.2014.10.002

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Sunday, October 25, 2015

On the Long Way Down: The Neurophenomenology of Ketamine

Is ketamine a destructive club drug that damages the brain and bladder? With psychosis-like effects widely used as a model of schizophrenia? Or is ketamine an exciting new antidepressant, the “most important discovery in half a century”?

For years, I've been utterly fascinated by these separate strands of research that rarely (if ever) intersect. Why is that? Because there's no such thing as “one receptor, one behavior.” And because like most scientific endeavors, neuro-pharmacology/psychiatry research is highly specialized, with experts in one microfield ignoring the literature produced by another (though there are some exceptions).1

Ketamine is a dissociative anesthetic and PCP-derivative that can produce hallucinations and feelings of detachment in non-clinical populations. Phamacologically it's an NMDA receptor antagonist that also acts on other systems (e.g., opioid). Today I'll focus on a recent neuroimaging study that looked at the downsides of ketamine: anhedonia, cognitive disorganization, and perceptual distortions (Pollak et al., 2015).

Imaging Phenomenologically Distinct Effects of Ketamine

In this study, 23 healthy male participants underwent arterial spin labeling (ASL) fMRI scanning while they were infused with either a high dose (0.26 mg/kg bolus + slow infusion) or a low dose (0.13 mg/kg bolus + slow infusion) of ketamine 2 (Pollak et al., 2015). For comparison, the typical dose used in depression studies is 0.5 mg/kg (Wan et al., 2015). Keep in mind that the number of participants in each condition was low, n=12 (after one was dropped) and n=10 respectively, so the results are quite preliminary.

ASL is a post-PET and BOLD-less technique for measuring cerebral blood flow (CBF) without the use of a radioactive tracer (Petcharunpaisan et al., 2010). Instead, water in arterial blood serves as a contrast agent, after being magnetically labeled by applying a 180 degree radiofrequency inversion pulse. Basically, it's a good method for monitoring CBF over a number of minutes.

ASL sequences were obtained before and 10 min after the start of ketamine infusion. Before and after the scan, participants rated their subjective symptoms of delusional thinking, perceptual distortion, cognitive disorganization, anhedonia, mania, and paranoia on the Psychotomimetic States Inventory (PSI). The study was completely open label, so it's not like they didn't know they were getting a mind-altering drug.

Behavioral ratings were quite variable (note the large error bars below), but generally the effects were larger in the high-dose group, as one might expect.

The changes in Perceptual Distortion and Cognitive Disorganization scores were significant for the low-dose group, with the addition of Delusional Thinking, Anhedonia, and Mania in the high-dose group. But again, it's important to remember there was no placebo condition, the significance levels were not all that impressive, and the n's were low.

The CBF results (below) show increases in anterior and subgenual cingulate cortex and decreases in superior and medial temporal cortex, similar to previous studies using PET.

Fig 2a (Pollak et al., 2015). Changes in CBF with ketamine in the low- and high-dose groups overlaid on a high-resolution T1-weighted image.

Did I say the n's were low? The Fig. 2b maps (not shown here) illustrated significant correlations with the Anhedonia and Cognitive Disorganization subscales, but these were based on 10 and 12 data points, when outliers can drive phenomenally large effects. One might like to say...
For [the high-dose] group, ketamine-induced anhedonia inversely related to orbitofrontal cortex CBF changes and cognitive disorganisation was positively correlated with CBF changes in posterior thalamus and the left inferior and middle temporal gyrus. Perceptual distortion was correlated with different regional CBF changes in the low- and high-dose groups.
  ...but this clearly requires replication studies with placebo comparisons and larger subject groups.

Nonetheless, the fact remains that ketamine administration in healthy participants caused negative effects like anhedonia and cognitive disorganization at doses lower than those used in studies of treatment-resistant depression (many of which were also open label). Now you can say, “well, controls are not the same as patients with refractory depression” and you'd be right (see Footnote 1). “Glutamatergic signaling profiles” and symptom reports could show a variable relationship, with severe depression at the low end and schizophrenia at the high end (with controls somewhere in the middle).

A recent review of seven placebo-controlled, double-blind, randomized clinical trials of ketamine and other NMDA antagonists concluded (Newport et al., 2015):
The antidepressant efficacy of ketamine ... holds promise for future glutamate-modulating strategies; however, the ineffectiveness of other NMDA antagonists suggests that any forthcoming advances will depend on improving our understanding of ketamine’s mechanism of action. The fleeting nature of ketamine’s therapeutic benefit, coupled with its potential for abuse and neurotoxicity, suggest that its use in the clinical setting warrants caution.

The mysterious and paradoxical ways of ketamine continue...

So take it in don't hold your breath
The bottom's all I've found
We can't get higher than we get
On the Long Way Down

Further Reading

Ketamine for Depression: Yay or Neigh?

Warning about Ketamine in the American Journal of Psychiatry

Chronic Ketamine for Depression: An Unethical Case Study?

still more on ketamine for depression

Update on Ketamine in Palliative Care Settings

Ketamine - Magic Antidepressant, or Expensive Illusion? - by Neuroskeptic

Fighting Depression with Special K - by Scicurious


1 One exception is the present study, which discussed the divergent anhedonia results (compared to  previous findings of reduced anhedonia in depression). Another example is the work of Dr. John H. Krystal, which includes papers in both the schizophrenia and the treatment-resistant depression realms. However, most of the papers discuss only one and not the other. One notable exception (schizophrenia-related) said this: is important to note that studies examining its effects on glutamateric pathways in the context of mood symptoms (178) may be highly informative for developing our understanding of its relevance to schizophrenia (111). Briefly, emerging models in this area postulate that ketamine may act as anti-depressant by promoting synaptic plasticity via intra-cellular signaling pathways, ultimately promoting brain-derived neurotrophic factor expression via synaptic potentiation (179) and in turns synaptic growth (178). In that sense, acute NMDAR antagonism may promote synaptic plasticity along specific pathways impacted in mood disorders, such as ventral medial PFC (180, 181, p. 916). Conversely, when administered to patients diagnosed with schizophrenia, NMDAR antagonists seem to worsen their symptom profile (182), perhaps by “pushing” an already aberrantly elevated glutamatergic signaling profile upward. Collectively such dissociable effects of ketamine may imply that along distinct circuits there may be an inverted-U relationship between ketamine’s effects and symptoms: depressed patients may be positioned on the low end of the inverted-U (178) and schizophrenia patents may be positioned on the higher end (183). Both task-based and resting-state functional connectivity techniques are well positioned to interrogate such system-level effects of NMDAR antagonists in humans.

2 Low-dose ketamine: target plasma level of 50–75 ng/mL was specified (in practice this approximated a rapid bolus of an average of 0.12 mg/kg over 20 s followed by a slow infusion of 0.31 mg/kg/h).

High-dose ketamine: target plasma level of 150 ng/mL was specified (in practice this approximated a rapid bolus of 0.26 mg/kg over 20 s followed by a slow infusion of 0.42 mg/kg/h).


Petcharunpaisan S, Ramalho J, Castillo M. (2010). Arterial spin labeling inneuroimaging. World J Radiol. 2(10):384-98.

Pollak, T., De Simoni, S., Barimani, B., Zelaya, F., Stone, J., & Mehta, M. (2015). Phenomenologically distinct psychotomimetic effects of ketamine are associated with cerebral blood flow changes in functionally relevant cerebral foci: a continuous arterial spin labelling study Psychopharmacology DOI: 10.1007/s00213-015-4078-8

Wan LB, Levitch CF, Perez AM, Brallier JW, Iosifescu DV, Chang LC, Foulkes A, Mathew SJ, Charney DS, Murrough JW. (2015). Ketamine safety and tolerability in clinical trials for treatment-resistant depression. J Clin Psychiatry 76(3):247-52.

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