There are three types of experiments one can perform in neuroscience: lesions, stimulations, and recording. Obviously, a particular study can use more than one of them.

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The most basic natural experiment that one can harness in neuroscience is to study lesions, due to problems in development, disease, and/or trauma.

Of these, perhaps the most striking lesions come from patients with severe hydrocephalus. Hydrocephalus is the accumulation of cerebrospinal fluid in the brain that causes ventricles to enlarge and compress the surrounding brain tissue.

A 2007 case study by Feuillet et al. of a 44-year old man with an IQ of 75 and a civil-servant career is probably the most famous, since they provide a nice brain set of brain scans of the person:

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LV = lateral ventricle; III = third ventricle; IV = fourth ventricle; image from Feuillet et al. 2007

A 1980 paper is also famous for its report of a person with an IQ of 126 and an impressive educational record who also had extensive hydrocephalus. But no image, so not quite as famous.

The 2007 case has been cited as evidence to a) question dogma about the role of the brain in consciousness, b) speculate on how two minds might coalesce following mind uploading, and c) — of course — postulate the existence of extracorporeal information storage. There are also some great comments about this topic at Neuroskeptic.

As far as I can tell, volume loss in moderate hydrocephalus is initially and primarily due to compression of white matter just adjacent to ventricles. On the other hand, in severe hydrocephalus such as the above, the grey matter and associated neuropil also must be compressed.

Most of the cases with normal cognition appear to be due to congenital or developmental hydrocephalus, causing a slow change in brain structure. On the other hand, rapid changes in brain structure due to acute hydrocephalus, such as following trauma, are more likely to lead to more dramatic changes in cognition.

What can we take away from this? A couple of things:

  1. This is yet another example of the remarkable long-term plasticity of both the white matter and the grey matter of the brain. Note that this plasticity is not always a good thing, but yes, it exists and can be profound.
  2. It is evidence for hypotheses that the relative positions and locations of neurons and other brain cell types in the brain is the critical component of maintaining cognition and continuity of consciousness, as opposed to their absolute positions in space within the brain. An example of a theory in the supported class is Seung’s “you are your connectome” theory.
  3. Might it not make the extracellular space theories of memory a little less plausible?

In the 1940s two Danish researchers, Erik Jacobsen and Jens Hald, tested a series of substances in an attempt to identify drugs that might rid the body of intestinal worms. After one of them worked in rabbits, Jacobsen tried it on himself, as he had a fun little habit of trying all of his invented drugs on himself.

“During the course of self-experimentation” as Larimer reports, both Jacobsen and Hald noted this substance — called disulfiram — led to a substantial increase in their sensitivity to the toxic effects of alcohol.

In late 1947 and 1948, Oluf Martensen-Larsen, an expert on the treatment of alcoholism, was able to convince his colleagues to allow him to try disulfiram in the treatment of alcohol abuse. In this classic paper, he reported on 83 patients that he had treated with disulfiram (also called Antabuse) for the treatment of their alcohol addiction.

At the time the mechanism was not known, but it was known that giving the drug prophylactically led people to become violently ill with hangover-like effects of alcohol. It is now almost certain that its effects are due to the inhibition of aldehyde dehydrogenase, which causes acetaldehyde to build up in the blood stream following alcohol consumption and cause all sorts of unpleasant toxicity.

In cultured cortical neurons, acetaldehyde causes a substantial loss of MAP2-positive neuronal processes, indicative of the fact that the toxicity of acetaldehyde does not spare the CNS:

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PMID: 11132090

One of the patients he described as having a successful reaction to the treatment was a middle-aged woman. After starting on disulfiram, she began to blush after taking only a mouthful of liquor. As Martensen-Larsen reports, “Her abstinence might be explained by her desire to avoid the humiliation associated with the blushing, but she insists that this is not the deciding factor, and that she has lost the taste for wine and spirits.”

Overall, he classifies 32/83 (39%) of patients as successes, 29/83 (35%) as partial successes as long as their blood and urine checks indicated that they will still on the drug, 13/83 (16%) as successes only as long as the physician can successfully encourage them to stay on the drug, and 9/83 (11%) as not responding to the drug, at least in because they refused to continue on it.

Disulfiram is still used today as a part of a comprehensive treatment for alcohol addiction that includes psychosocial factors as well.


Larimer R 1952 JAMA Treatment Of Alcoholism with Antabuse. doi:10.1001/jama.1952.03680020013004

Arghya Pal, Raman Deep Pattanayak, Rajesh Sagar. (2015) “Tracing the journey of disulfiram: From an unintended discovery to a treatment option for alcoholism.” Journal of Mental Health and Human Behavior. DOI: 10.4103/0971-8990.164826

Martensen-Larsen O. Treatment of alcoholism with a sensitizing drug. Lancet 1948;2:1004. Back to cited text no.

Wan JY, Wang JY, Wang Y, Wang JY. A comparison between acute exposures to ethanol and acetaldehyde on neurotoxicity, nitric oxide production and NMDA-induced excitotoxicity in primary cultures of cortical neurons. Chin J Physiol. 2000;43(3):131-8.

This classic 2009 review paper by Fletcher and Frith, currently cited 456 times, attempts to explain the two major positive symptoms of schizophrenia, hallucinations and delusions, as due to a common high-level cognitive mechanism.

But first, they consider one of the simplest hypotheses: might people with schizophrenia have disordered reasoning in general? The authors reject this hypothesis because patients with schizophrenia do not have problems with logic in general; at least in the n = 32 study they cited, control as opposed to deluded people were actually slightly more likely to fall for fallacies in logical questions.

Instead,Fletcher and Frith’s hypothesis relates to a failure to correctly perform conditional reasoning.

As they point out, stimuli that do not challenge a belief are usually ignored, which is often necessary in order to deal with the large number of stimuli in one’s environment.

Intriguingly, in animals, this prediction error-dependent learning is highly dependent on the dopaminergic system. And there is a wealth of evidence showing that the dopamine system is implicated in schizophrenia, including the ventral striatum.

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Berns et al., in a 2001 fMRI study, showed that the bilateral nucleus accumbens (a part of the ventral striatum) is involved in responses to predictable stimuli 

Their hypothesis, then, is that there is a quantitative divergence in the prediction error-dependent learning for every day stimuli in schizophrenia.

This leads normal stimuli to feel unduly important and thus makes properly attending to one’s environment challenging. This can explain delusions, because people must attempt to explain why those stimuli feel so surprising.

This could also make internal thoughts (which are perceived stimuli just like any other) appear more likely to be under external rather than internal control, because they are imbued with a particular sense of surprisingness. This, of course, can explain hallucinations.

Of course, this is just a model and is probably flawed in various ways, but it’s a pretty thorough one and worthy of consideration.


Fletcher PC, Frith CD. Perceiving is believing: a Bayesian approach to explaining the positive symptoms of schizophrenia. Nat Rev Neurosci. 2009;10(1):48-58.

A few weeks an interesting preprint from Antilla et al. was published. They set out to measure the genetic correlation between a variety of brain disorders — both “psychiatric” and “neurologic” — by comparing risk markers from a set of 23 different GWAS’s. They called themselves the “Brainstorm consortium” (for which they win creativity points). A major finding in their paper is that there is a substantial correlation between psychiatric disorders (e.g., OCD, schizophrenia, MDD, bipolar disorder), while there is less or no correlation among neurologic disorders (e.g., Alzheimer’s, Parkinson’s, MS). This data set is based on comparing polygenic risk variants from individual studies, and it’s certainly possible to draw too strong of conclusions from this type of data, as it is confounded by the societal structure of the people who participated in the studies, among other factors. That said, this should stimulate a number of interesting follow-up studies. One of their most interesting sections is on the genetic correlations between these disorders and other traits:

Two correlations especially jump out to me here:

  1.  The positive correlation between autism spectrum disorder risk and variants associated with measures of cognitive performance. This fits with at least one finding that there is a positive association between ASD prevalence and socioeconomic status, which is sometimes attributed to increased paternal age, but as this study shows, that is potentially not the whole story. I’m certainly not an expert in ASD epidemiology and this is just my initial impression, and I could totally be off.
  2. The inverse correlation between variants associated with measures of cognitive performance and risk of stroke and intracerebral hemorrage. This fits with my priors that good blood flow is critical for proper brain function. In my experience is not as widely known by people without a medical background (such as myself prior to my preclinical med school training).
Antilla et al. 2016 Analysis of shared heritability in common disorders of the brain. doi:http://dx.doi.org/10.1101/048991

Classic Paper: Elkes J, Elkes C. Effect of chlorpromazine on the behavior of chronically overactive psychotic patients. Br Med J. 1954;2(4887):560-5

In 1950, a group of anesthesiologists in France were trying to find new drugs for anesthesia. They tested the newly synthesized drug chlorpromazine on animals (dogs, rodents, and mice) and found that it led to drowsiness and indifference to aversive stimuli.

Since this was the 1950’s, they were able to quickly try it on people as a booster for anesthesia. They found that people who took chlorpromazine did not lose consciousness, but it did have a profound calming effect. Quickly people thought of trying it on patients with psychosis, for which the available treatments were very limited.

This study by Joel Elkes and Charmian Elkes, who were married, was the first to report a placebo-controlled trial on the effect chlorpromazine in psychosis. It appears that the majority of the data collecting and work was done by Charmian, rather than Joel. Screen Shot 2016-04-11 at 8.19.22 PM

They used a classic crossover study design, testing each patient on both chlorpromazine and an inert placebo (although they do not use the word “random”). They used notes written by the doctors and nurses that were blind to the treatment type to decide whether or not the patient had improved.

Of the 23 patients with a type of psychosis in their study, 7 (30%) showed “definite improvement” when they were taking the drug compared to when they were not, 11 (48%) showed “slight improvement,” and 5 (22%) showed “no improvement.”

Other interesting notes from the paper:

  • They describe the effect of chlorpromazine as symptomatic, since the psychosis itself did not abate: “the essentially symptomatic nature of the response has already been stressed, and cannot be overemphasized. Although affect became more subdued, and attitude and behaviour reflected this improvement, the ingrained psychotic thought disorder seemed to be unchanged.”
  • Because of their detailed records, they noted significant weight gain in 9/23 of the patients (in all of whom the drug led to at least a slight improvement), which has been borne out in both chlorpromazine and in the drug class in general: almost all antipsychotics result in weight gain. Of this effect, they say: “For the present we are inclined to attribute this to improved eating habit as the patients became less tense, less preoccupied, or less assaultive; though more direct metabolic effects of the drug cannot be excluded.”
  • They also tried it on 3 patients with senile dementia, all of whom had “no improvement.” This is yet another example of how Alzheimer’s is where drug discovery goes to die.

Notably, the mechanism remained pretty unknown until the mid-1960s, when it was shown that dopamine metabolites correlated with the chlorpromazine dose given to animals. In 1976, Seeman et al. found a nearly perfect correlation (on the log-log scale) between the ability of antipsychotic drugs to displace haloperidol from binding to the dopamine receptor and the clinical dose required for its effect.

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Seeman et al., 1976

Interestingly, you can see in this figure that chloroprazamine actually has one of the less strong dopaminergic affinities and higher doses required for controlling schizophrenia. Despite this, it and its derivatives have on to become some of the most game-changing psychiatric drugs of all time.


Shen WW. A history of antipsychotic drug development. Compr Psychiatry. 1999;40(6):407-14.
Elkes J, Elkes C. Effect of chlorpromazine on the behavior of chronically overactive psychotic patients. Br Med J. 1954;2(4887):560-5.
Bak M, Fransen A, Janssen J, Van os J, Drukker M. Almost all antipsychotics result in weight gain: a meta-analysis. PLoS ONE. 2014;9(4):e94112.

Seeman P, Lee T, Chau-wong M, Wong K. Antipsychotic drug doses and neuroleptic/dopamine receptors. Nature. 1976;261(5562):717-9.

Classic Paper: Cade JF. Lithium salts in the treatment of psychotic excitement. Med J Aust 1949; 2:349-352

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some wells in the British Isles were known for their salubrious effects on mental illness; this may have been due to their lithium content

Prior to 1949, treatments for mania were limited. That year, John Cade published a paper showing the usefulness of lithium in treating patients with mania (“psychotic excitement”).

Interestingly enough, the finding was apparently a surprise to Cade. He was studying guinea pigs in order to see whether uric acid added to the convulsive toxicity of urea, but he needed to find a way to make uric acid soluble in water to be able to inject it into the guinea pigs. (Confusingly enough, urea and uric acid have almost nothing to do with one another chemically.)

For this, he used the lithium salt of urate, and was surprised to find that it was protective against the urea-induced convulsions. He then injected lithium carbonate alone into guinea pigs, and noted that after a couple of hours, they became lethargic and unresponsive to stimuli.

Skipping straight from this effect in guinea pigs (not even a disease model!! — this would never be allowed today) to humans, Cade then reports on 10 cases of patients with mania who were successfully treated with lithium, including longitudinal cases of chronic mania where the mania subsided during lithium treatment and recrudesced when lithium was discontinued.

Other interesting aspects of this paper:

  • Cade notes that historically, water from certain wells was associated with improvements in mental illness, and speculates that “it is very likely that their supposed efficacy was a real efficacy and directly proportional to the lithium content of the waters.”
  • Cade notes that lithium treatment “would be much preferred” to what is usually now considered the cruel treatment of prefrontal leucotomy, even though this (1949) was the year that the Nobel prize was awarded for it, and its use continued into the mid-1950s.
  • All of the cases reported on were men between ages 40 and 65 years old, indicating a total lack of evidence for generalization of the effect across more diverse patient populations.

Recent meta-analysis (2013) has shown that antipsychotics are more effective than lithium in the treatment of acute mania (e.g., the standardized mean difference in manic symptoms for haloperidol is -0.56, while for lithium it is -0.37), but lithium is still often used in combination with antipsychotics in the treatment of mania.

Overall, this short paper is among the best I’ve read in terms of scientific puzzle solving, although you could argue that Cade got lucky.


Cade JF. Lithium salts in the treatment of psychotic excitement. 1949. Bull World Health Organ. 2000;78(4):518-20.

Cipriani A, Barbui C, Salanti G, et al. Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis. Lancet. 2011;378(9799):1306-15.

Doig MT, Heyl MG, Martin DF. Lithium and mental health. J Chem Educ. 1973;50(5):343-5.

In everyday life, your muscles, metabolism, and nervous system work together to ensure that your cerebral blood flow meets the metabolic needs of your various brain regions. So if you are trying to scrutinize an impressionist painting, your body will likely relocate more blood flow to your visual cortex.

Following a stroke, this cerebral blood flow regulation is impaired. But, the degree and spread of the impairment is unknown. To investigate this, Hu et al. measured systemic blood pressure (BP) and used a transcranial doppler to measure cerebral blood flow velocity (BFV) at the same time.

In their model, better regulation of cerebral blood flow corresponds to a sharper phase shift between blood pressure (BP) and cerebral blood flow velocity (BFV). Individuals with the highest score of a 9 on their autoregulation index (ARI) have more regulation than those with the lowest score of 0, which corresponds to no phase shift.

When they compared patients who had experienced MCA infarcts (a common type of stroke) and healthy controls, they found that stroke patients had significantly less phase coupling between blood pressure and cerebral blood flow. This effect was pronounced over a wide range of blood pressure oscillation frequencies.

Given enough time and the right conditions, can the body repair its ability to regulate cerebral blood flow following a stroke? When the researchers examined this, they found no statistically significant difference between the BFV-BP phase difference and time since stroke.

But, that doesn’t mean that there’s a statistically significant lack of difference. So, further longitudinal studies will be needed to help clarify whether, in certain people in certain environments, the brain improves its cerebral regulation following stroke.


Hu K, Lo M-T, Peng C-K, Liu Y, Novak V (2012) A Nonlinear Dynamic Approach Reveals a Long-Term Stroke Effect on Cerebral Blood Flow Regulation at Multiple Time Scales. PLoS Comput Biol 8(7): e1002601. doi:10.1371/journal.pcbi.1002601