An Effort To Distance Critical Psychiatry From Antipsychiatry

I read the paper “Critical psychiatry: a brief overview” by Middleton and Moncrieff. This paper was the basis for the commentary by Peter Tyrer in the previous post on this blog. The authors try to make an argument to differentiate critical psychiatry from antipsychiatry. They claim that critical psychiatry offers constructive criticism of the field whereas antipsychiatry seeks to abolish the field. Constructive criticism needs to be valid criticism I hope to point out why critical psychiatry does not meet that threshold.

One of the interests for me in reading this paper was to see if critical psychiatry in fact could be distinguished from typical antipsychiatry rhetoric. That might be the easiest way to illustrate a significant difference. An associated strategy might be to show that critical psychiatry had origins that were clearly independent of antipsychiatry.   The authors suggest multiple common origins.  They both have the same heroes - Szasz and Foucault. They both draw heavily on the defective ideas of Szasz and Foucault. These ideas have no scientific basis and are not logically derived.

Social control is one concept that ties in what the authors claim is “controversy” about the institution of 19^th century psychiatry and the ideas of Szasz and Foucault. By the authors own definition Szasz trivializes serious mental illness as a social disorder and socially deviant behavior rather than a potentially lethal illness. In order to consider a mental illness to be a true disease, Szasz believed it would have to be a “neurological” illness.  That does not recognize that a significant number of these disorders have no known pathophysiological mechanism.  Szasz and the authors paint themselves into a corner with this construct given the clear medical, neurological, and substance induced disorders listed in any diagnostic manual for psychiatry. They also seem to not realize that these distinctions are all arbitrary definitions by Szasz. Most medical professionals and lay people do not believe that a specific pathophysiological mechanism is the basis for disease, illness, or treatment in most cases. For the antipsychiatry and critical psychiatry adherents of Szasz this is one of their most predictable arguments.

On the issue of social control, the antipsychiatry arguments are as weak. The authors explain Foucault’s position as:

“Thus, the birthplace of institutional psychiatry can be considered arrangements for managing unproductive behaviour in a system of wage labour and industrial production. The growth of psychiatry in the 19th century legitimated this system by presenting it as a medical and therapeutic endeavor.”

I really doubt that Foucault was accurate in his historical observations.  German psychiatry at the time was clearly focused on persons with significant psychopathology and who could eventually be discharged as well as the biological basis of psychopathology. Have psychiatrists ever had the influence to run governments and dictate government policy? What ever spin Foucault could put on old history we all know what is happening now. Psychiatry is nearly completely marginalized.  Despite the antipsychiatry movement there is widespread agreement that there are too few psychiatrists and that people do not have enough time with them.  That process also highlights the true agents of social control.  Federal and state governments have supervised rationing bed resources to the point where they are extremely low.  At the same time there has been a huge increase in the mentally ill who are incarcerated, making county jails the largest psychiatric institutions in the country. Los Angeles County jail is building a new facility that is designed to hold a population with mental illness. They are calling it the Mental Health Treatment Center.  Foucault's speculation has not stood the test of time. There should be no doubt that the true agents of social control are federal and state governments, law enforcement, and businesses that profit from their relationships with government officials and not a marginalized medical specialty.  

The authors also march out the old Foucault quote “psychiatry is a moral practice, overlaid by the myths of positivism”.  Philosophers have the annoying practice of coming to a conclusion that is not backed up by any data or proof. That may be why Foucault also has to discredit positivism. He is basically in his own little parallel universe.  Let’s forget about the fact that no psychiatrist I have ever met was trained to exert social control and manage “unproductive behavior” by putting the poor and disabled into almshouses. Present day psychiatrists in the US are most commonly battling with insurance companies to get minimally adequate care for their patients.  That insurance company rationing has also resulted in the bed crunch that leads to incarceration, chronicity, and associated medical problems. Foucault’s proclamations about psychiatry have not withstood the test of time and in the modern world are wrong. 

  

An offshoot of the social control speculation is the authors comments about the sick role:

“Psychiatry’s institutional functions are legitimated by the designation of its clients or patients as ill or ‘sick’.”

They speculate that when the designation occurs the person is relieved from their social responsibilities as long as they play ball and remain in a passive sick role following the advice of their psychiatrist. Unfortunately for the authors they seem to have no real-world experience in what happens to people with psychiatric disabilities. They live in poverty. In the US, they may have to spend a much larger portion of their income on medical expenses. They have significant medical morbidity and have less access to care.  Substandard living conditions exposes them to more violent crime than the average person. They are at higher risk for incarceration. If they receive assistance from the state or federal government, these stipends can be reduced or stopped at any point resulting in homelessness – another significant risk in this population.  All of these factors combine to illustrate that there is no contract with society.  American society has shown time and time again – persons with mental illness are the first people thrown under the bus. So much for another critical psychiatry theory.

The final section is a recap about social control and they have an interesting paragraph where they blame psychiatry for both homosexuality as an illness and drapetomania as an illness.  No mention of the fact that Spitzer changed that designation about homosexuality in 1973, decades before the rest of the world caught on (some still have not).  Blaming psychiatry for drapetomania is standard antipsychiatry rhetoric. Anyone reading that word should realize this. It was a term coined in 1851 by Samuel Cartwright, an American physician to suggest that when slaves ran away it was a sign of mental illness. Antipsychiatrists have locked onto to this term since Whitaker put it in his provocative book Mad In America (p 171) as something else to blame psychiatrists for. The only problem is that Cartwright was not a psychiatrist and his off the wall theories were widely discredited at the time. The term has nothing to do with psychiatry or any psychiatric diagnostic system. Anyone using either homosexuality or drapetomania as examples of a powerful group (implicitly psychiatry) defining socially repudiated behavior as a mental illness to eradicate or control it (the authors words) – is by definition an antipsychiatrist.

The authors proceed to discuss treatment and how it differs if provided by critical psychiatrists.  This discussion contains very little that is remarkable.  They suggest that psychotherapeutic outcomes are broadly similar and discuss very broad definitions of psychotherapy. Anyone familiar with psychotherapy would not agree with these broad generalizations. They provide no real evidence for their conclusion that there are obstacles in place that discourage the relationship dimensions of therapists and encourage “paternalizing and instrumental approaches”.  It sounds to me like they are not approving of research based psychotherapies.   

On the medical side of things, I have serious questions about whether they do anything at all that is medical.  They suggest that psychiatry needs to be affiliated with medicine in order to get professional legitimacy. They have apparently never picked up a copy of Lishman’s Organic Psychiatry, Lipowski’s Delirium: Acute Confusional States, or Principles and Practice of Sleep Medicine by Kryger, Roth, and Dement.  Professional legitimacy is a two way street and psychiatry gives as much as it gets.  They can also find those biomarkers they are looking for in any sleep medicine text.

The section on “drug treatment” explains the critical psychiatry theory of a “drug centered” model.  In this model, there are no specific mechanisms of action – only alterations in normal mental processes, emotion, and behavior.  They include a table showing that the effects of most modern psychiatric medications depend on producing sedation, cognitive impairment, dysphoria, and loss of libido.  When I read this section I had three thoughts.  The first is that this table contains list of side effects.  I had to look again to confirm that the authors are calling them psychoactive effects.  The second is that none of the critical psychiatrists treats anyone with severe psychiatric disorders or monitors side effects very well.  The most striking feature of treating people with severe illnesses is when their acute symptoms of hallucinations, delusions, mania, or severe depression go away. The associated goal is when their side effects are managed so that they have none.  Not noticing either of these effects may be because you are just not treating very ill people. My third thought was that the authors just don’t know very much about pharmacology.  We are currently talking about decades of study of some of these systems where the behavioral pharmacology and imaging studies have been done. If you don’t know that stimulants can cause hallucinations and delusions, that non stimulant dopamine receptor agonists can do the same thing and that dopamine receptor antagonists can reverse these effects – you have just not been paying very much attention. This is basic pharmacology that every psychiatric resident should know.

The authors conclude that “critical psychiatry is not antipsychiatry” but the problem is they have not offered any compelling arguments to back that statement. If anything, the bulk of their discussion illustrates that their philosophical origins and rhetoric against clinical aspects of modern psychiatry is right out of the antipsychiatry playbook.  They claim to be not be anti-science and have clearly rejected modern pharmacology and brain science in favor of a meaningless theory of drug effects.  The closing paragraphs on the existence of social problems and the importance of the therapeutic relationship is nothing new to the practice of psychiatry - everybody does it.

The only logical conclusion is that critical psychiatry is antipsychiatry.  Just like Szasz and Laing they eschew the term, but there is just no getting around it.  I want to end with a quick note about the practical implications of critical psychiatry coming out into the light. The first is that clinicians doing the work every day should not be surprised to see this rhetoric surface time and time again. There is nothing innovative about critical psychiatry - how could there be? Nothing will deter them from making these arguments in the foreseeable future.  My concern is the potential impact on patients. I have certainly seen patients affected by antipsychiatry cults. I have concerns about the effects in large health care organizations. Is it just money that caused psychiatric resources to be cut to the bone and our patients incarcerated or is there somebody making these decisions who embraces critical psychiatry or antipsychiatry?

At the academic level, the best way to deal with these biases against psychiatry is to leave the people perpetuating these biases back in the mid-19th and 20th centuries. Psychiatry has given many of these authors plenty of space in journals and debates.  They thrive on freedom of speech and expression. I think there is a problem with academic or clinical departments allowing the expression of information that in many cases reflects poor scholarship, is largely rhetorical, and in some cases is patently false. No other medical departments do this. 

The question is where and when that line should be drawn and as readers may have guessed - my threshold is lower than most.      

George Dawson, MD, DFAPA



Supplemental:

In their Szaszian efforts to act like psychiatric disorders are not illnesses, diseases, or diagnoses, antipsychiatrists typically refer to them using the pejorative term "labels".  The following philosophical cartoon illustrates why a psychiatric diagnosis is no more a label than a hot dog is a sandwich.  Cartoon here. 

Ref:

Middleton H, Moncrieff J.  Critical psychiatry: a brief overview. BJPsych Advances (2019), vol 25, 45-54.    

Critical Psychiatry or Antipsychiatry?

Peter Tyrer wrote a commentary on Critical Psychiatry in a recent edition of British Journal of Psychiatry Advances.  It was in response to a paper by Middleton and Moncrieff that focuses primarily on distancing critical psychiatry from antipsychiatry. Dr. Tyrer is very clear about the fatal flaws of critical psychiatry. He takes on Middleton and Moncrieff’s false dichotomy between medicine psychiatry and characterizes it as "arrant nonsense". He cites a few of the many lines of evidence that psychiatry developed as a medical discipline and that great majority of us are still on that pathway.

He also takes on the pseudoscience and philosophical aspects of critical psychiatry most notably the lack of positivism. His definition positivism is “a philosophy that argues that understanding can only be achieved by logic and scientific verification and that other philosophical systems are therefore of no value”. That makes psychiatrists in the training program of psychiatrists positivist in nature. This is a significant difference since much of critical psychiatry does not depend on logic or science.   That is an unappreciated difference for many people who use philosophy to criticize psychiatry. I have an excellent example on this blog of a philosopher who decided that the DSM-5 was really a recommended blueprint for living by psychiatrists. It was clear from his position that he had no knowledge of the DSM-5, had not discussed it with a psychiatrist, and did not know how it was applied. Even those limitations did not prevent him from giving a philosophical opinion on what was wrong with the DSM-5. That is a clear example of criticism that has no value.

Dr. Tyrer’s second major point has to do with the critical psychiatrists criticism of the diagnostic process. He had co-authored a book on personality disorders for the general public and apparently got a “storm of protest and hostile reviews from service users”. The critical psychiatrist writing the review suggests that this was due to the standard medical sequence of diagnosis and then treatment. Apparently the critical psychiatry thinking is that people can be “treated” or not without making a diagnosis. One of the distinguishing characteristics of critical psychiatry is vagueness. In reading the writings of critical psychiatrists how they actually practice psychiatry is unclear. Why people see critical psychiatrists is really not clear. The outcomes of critical psychiatry practice is even less clear. The associated issue illustrated here is that critical psychiatry is a social media magnet for people who are self proclaimed experts who find it easy to embrace rhetoric rather than study science.

Dr. Tyrer’s commentary starts out in a charitable way where he suggests that critical psychiatry may have a useful role in pointing out there is frequently exuberance about a particular new therapy that never pans out. In my experience, noncritical psychiatrists and average clinical psychiatrists provide the best criticism and feedback in that area. He incorrectly cites “chemical imbalance” theories as legitimate criticism by critical psychiatrists. In my library I have 40 years of psychopharmacology texts and not a single one of them refers to “chemical imbalance”. To me chemical imbalance is a red herring marker of both anti-psychiatrists and critical psychiatrists. He points out the importance of culture and suggest that this is another area where critical psychiatrists may have a role. The role of culture has been discussed in the DSM, many departments of psychiatry have cross-cultural departments with interpreters, and in the past 20 years I’ve attended numerous conferences where cross-cultural psychiatry was either the main component or one of the significant lectures. I doubt that critical psychiatry as had anywhere near the impact of regular psychiatrists who go to work every day and practice cross-cultural psychiatry. He cites “coercion” in psychiatry is another area where critical psychiatry may have some legitimacy. In fact, every state in the United States as safeguards written into their statutes that describe the circumstances where involuntary treatment may be ordered by a court. Critical psychiatry and anti-psychiatry continue to confuse the legal system, psychiatry, and involuntary treatment of mental illness whenever it is convenient.

Dr. Tyrer also suggests that critical psychiatry has a role in “correcting the growing belief that mental illnesses are just diseases of the brain and can soon be transferred to neurology”. It is no longer the early 20^th century. The neuroscientific study of the brain and mind is growing exponentially. As we appreciate that complexity it should be apparent to everyone in the field that no single practitioner or scientist will be able to master all of that information. Psychiatrists are not neurologists even though many of us share the same personality characteristics. Psychiatrists are still trained in the importance of the interpersonal relationship and its meaning whether or not the underlying biology of the process is completely known or not. This is an ongoing scientific endeavor also occurs at the clinical level and I think it is unlikely that the hundreds of newly identified clinical entities will ultimately be classified as neurological conditions.

I agree completely with Dr. Tyrer’s main points but as noted above don’t think he went far enough.  Critical psychiatry really is not an exercise in scientific criticism - it is an exercise in rhetoric. Speaking to his metaphor critical psychiatry is not "becoming Luddite" - it has always been.  He does not give the field of psychiatry enough credit in the area criticizing itself. He also gives critical psychiatry too much credit for constructive criticism while pointing out that they have created “increasingly destructive commentaries”.  He points out that critical psychiatry is adding little knowledge to the field and serving a brake on progress but does not comment on significant conflict of interest that exists with much of this criticism.

There is also a question of how much harm is caused by these destructive commentaries and anti-psychiatry websites and anonymous posters suggesting to readers that the treatments working for them are toxic and that psychiatrists are inherently bad people. As physicians we need to be very explicit about that problem.

I plan to read the Middleton and Moncrieff paper and post a critique here the end of the weekend.  I have already done much of that work on this blog. It will hopefully be useful to see what their positions really are.

George Dawson, MD, DFAPA

Reference:

1.  Tyrer P.  Critical psychiatry is becoming Luddite. BrJPsych Advances 2019, vol 25: 55-58.

Medical Care Of The Seriously Mentally Ill - The Way It Should Be Provided

I was impressed with the week's Case Records of the Massachusetts General Hospital in the New England Journal of Medicine for a couple of reasons. First, it seems to be a continuation of a renewed effort to cover psychiatry and the medical interface.  This has been done before.  I used to track how many references to psychiatry or psychiatric symptoms there were in this feature. Over about 20 years - I think I came up with 5-10 references per year.  The discussants were generally not psychiatrists because the symptoms originated from neurological or medical disorders.  This case is a patient with obvious psychiatric illness occurring in the common context of an inadequate history and no collateral information.  Secondly. it discusses how care should be provided to these patients and in today's reality of severely rationed care, that is extremely important.  My goal with this post is to point out some of the lessons that I think are important from this case, based on 22 years of experience providing the same level of care that the authors do here. The case itself is presented in detail and I will not repeat those details here.

The patient in this case is a 48-year-old woman who presents to the emergency department with "prickling and tingling" in the palm of her right hand.  She presented about 5 hours after she had previously been discharged for evaluation of the same problem.  She had been discharged with a list of shelters and hotels but came back saying that she was concerned that the hotel staff would "gas" her or perform "unwanted sleep studies" on her.  The main case discussants were psychiatrists who presented all of the review of systems, mental status exam findings, physical findings, and laboratory findings.  She had a normal physical exam and the mental status exam was remarkable for mild cognitive impairment on a standard cognitive screen, psychosis in the form of loosely organized paranoid delusions, grandiosity, pressured speech, and labile affect.  The patient also had impaired judgment and because of the concern about her ability to care for herself-she was admitted on an involuntary basis. 

The differential diagnosis of the psychiatric disorder from the perspective of a primary or secondary psychosis is discussed in detail.  Nine major categories of disease are covered as well as specific possibilities in each category.  The discussions include commentary on why a particular diagnosis is likely or not.  Following that discussion the psychiatrist presents the most likely psychiatric and physical diagnosis to account for the presentation.  Reading through this exercise, I thought that the discussion was outstanding and potentially much more enlightening that a vague abbreviated continuing education exercise.  I recommend that residents read through this exercise and think carefully about the decision points presented by the psychiatrist-discussant.  I will add that my inpatient colleagues and I have made the diagnoses given in this proposed two diagnosis list many times.  We also began screening for the medical problem in the exact same way suggested in this article starting about 20 years ago. Anyone interested in this process should read this article in detail.  I consider it to be a great example of the medical thinking and skills required to be a psychiatrist.

A hematologist also discussed the findings including explaining nuances of the laboratory results and confirmed the diagnosis.

An added bonus in this case was a discussion of the difficulties in making medical diagnoses in psychiatric patients with severe mental illnesses by Dr. Freudenreich.  He identified the difficulty in the interview situation as a lack of reliable information and no collateral information generally available in emergency situations.  He used a term "diagnostic overshadowing" or attributing physical symptoms to a psychiatric disease (the old "it's all in your head").  He suggests a three question approach to avoid that kind of problem by taking into account the psychiatric diagnosis, whether a reasonable evaluation of common problems has been done, and whether or not the psychiatric illness contributes to the medical problem.  In  my experience, I have seen flat out denial that a problem exists - ranging from diabetes mellitus to lung cancer to be a major obstacle to both acute and ongoing care.   

Another aspect of appropriate care of populations with severe psychiatric disorders is the ability to establish dialogue with that person.  Psychiatrists are used to talking with people who are delusional, hallucinating, and who have formal thought disorders.  A lot of physicians do not have that experience or interest and that results in truncated interviews and not much exchange of information.  Another aspect of the psychiatric interview is that the psychiatrist is always making determinations about whether what is being said by the patient is really accurate or whether it is distorted or symbolic communication.  That process helps to determine what the physical concerns are and to what extent they need to be evaluated. 

Providing care based on the inability to care for oneself rather than dangerousness is a key part of this case.  At one point the authors point out that the patient was admitted on an involuntary basis. Subsequent to that admission she was diagnosed and definitively treated for a condition that is at the minimum severely disabling and in the worst case fatal.  She had been released from a previous emergency department. I can say without a doubt that she would have been released from any emergency department in the state where I currently work. Minnesota has been living the myth that there is a "shortage" of psychiatric beds for about 30 years now without acknowledging that the state government is directly responsible for the shortage.  One of the commonest rationales for discharging people with severe mental illness and vague medical complaints to the street is that they are not "dangerous".  Like every other state there is a gravely disabled standard for emergency holds that allows for the involuntary admission based on disability due to mental illness. Like every other state - Minnesota ignores it.

In summary this case report is much more than an exercise in the differential diagnosis of psychiatric and medical disorders. This case report represents a standard of care for persons with severe mental illness. Any reader of this post who is familiar with the lack of standards of care for this population in the US healthcare system doesn't have to imagine that this person could have been repeatedly discharged from numerous emergency departments, sent to jail for trespassing, or given a bus ticket to the next town.  Imagination is not required because we have all seen it happen.  There are numerous rationalizations, but saving money by not caring these folks is the overriding factor.  Health care systems, state governments, and county governments have all turned their backs on them.  In the midwest, the only time the homeless get a break is when the temperature drops to 20 below and decisions are made to free up more resources so they don't die on the streets. This case illustrates that a warmer environment is no less hostile if you can't get the medical care that you need.

Kudos to the psychiatrists and physicians providing this level of care wherever they can and the NEJM for raising awareness on this issue. The larger societal issue is why this level of care is not available everywhere and why persons with mental illness cannot expect the same level of care as medical or surgical patients.


George Dawson, MD, DFAPA


Reference:

Hogan C, Little BP, Carlson JCT, Freudenreich O, Ivkovic A, Baron JM.  Case Records of the Massachusetts General Hospital: A Woman With Delusional Thinking and Paresthesia of the Right Hand. N Engl J Med 2019; 380: 665-674. Link


Other Case Records of the Massachusetts General Hospital:

Shtasel DL, Freudenreich O, Baggett TP. Case Records of the Massachusetts General Hospital: Case 40-2015. A 40-Year-Old Homeless Woman with Headache, Hypertension, and Psychosis. N Engl J Med. 2015 Dec 24;373(26):2563-70. doi: 10.1056/NEJMcpc1405204. PubMed PMID: 26699172.

Irwin KE, Freudenreich O, Peppercorn J, Taghian AG, Freer PE, Gudewicz TM. Case Records of the Massachusetts General Hospital: Case 30-2016. A 63-Year-Old Woman with Bipolar Disorder, Cancer, and Worsening Depression. N Engl J Med. 2016 Sep 29;375(13):1270-81. doi: 10.1056/NEJMcpc1609309. PubMed PMID: 27682037.


Graphics Credit:

Graphic of the organometallic compound that is the key to this case was downloaded from PubChem.

Stochastic Processes In Human Biology

I was reading an important research article recently and encountered a term that I had not see in a while.  That word was stochastic. Physical science and engineering undergraduates probably encounter these words with different frequencies - most often as the expression stochastic process. As a chemistry and biology major, the main contact I had with the term was in what is typically considered the most mathematical of undergraduate chemistry courses - Physical Chemistry (PChem).  In the days I was an undergraduate we used a text by Moore.  In striving to stay in touch with the field I got a copy of a more current PChem text by Atkins several years ago.  The main reference to stochastic processes in both is the random walk problem.  In Moore it is in the problem set for the chapter on Kinetic Theory and and in Atkins it is in a separate supplement at the end.  That supplement is entitled Random Walk, illustrates how a random walk in one dimension can be used to derive an equation that estimates the probability of a particle being at a distance from the origin in a specified time during diffusion.  I won't include the equation here since there are a number of books and online sites where the derivation is available.

The authors of the research article were using it to describe a component of neuronal activity in the reward center of rats.  In their discussion of the term, they point out that brain complexity precludes the prediction of final outcomes from initial states. In the paper the authors were faced with explaining why a specific population of mice continued to self-stimulate dopaminergic neurons in the ventral tegmental area (VTA) via a optogenetic dopamine- neuron self-stimulation (oDASS) via an optic fiber despite punishment while another group of mice did not.  The details are included in the graphic at the top of this post.  To quote the authors on this phenomenon:

"Why only a fraction of mice lose control remains to be determined; the emergence of the two groups is even more surprising given the high degree of genetic homogeneity of the mouse line used here (our Dat^cre (also known as Slc6a3^cre) mice were backcrossed for more than ten generations into the C57BL/6J mouse line), and may reflect a case of stochastic individuality" (p. 320)

One of the key elements of this type of experimentation is minimizing variance form genetic and environmental factors.  The mice used in this experiment are inbred for several generations and in this case had a homozygous knock-in variation for dopamine transporter (DAT).  Colonies are developed to raise heterozygous mice with a greater expression of DAT for experimentation on these systems.  The idea behind backcrossing the mice for more than ten generations reduces the phenotypic variation but as noted in reference 2, there have been 30 years of experimentation of inbreeding mice and that reduces the phenotypic variance by 20-30%.  Although the C57BL/6J mouse line has its DNA characterized - I could not find any numbers for shared DNA on an individual to individual mouse basis.  As an example, in humans the following percentages of shared DNA would be expected identical twins (100%), parent-child (50%), grandparent-grandchild (25%), and first cousins (7.3-13.8%).

The experiment looked at these mice bred for a low degree of phenotypic variation who were all rained in similar environments.  All of the mice were trained for oDASS and then  subjected to foot shock as a punishment.  As noted in the graphic, 60% persevered despite the punishment and 40% renounced or had a marked decrease in oDASS after punishment. Both of these responses were considered distinct behavioral phenotypes.  The underlying molecular mechanisms were also studied.

The paper by Honegger and de Bivort (2) takes a more detailed look at examples of stochasticity. From a behavioral standpoint, they define stochastic individuality as non-heritable inter-organism behavioral variation.  The lack of concordance between identical twins is cited as a prime example. Beyond genomics they argue that stochastic individuality implies that if we know all about the basis of a trait at the -omics level and all of the relevant environmental factors – the behaviors will remain "beyond reliable prediction".  They review some examples from the animal kingdom. Marbled crayfish and pea aphids reproduce by apomictic thelytoky - that is all of the individuals are female and reproduction is clonal - therefore all individuals have the same genome.  Despite this individual display significant variation in locomotion and social behavior. They consider nutritional variances, self reinforcing circuits involving nutrition and behavior, and variation in biophysical developmental processes as possible mechanisms.  In the case of mice, highly inbred mice raised in the same environment vary significantly in their exploration of the environment. Individual mice that actively explore the environment have more robust hippocampal neurogenesis.

The authors detail and number of possible mechanisms underlying stochastic individuality including:

1.  A small number of effects at the molecular level promotes stochasticity.  Random fluctuations in RNA polymerase binding to DNA over time leads to fluctuating mRNA in the cell over time. There are also a host of possible mechanisms operating on small gene sets that lead to large combinations of possible outcomes.  An example given is T-cell biology in humans.  T-cells are essential for normal immunity in humans and the system can use a number of genetic mechanisms to generate a a very large number of T-cell receptor types (1015 to 1020 ) from a small number of genes (4).  The authors of this article discuss the fact that T-cell receptor diversity cannot be estimated by a priori assumptions suggesting this is a stochastic rather than deterministic process.

2.  Positive feedback in gene networks amplify fluctuations and can cause jumping between discrete states or bistability.  An example from the literature is cell quiescence, and there is thought to be a stochastic process involving a specific protein (5,6) that leads to the transition from active proliferation ( a number of states) to quiescence and back again.  

3.  Biological processes are systems that are non-linear, multidimensional, and have significant feedback and therefore are often chaotic.  Initial small differences will be amplified.  There are several disorders that occur with different concordance in identical twins (seizure disorders, cardiac arrhythmias) that could occur as the consequence of this process.  Biological systems that move large amounts of information across these systems are most susceptible.

4.  Somatic mosaicism – as cellular differentiation and proliferation occur genomic alteration can occur in new cells or their progeny. Transposons are active mobile DNA elements that can excise and re-insert into new positions in the genome leading to different cell genetics and tissues from the same progenitor cells.  In my current neurobiology lecture I discuss various level of brain complexity and give examples of 90 subtypes of potassium channels and significant numbers of vesicle trafficking proteins (7) in neurons.  Wilhelm, et al (7) reconstruct a 3D model of a synapse that contains 60 different in varying copy numbers. In the supplementary data they investigate a total of 100 different synaptic proteins and show that the copy numbers of each protein vary from 10 to 22,000 (Fig. S5).

The complexity of the synaptic proteins and their number may seem impressive and have the complexity to produce an apparent stochastic result. Looking at what might happen if these proteins are all modifiable by one of the mechanisms in the Honegger and de Bivort paper is more impressive.  The authors discuss alternative gene splice forms using a Drosophila example.  Proteins are typically formed in eukaryotic cells when the exon portions of the gene are cut and spliced from the intron or noncoding segment of a DNA or corresponding RNA transcript. Alternative splicing involves splicing that occurs in a way that some segments are altered or skipped. The result is multiple proteins being encoded by the same gene. A few examples are illustrated in the following graphic.

  

The nervous system implications of alternative splicing include recognizing that this occurs at every level of neuronal organization (8) and it has already been implicated in neurological diseases like amyotropic lateral sclerosis (ALS).  To get a quick look at what research may have already been done in this area I surveyed Medline for references to "alternative splicing" and "protein isoforms" for all of the neuronal proteins listed in the table of neuronal proteins listed in table S2 from reference 7.  As noted in the table there are probably over a thousand references unevenly distributed across these proteins indicating a significant amount of research on both the mechanism and classification of neuronal protein isoforms - many of which impact neuronal function and may be responsible for stochastic outcomes.

Research On Neuronal Protein Alternative Splicing and Isoforms
Protein	Alternative Splicing references?	"Protein Isoforms"[MeSH Terms] + Protein references?
SNAP 25	+	+
VAMP 2	+	+
α-SNAP	+	+
α/β-Synuclein	+	+
AP 180	+	+
AP 2 (mu2)	+	+
CALM	+	+
Calmodulin	+	+
Clathrin heavy chain	+	+
Clathrin light chain	+	+
Complexin 1,2	-	+
CSP	-	+
Doc2A/B	-	-
Dynamin 1,2,3	-	+
Endophilin I,II,III	-	+
Epsin 1	-	+
Hsc70	-	+
Intersectin 1	+	+
Munc13a	-	-
Munc18a	-	+
NSF	+	+
PIPKIγ	-	+
Rab3	+	+
Rab5a	-	+
Rab7a	-	+
Septin5	+	+
SGIP1	-	-
Synapsin I.II	+	+
Syndapin 1	+	+

At this point I am wrapping up this post with a list of stochastic mechanisms to follow in subsequent posts.  This is an important concept for psychiatrists interested in individual differences in behavior and well as unique conscious states to know about. It has the potential for greatly increasing the explanatory power of why there is so much heterogeneity in presentations of illness and outcomes.  It has the potential for providing a clearer understanding of the neurobiological substrates of behavior.  The distinct behavioral phenotypes in the experiment noted in the beginning of this post is a clear case in point.


George Dawson, MD, DFAPA




References:

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Supplementary:

The Kyoto Encyclopedia of Genes and Genomes (KEGG) currently lists 40 alternative splicing factors. Link

Graphics Credit:

1:  Top graphic -> me.

2:  Alternate splicing graphic from VisiScience per their purchasing agreement.

Click on either graphic to enlarge.