Unified Field Theory of Psychopath Brain Development: Retinoid Toxicity

Psychopaths are reported to have a ginormous striatum – almost 10% bigger than normal. What’s up with that?

So, of course, having anonymous blogger’s privilege and no scientific reputation to uphold,  this post is to take a giant speculative leap that the psychopathy is really a result of  one-two punch in utero: The enlarged striatum is possibly induced by retinoic acid overload, and this retinoid overload  upregulates CD38 — which then activates immune cells in the brain (microglia). Result: Overgrown striatum constantly hungry for dopamine, white matter disconnects, and who knows what else.

Just to be clear, the striatum is instrumental that feeling of reward — it’s involved in the serotonin and dopamine pathways — and apparently is something of gatekeeper (behind the frontal cortex)  in impulsivity, or making bad decisions.  The paper about large striatums in psychopaths:

Glenn AL, Raine A, Yaralian PS, Yang Y., “Increased Volume of the Striatum in Psychopathic Individuals,” Biol Psychiatry. 2009 Aug 14. [Epub ahead of print] doi:10.1016/j.biopsych.2009.06.018

(The authors of course had no such flying leap of speculation).

Backing up, lots of people have striatum issues. An enlarged striatum is found in autistic folks, meth addicts, and others afflicted with clinically categorized conditions.

What’s an enlarged striatum got to do with it ? (WARNING: SPECULATIVE LEAP AHEAD).

What makes the striatum big?  Possibly retinoids (vitamin A and its congeners) – if you have a big one, retinoic acid may be the thing that controls how big it gets when you’re in utero – some brain effects of retinoids:

• Retinoic acid is  involved in developing a striatum; and excess retinoic acid causes enlargement
• Retinoic acid may play a role in neural plasticity;
• Retinoic acid seems to tune the set point for brain cell plasticity;
• Retinoic acid   re-grows striatum after a stroke ( in rats)
• A retinoic acid receptor agonist protected brain dopamine neurons from inflammatory degeneration (via a brain derived neurotrophic factor pathway).
• Neither here nor there, retinoic acid is what grows back the tail of a salamander when it’s cut off — it is involved with limb patterning and regeneration;
• It’s also in wrinkle and zit cream.
• Retinoic acid (or at least its receptors)  is involved in inflammation;
• Retinoic acid upregulates CD38 in cancer cells (and CD38 upregulates oxytocin; here is  the oxytocin category page);
• Although it is unclear how you get excess retinoids apart from diet or over medication, one thing is that there are retinol binding proteins. In young, healthy women who smoke, retinol binding protein 4 levels were elevated. To me, this indicates more transport of  endogenous and dietary retinoids –  perhaps across the placenta.

Retinoic acid, which is a form of Vitamin A, has been known for some time to cause psychiatric symptoms in some patients when given in the wrong dose:

• Psychiatric effects of retinoic acid (in the form of a Vitamin A overdose) was first noted in the 16th century by Arctic explorers who ate polar bear liver or seal liver . They reported symptoms of drowsiness, irritability, severe headaches, nausea and ‘irrational’ behavior, later confirmed by the Australians in Antarctica on an ill-fated jaunt where a dog sled full of supplies vanished down a crevice,  leaving the explorers Dr. Mawson and Mr. Mertz  to eat the remaining dogs — including their livers. Apparently dog liver contains toxic doses of Vitamin A, and Dr. Mawson so notes Mr. Mertz’ delirum and agitation in his death throes (that’s just a story I found interesting — see below for the coincidence);
• Isotretinoin (a form of retinoic acid) in acne meds is associated with a bunch of psychiatric symptoms, like depression and suicidality (massive review article here).
• Retinoic acid is involved in affective orders.

Now, the story gets interesting at the intersection of inflammation and emotion:  the molecule that seems to be constantly positioned and directing traffic is CD38.

CD38** is a both an inflammatory marker and an upregulator of oxytocin.

To make matters more interesting, recall one thing that upregulates CD38 :  Retinoic acid.

One of the things CD38 does is activate microglia, the immune/housekeeper cells in the central nervous system.

So:  More retinoic acid, more CD38, more microglia activation.

There are some immune theories out there for various neuro-disorders:

• Autistic spectrum is  theorized to be a neuroimmune reaction at its root;
• There is an autoimmune theory of addiction;
• Tourettes patients exhibit autoimmune antibodies against the caudate nucleus (part of the striatum), and administration of IgG is reported to decrease the severity of tics and other symptoms.
• Striatal neuroinflammation induces Parkinson’s like symptoms in rats,
• Post-mortems on human Parkinsons patients’ brains reveals particular neuroinflammatory profiles

OK, here’s the dot-connected picture:

In utero, there is some kind of retinoid toxicity to the fetus  (indued by who knows what, vodka tonics, Virginia Slims, Jungle Gardenia perfume, leopard print hotpants. . . or, war, trauma, chronic stress. . .  I digress). This results in an increase of retinol binding proteins that speed up whatever retinoids the mother has. This crosses the placenta, drops off the retinoic acid, and overloads the fetus. (I’m way totally guessing).

This fetal retinoic acid overload results in a ginormous striatum, chock full of dopamine neurons (because retinoic acid receptor agonists have a protective effect on dopaminergic neurons, see above).

The excess retinoic acid upregulates  fetal CD38 which then and activates the fetal microglia. My guess: this is where the white matter potholes come from — from fetal microglia acting against developing white matter tracts. But since retinoic acid is teratogenic, who knows.  Regardless, there would be some minor physical asymmetries from uneven and random retinoic patterning activity.

Now for the weird coincidence:  after I put down all the bullet points and developed the retinoid toxicity hypothesis (I thought it was more of a neuroinflammation) I found this paper:

“On the association between low resting heart rate and chronic aggression: Retinoid toxicity hypothesis” by  Anthony W. Mawson.

First, “Mawson” was the name of  leader of the ill-fated Australian trip to Antarctica, where Mr. Mertz became the first and only known death attributed to Vitamin A overload. Now a new Dr. Mawson came up with my theory over a year ago.  Mawson and Mawson. Wow.

And I had no idea about the whole polar bear liver/sled dog liver thing until I started looking into retinoic acid overload effects.  So is both the theory and the name a Coincidence?  Is the voice of Mr. Mertz speaking to us from beyond the grave saying, “don’t eat polar bear/sled dog liver pâté . . . “  One can never be too prepared, as the Australians in Antarctica have taught us all.

The new Dr. Mawson abstract:

Low resting heart rate is a strong and consistent predictor of conduct disorder and chronic aggression. Explanations such as fearlessness and low arousal-induced stimulus-seeking have been offered, assuming a causal association between the phenomena, but the origin of low heart rate and its significance for understanding aggression and violence remain obscure. Retinoids (vitamin A and its congeners) play important roles in embryogenesis and neural development. Several lines of evidence also suggest a causal role of retinoids in aggression as well as cognitive and mood disorders. The hypothesis is proposed that retinoid overexpression in utero induces, via a noradrenergic-to-cholinergic switch, alterations in cardiac functioning and hemodynamics resulting in low resting heart rate, brain structural and functional changes, minor physical anomalies, and persistent aggression. Retinoid toxicity occurring early in pregnancy could represent a final common pathway by which various prenatal challenges result in conduct disorder and chronic aggression (e.g., maternal cigarette smoking, alcohol consumption, drug use, exposure to environmental chemicals, stress, trauma or infection). Implications of the model for understanding related aspects of chronic aggression are discussed, as well as strategies for prevention and treatment.

---

*Psychopaths also have white matter disconnects between the frontal lobes and the limbic system — throwing a roadblock in the way of feeling bonded or compassion for anyone.  (See here for a Reuters report and here for my blog post on psychopath white matter disconnects.) So you can see the psychopath algebraic equation:

big striatum + white matter potholes =  high need for reward and low affective empathy (compassion)  =  power hungry

**All the functions of CD38 aren’t yet determined, but one guess is that it is something of a pit stop – energizing various target molecules (via tyrosine phosphates).  So, is CD38 an immune modulator or a cell signaller? Both! This is reminscent of the SNL episode, “It’s a floor wax and a dessert topping!”

Tags: neuroscience, psychology, psychopath, research, retinoid, sociopath, teratogenic