Hi everyone,
Wow Biomiast, you’ve done a lot of research on the spindle neurons! I’ve never heard of psychopathy being related to gastrointestinal disorders, so I thought your finding was curious. I apologize for not getting back to you sooner; it took me a while to understand the VEN’s and their functions, since I’m a very slow learner. I’ve tried to find some connections between serotonin 2b, neuromedin b, and Gastrin Releasing Peptide with gluten and thus psychopathy; I don’t believe that I’ve found any “smoking gun” connections, although your research has led me to find some interesting data. Thank you so much for your hard work. I will look forward to any new dots to connect you may find in your free time. :)
For the serotonin 2B, I haven’t found anything yet that could specifically link it to gluten. I haven’t even found a page that suggests opiates could be agonists to them! But there is this page that links to other serotonin receptors, FWIW:
_http://www.medicalnewstoday.com/articles/33784.php
""Number of serotonin receptors influences brain's response to fear and stress
Using positron emission tomography (PET), which provides three-dimensional detail of the distribution of molecular structures, the researchers were able to examine the availability of the two receptors for serotonin in specific regions of subject's brains, including the amygdala and subgenual prefrontal cortex. One of these receptors, the 5-HT1A, causes neurons to be inhibited when serotonin binds to it. In contrast, binding to the other receptor, the 5-HT2A, causes the cell to be excited.
The same subjects also underwent testing with functional magnetic resonance imaging (fMRI), which shows the areas of the brain that are engaged during different tasks. The researchers used their standard protocol whereby subjects were shown black-and-white photos depicting angry and fearful facial expressions, a simple yet highly sensitive tool that shows how the amygdala reacts to important environmental stimuli.
Those subjects in whom PET showed a higher number of serotonin 5-HT1A receptors relative to 5-HT2A receptors in the subgenual prefrontal cortex had less brain activity in this region during fMRI, as would be expected, since 5-HT1A is the inhibitory receptor. Yet, in these same subjects, the amygdala was much more stimulated than those who had a lower 5-HT1A-to-5-HT2A ratio or just more of the 5-HT2A receptors. In essence, the researchers found that these specific serotonin receptors seem to help control the extent to which any rational "discussion" takes place in the subgenual prefrontal cortex. And absent the voice of reason, the amygdala can behave as it wishes.
I’ve had more luck with the GRP:
_http://informahealthcare.com/doi/abs/10.3109/00365528309181579
""Before treatment the celiac patients had enhanced gastrin response and normal PP response compared with normal controls. After gluten withdrawal the integrated gastrin release was reduced to normal in the responders (275 versus 114; p < 0.05) but remained elevated in the nonresponders (231 versus 204)
So I guess gluten causes the gastrin-releasing peptide to go into overdrive in celiacs. Why did it have no response in others? Perhaps leaky gut, or toxicity? The function would make sense because GRP regulates epithelial cells, which are inflamed in celiacs.
On a side note:
_http://ajpgi.physiology.org/cgi/content/full/288/4/G718
""Neuromedin B and its receptor are mitogens in both normal and malignant epithelial cells lining the colon
_http://bio-synthesis.blogspot.com/2009/08/gastrin-releasing-peptide-grp-and_25.html
“”GRP is released by the post-ganglionic fibres of the vagus nerve, which innervate the G cells of the stomach and stimulate them to release gastrin. GRP can directly stimulate pepsinogen release from chief cells by a specific GRP receptor that mobilizes intracellular calcium. GRP has a prominent role as a tumor marker in the diagnosis of small-cell lung carcinoma. It regulates numerous functions of the gastrointestinal and central nervous systems, including smooth muscle cell contraction, and epithelial cell proliferation and is a potent mitogen for neoplastic tissues6.
_http://www.nutramed.com/celiac/celiacallergy.htm
""A cell-mediated type of allergy leads to a host of complicated consequences, especially increased permeability of the gastrointestinal tract (GIT) with more problems downstream. The surface lining of the digestive tract is the largest and most critical interface between you and your environment. In the small intestine, the lining epithelial cells are involved in immune processes. They transfer immunoglobulins produced by lamina propria B-lymphocytes to the surface and interact with other cells of the immune system to induce an inflammatory response to stop microbial invasion. The surface epithelium processes food antigens, and presents antigens to lymphocytes. Both epithelial cells and intraepithelial lymphocytes participate in inflammatory reactions. Epithelial cells proliferate in celiac disease. Crypt hyperplasia is a common tissue response to mucosal damage in food allergy and infection.
It seems that calcium channels may have something to do with it as well:
""The GRP and neuromedin B (NMB) are structurally related to BB and exist within the mammalian small intestine... A series of potent GRP antagonists have been developed by modification of the COOH terminus of N-acetyl-GRP-20-27. The most potent member of this series, N-acetyl-GRP-20-26-0CH2CH3, obtained by modification of the COOH-terminal region of this peptide blocks GRP-stimulated mitogenesis, inhibits GRP-dependent release of gastrin and blocks GRP-induced elevation of [Ca2+]i in vitro2.
Which leads to this:
_http://www.koreatimes.co.kr/www/news/tech/2010/06/133_61680.html
""The research team, led by Shin Hee-sup of Seoul's Korea Institute of Science and Technology (KIST), suggests that the medial pain system, the area of the brain that represents pain affection, has a key role in the social learning of fear by observation.
Also, the L-type calcium ion (Ca2+) channels, which are known to contribute to synaptic transmission and neural excitability in the anterior cingulated cortex (ACC) ― part of the medial pain system ― is also required in the learning process for fear, the scientists said.
"If the brain's medial pain system doesn't act normally, a person will not be able to properly recognize the pain and fear of others, and this could be related to a variety of conditions, such as psychopathic personality disorders," Shin said.
"By identifying the brain regions and mechanism related to fear learning and discovering the role of the L-type Ca2+ channels, we believe that we have made an important discovery in the efforts to develop treatments for mental illnesses related to fear learning by social observation."
The inactivation of the ACC and parafascicular or mediodorsal thalamic nuclei, which are the other parts of the medial pain system, substantially impaired this observational fear learning in the animals, the study said.
The deletion of the L-type Ca2+ channels in the ACC also impaired observational fear learning and reduced the behavioral pain responses.
So maybe calcium affects our ability to fear and empathize? Maybe its effects on the brain have to do with its role in detoxing heavy metals? I’m not sure if the above implies that GRP opens calcium ion channels, though.
On a side note, glutamate, which is found in great amounts by weight in wheat, opens calcium channels.
Neuromedin B apparently releases calcium, too, if I'm understanding the med lingo correctly.
_http://www.wikigenes.org/e/gene/e/4828.html
We examined the effect of two des-Met-bombesin analogues, [(CH3)2CHCO-His-Trp-Ala-Val-D-Ala-His-Leu-NHCH3] (ICI 216140) and [D-Phe6,des-Met14]bombesin(6-14) ethylamide (DPDM-bombesin ethylamide), on neuromedin B-induced Ca2+ and [3H]arachidonate release in BALB 3T3 cells transfected with human neuromedin B receptors [30].
Here’s something that has more to do with VEN’s:
_http://webcache.googleusercontent.com/search?q=cache:vlyWL2cTmO4J:www.recovery.ca.gov/viewAwardDetails.do%3FtasNumber%3D75-0845%26awardId%3D2883%26isFederalAward%3Dtrue%26category%3DScience%2Band%2BTechnology+%22von+economo+neurons%22+cytokines&cd=10&hl=en&ct=clnk&gl=us&client=firefox-a
""This proposal is to support a collaboration between the laboratories of John Allman and Barbara Wold to investigate gene expression in laser micro-dissected cell populations in autopsy brains of well-phenotyped autistic individuals versus age and sex matched controls using a recently developed techniques, RNA-Seq. RNA-Seq will be interpreted in the context of SNP and copy number variation (CNV) genotyping. FI (Fronto Insular Cortex) and ACC (Anterior Cingulate cortex) are functionally implicated in social interaction and reciprocity, in empathy, and in the awareness and regulation of bodily functions. These functions are crucially affected in autism. Unlike other homeostatic systems, including those in the hypothalamus, the FI/ACC system appears to have direct access to consciousness and motivation. Analysis of initial RNA-Seq on FI samples produced two coherent gene networks that differ between autistics and neurotypical controls. Immunostaining for several network members has begun to show how networks map onto the cellular circuitry. Specifically, at the cell level, FI and ACC contain large bipolar cells (Von Economo neurons, VENs) that are distinctive features of these structures in apes and humans. We found that VENs express receptors for the cytokines interleukin 4 (IL4R) and interleukin 6 (IL6R) in normal and autistic subjects, and RNA-Seq identified a prominent gene network related to inflammation which is strongly up-regulated in a subset of our autistic cases (autism-A). This network is centers on IL6 and includes ATF3, SOCS3, and GADD45B, which are selectively expressed in VENs. Microglia, the immune cells of the nervous system, are numerous and are in the activated state in autism-A, making a likely signal source. Our remaining autistic cases comprise an autism-B group, which is characterized by increased expression of genes in the presynaptic terminal including NRXN1 (neurexin 1), which provides Velcro-like binding to neuroligins in the post-synaptic membrane. NRXN1 is one of the genes most strongly and consistently associated with autism. NRXN1 has many splice variants which could provide specificity in formation or strength of synaptic connection. To probe these networks more deeply; to assign gene expression and splice isoforms to their proper cells; and to discover remaining differences in autistics, we propose generation-2 RNA-seq on laser-dissected cells. Thus VENs and other key cell types are rare (<5% of cells in FI). This reduces their transcriptome completeness: genes under- expressed in autism relative to controls will be especially affected. Successful laser capture can overcomes this hurdle. We also propose deep RNA sequencing for NRXN1 isoforms and other complex families that may be uncovered. PUBLIC HEALTH RELEVANCE: We seek to understand the cellular bases of autism by using a new technology, RNA-Seq, to determine differences in gene expression in autopsy brains of subjects with well described autism versus age and sex matched neurotypical individuals. We have investigated two specific cortical areas involved in self-awareness and social reciprocity which are abnormal in autism and have found increased expression in a network of genes related to inflammation in autism group A, whereas the remaining cases, autism group B, have increased expression in a network of genes related to synapses. We propose to use laser micro-dissection to investigate gene expression in specific neuronal and non-neuronal populations in the cortical areas of interest in the autism-A, autism-B and control groups.
Gluten, I think, causes inflammatory cytokines to be produced in the intestines. I don’t know what kinds it specifically produces, but since the particles in wheat crosses the BBB, these cytokines can wreak all kinds of havoc in the VEN’s, I assume:
_http://www.wisegeek.com/what-is-interleukin-6.htm
""While interleukin-6 is vital for optimum immune functioning, the downside is having too much of a good thing. Impaired or uncontrolled interleukin-6 gene expression can produce unwanted immune responses and lead to a variety of diseases, including autoimmune disorders. Patients with rheumatoid arthritis, for example, typically have elevated levels of interleukin-6 in their synovial tissue. To combat this dysfunction, researchers continue to investigate different ways to inhibit binding of interleukin-6. This includes development of an anti-interleukin-6 receptor antibody.
To connect that to gluten:
_http://www.medscape.com/viewarticle/568856
""Concentrations of IL-6 also diminish with a gluten-free diet (GFD).[14]
_http://www.psychologytoday.com/blog/the-new-brain/200912/baby-blues-search-beyond-neurons
""One of the main chemical signals marshalling a cellular response to infection are called cytokines. Genes for several cytokines were suppressed in women with postpartum depression. Cytokines are released into the blood by white blood cells, but microglia release cytokines in brain tissue. Cytokines have powerful effects on the excitability of neurons and they regulate cell division and cell development. Recent research, for example, has shown that cytokines released by microglia contribute to chronic pain and addiction to opiate drugs.
Neuromedin B has something to do with alkaline phosphatase:
_http://sites.google.com/site/jccglutenfree/thestory
""The discovery of something called Gluten Sensitivity/Celiac Disease led us to a probable answer for my daughter K's many years of symptoms. She is now a young adult, but her symptom list during her childhood years includes: joint and bone pain, rashes and hives, mood swings, frequent general illness, sinus and throat infections, sleep disturbances, stomach aches, dry eyes and mouth, frequent canker sores, defective dental enamel, muscle spasms, back pain, seizures, chronic asthma, and a variety of abnormal labs along the way including abnormal high alkaline phosphatase, abnormal high CK, abnormal low potassium, repeated abnormal low ALT/AST (which can indicate B6 deficiency), and some other borderline low values, ...but none abnormal ENOUGH to raise concern.
_http://www.wikigenes.org/e/gene/e/4828.html
NMB induced a larger percent change in alkaline phosphatase secretion than GRP with a half maximal response at less than 1 nM NMB [31].
I’m not sure if this is relevant, but I remember someone mentioning the Ventral Tegmental Area:
("Neurofilament Proteins and the Mesolimbic Dopamine System:
Common Regulation by Chronic Morphine and Chronic
Cocaine in the Rat Ventral Tegmental Area")
""It is uncertain what impact such alterations in NFs [neurofilament proteins] would
have on the functional properties of the VTA. NFs are known
to be associated with axonal transport (Hoffman and Lasek,
1975; Tytell et al., 198 1; Hammerschlag and Brady, 1989) although
the precise role subserved by NF proteins remains unknown.
A variety of in vivo manipulations, including axotomy,
aluminum intoxication, and chronic P,P’-iminodipropionitrile
intoxication are all known to lead to decreased NF levels and
to decreased rates of axonal transport (Hoffman et al., 1984;
Tronosco et al., 1985; Goldstein et al., 1987; Watson et al.,
1989). Furthermore, increased phosphorylation of NFs is also
correlated with decreased rates of axonal transport. There is a
progressive increase in the degree of phosphorylation of NFs as
they are transported from the cell body along the axon (Sternberger
and Sternberger, 1983; Hoffman et al., 1985; Carden et
al., 1987; Nixon et al., 1987; Pestronk et al., 1990) which has
been proposed to be the mechanism by which NF velocity becomes
progressively decreased as NF proteins are concomitantly
transported distally (Carden et al., 1987; Lee et al., 1987). In
addition, in vivo axotomy (Goldstein et al., 1987) and chronic
&3’-iminodipropionitrile intoxication (Watson et al., 1989) also
lead to increased phosphorylation of NFs, in concert with decreasing
total levels of these proteins. Finally, NFs from rats
made experimentally diabetic exist in an increased state of phosphorylation
(Pekiner and McLean, 199 1), which also correlates
with the decreased axonal transport rates observed in diabetic
animals (Macioce et al., 1989).
Given the above evidence, our findings that NFs are (1) decreased
in total amount and (2) present in an increased state of
phosphorylation in the VTA after chronic morphine and cocaine
treatments imply conditions of decreased axonal transport within
this brain region. Indeed, we have recently found that chronic
morphine does impair axonal transport in the mesolimbic dopamine
system (Beitner-Johnson and Nestler, 1992).
And gluten and casein slow down electrical activity, so I believe the above study should apply to what is said here:
_http://depression.about.com/cs/diet/a/foodallergies.htm
""Additionally, the morphine-like substances derived from the incomplete digests of dairy and cereal grain proteins are other dietary factors which may alter mood by depressing CNS serotonin, dopamine and norepinephrine levels (5). The reduced number of platelet receptors for serotonin found in patients with celiac disease, which is also caused, at least in part, by dietary factors, again points to food as a factor in some cases of depression.
Serotonin is an important neurotransmitter which is needed for sleep onset, mood regulation, carbohydrate craving and consumption, and a host of other functions (7). But there are other means to manipulate its presence in the brain.
Investigations of abnormal electrical activity in more than two thirds of untreated children with celiac disease has indicated that most of them normalize following dietary restriction (17, 18). These findings suggest that caseomorphin and gluten-derived exorphins are at the root of such abnormal electrical activity in the brain. Since such substances act as depressants, slowing neurotransmission, it should not be surprising if the intestinal permeability, and digestive enzyme deficiencies found in celiac disease were also found in many folks suffering depression. This is underscored by the reports that depression is a very common symptom of celiac disease (19, 20, 21, 22, 23, 24, 25, 26). More on this point can be found at: http://www.gluten-free.org/reichelt.html
Since you discussed brain structure relating the the corpus callosum in your first findings, maybe this on the striatum will interest you:
_http://neurologicalcorrelates.com/wordpress/2009/09/04/unified-field-theory-of-psychopath-brain-development-retinoid-toxicity/
""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.
Then there’s this:
_http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T7W-3VXNJDJ-B&_user=10&_coverDate=04%2F19%2F1996&_rdoc=1&_fmt=high&_orig=search&_sort=d&_docanchor=&view=c&_searchStrId=1369688475&_rerunOrigin=google&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=fd80c10514ebb802b0029287b4e3c3c5
“”Gliadin nanoparticles were found to be excellent carriers of all-trans-retinoic acid
However, retinoic acid is anti-inflammatory, so I don’t see how it could increase the stratium. I don't have the evidence to connect the gliadin with the inflammation, but I think it's more likely.
Then there’s something on METH users and the corpus callosum:
_www.ncbi.nlm.nih.gov/pubmed/15860336
""BACKGROUND: Little is known about structural brain abnormalities associated with methamphetamine (METH) abuse; therefore, we aimed: 1) to evaluate possible morphometric changes, especially in the striatum of recently abstinent METH-dependent subjects; 2) to evaluate whether morphometric changes are related to cognitive performance; and 3) to determine whether there are sex-by-METH interactions on morphometry. METHODS: Structural MRI was performed in 50 METH and 50 comparison subjects with the same age range and sex proportion; quantitative morphometric analyses were performed in the subcortical gray matter, cerebellum and corpus callosum. Neuropsychological tests were also performed in 44 METH and 28 comparison subjects. RESULTS: METH users showed enlarged putamen (left: + 10.3%, p = .0007; right: + 9.6%, p = .001) and globus pallidus (left: + 9.3%, p = .002; right: + 6.6%, p = .01). Female METH subjects additionally showed larger mid-posterior corpus callosum (+ 9.7%, p = .05). Although METH users had normal cognitive function, those with smaller striatal structures had poorer cognitive performance and greater cumulative METH usage. CONCLUSIONS: Since METH subjects with larger striatal structures had relatively normal cognitive performance and lesser cumulative METH usage, the enlarged putamen and globus pallidus might represent a compensatory response to maintain function. Possible mechanisms for the striatal enlargement include glial activation and inflammatory changes associated with METH-induced injury.
Meth is not an opiate, however, so this has nothing to do with gluten. It does increase levels of dopamine, serotonin, and norepinephrine [fight or flight hormone], though.
And if it’s any interest to you, I found a possible link between casein and psychopathy:
_www.crimetimes.org/96c/w96cp6.htm
""Walsh studied 24 pairs of brothers. Each pair lived together, and included one violent, delinquent sibling and one sibling with no academic or behavioral problems. Hair samples taken from the non-delinquent siblings revealed no abnormalities, while samples from the delinquent siblings showed two markedly abnormal patterns. One pattern of biochemical abnormalities ("type A") was seen in subjects who exhibited episodic violence, while another ("type B") was found in psychopathic subjects who showed no conscience or remorse, were pathological liars, and often tortured animals or set fires as children.
A controlled study by Walsh et al. of 192 violent and non-violent males found the same pattern: 92 of 96 violent subjects had type A or type B biochemical profiles, while only five of the 96 non- violent subjects had abnormal profiles.
According to Walsh, type A subjects have elevated serum copper, depressed plasma zinc, high blood lead levels, and abnormal blood histamine levels. Hair analysis reveals an elevated copper- to-sodium ratio that Walsh calls "quite striking." Type B subjects have elevated blood histamine, low plasma zinc, and elevated lead levels, and hair samples show a depressed copper-to-sodium ratio. Walsh also has identified "type C" and "type D" profiles associated with low-to-moderate levels of aggression.
Much of Walsh's attention has focused on psychopaths, and in particular on murderers. For instance, he says, tests performed on Charles Manson, serial killer Henry Lee Lucas, and James Oliver Huberty (of the McDonald's massacre) revealed a type B pattern of biochemical abnormalities. (Walsh says that only « of one percent of the general population, but between 20% and 60% of studied prison populations, exhibit the type B pattern.) Patrick Sherril, who killed several people in a Post Office rampage, was "an intense type A person," Walsh says, adding that "his most striking factor was his blood lead and cadmium levels."
wiki: Casein has been documented to break down to produce the peptide casomorphin, an opioid that appears to act primarily as a histamine releaser.
So milk protein releases histamine, which has been found to be elevated in psychopaths.
Well, that’s all I found that was somewhat relevant to the discussion. Hope it helps! Thanks for replying everybody! :)
(Edited for typos.
)
