Read the Fine Print

Most scientists first learn their grant-writing skills in graduate school or as post-docs.  One of the rules that you didn’t find clearly spelled out in the instruction manual was “Find the hook”.  What trendy scientific issue will be conclusively dealt with only if your research project is funded? In the late 60s and early 70s when I was most interested in writing a research grant, the answer was “cancer”.  Your research seemed to have a better chance of being funded if it somehow dealt with a better understanding of this disease.  Today, the approach appears to be the same, but with a very different hook.  Research dealing with mental illness and addictions seems to get a great deal of attention.  But, as with cancer in the sixties and seventies, you need to read beyond the headlines to see what really was accomplished (if anything).

I subscribe to a couple of on-line medical alert emails and find them very useful.  Frequently I see a headline dealing with a better understanding of some psychiatric issue.  Further reading usually dispels my curiosity since I have little interest in treating depression in mice.  But today I really got bothered.  Not one, but two, articles heralded new possibilities in treating depression and addiction to smoking.  The articles are cited at the end of this blog.  One seemed fairly objective and was entitled “Transcranial Magnetic Brain Stimulation”.  The other offered much more promise:  “Discovery Of Nicotine Addiction Brain Mechanism May Lead To New Anti-Smoking Drugs”.  Sounds good, right?  New treatments that will help people with mental illness or addiction – everybody is in favor of that.

You have to read through half the article before you find out these studies were not done on people, but on mice.  The assumption is that the brain chemistry of mice is fairly similar to that of humans.  There are enough data out there to indicate that this is not always true, so researchers need to be very cautious in their statements.  Yes, it’s better from a research ethics standpoint to work on mice brains than human brains.  Yes, maybe (Stress the maybe) this work might lead to something someday.  But it is very unlikely that it will do most of us any good.

The bigger issue deals with the materialistic assumption that our behavior is determined by our brain chemistry.  There is ample data to indicate that changes in behavior and thinking have profound effects on brain structure and brain chemistry (another blog topic, perhaps?).  As long as scientists focus primarily on neurochemical theories of psychiatric illness, addiction, and other behaviors, we will be missing a great opportunity to explore valuable aspects of the mind-brain connection and we will miss many useful connections between behavior and biochemistry.

Benali, A., Trippe, J., Weiler, E., Mix, A., Petrasch-Parwez, E., Girzalsky, W., Eysel, U.T., Erdmann, R. and Funke, K. (2011) Theta-burst transcranial magnetic stimulation alters cortical inhibition. J. Neurosci., in press.

Mix, A., Benali, A., Eysel, U.T., Funke, K. (2010) Continuous and intermittent transcranial magnetic theta burst stimulation modify tactile learning performance and cortical protein expression in the rat differently. In: Eur. J. Neurosci. 32(9):1575-86. doi: 10.1111/j.1460-9568.2010.07425.x. Epub 2010 Oct 18.

Christie D. Fowler, Qun Lu, Paul M. Johnson, Michael J. Marks, Paul J. Kenny.  “Habenular [alpha]5 nicotinic receptor subunit signalling controls nicotine intake.”
Nature Published online 30 January 2011   DOI:10.1038/nature09797

Is Giving Genetically Determined?

Is our inclination to charity a function of our genes?  Do we donate to help others based on our brain neurochemistry?  Scientists at the University of Bonn, Germany seem to think so.  They studied the degree of giving to help a poor child after the research participant had undergone a demanding computer task for which they were paid.  Those who had a specific variant of a certain gene gave more money to the charity than those with a different variant of the gene.  Therefore, the researchers concluded that altruism (in this case, donating money without any return benefit) was at least partially determined by genetics.

Well, that sounds good if you accept the basic ideas on modern evolutionary psychology (or “social neuroscience” as some have taken to calling this field of study) which assume that all our behaviors are determined (at least in part) by our biochemical make-up. But what does this paper really show?  If you only read the summary on a news site such as Medical News Today (http://www.medicalnewstoday.com), the data sound very convincing.  But a close look at the actual paper suggests there are flaws in the conclusions.  So what’s really happening?

The gene under consideration codes for an enzyme known as catechol-O-methyl -transferase (or COMT for short).  This enzyme is found in the brain and other tissues and is involved in the deactivation of the neurotransmitters dopamine and norepinephrine. The neurotransmitters interact with a part of the brain known as the prefrontal cortex, which helps regulate personality, behavior inhibition, and emotion, among other things.  Low brain levels of dopamine have been associated with depression, schizophrenia, and other behavioral issues.  Dopamine is considered a “reward” or “pleasure” neuro-transmitter, with increased levels associated with enhancement of psychological well-being.

There are two major forms of the enzyme: a “long” form found in the brain and a shorter form found in other tissues.  In addition, each form has structural variants that affect the amount of deactivation of dopamine produced by that variant.  The study involved analysis of DNA obtained from a mouth swab, looking specifically for genes associated with the COMT variants.  The variant with two valine substitutions (Val/Val) has the highest level of dopamine inactivation, a one-valine substitution (Val/Met) has an intermediate degree of inactivation and the variant containing two methionines (Met/Met) has the lowest amount of dopamine inactivation.  So, the assumption is that people with the Val/Val variant will have the lowest amount of dopamine available to interact with the prefrontal cortex while those with the Met/Met variant will have a higher level of dopamine; the Val/Met variant should have intermediate levels of dopamine influencing the prefrontal cortex and behavior.

The data reported show that people with the two COMT variants leading to lower amounts of dopamine donated significantly more money than those than those with the Met/Met variant which should give rise to higher amounts of dopamine in the brain.  The researchers concluded that the Val/Val and Val/Met variants could be associated with higher levels of altruism.  However, there are a number of flaws in the study that could lead to different conclusions.  Let’s take a look at some of these flaws.

COMT is not the only enzyme involved with the breakdown of dopamine and similar neurotransmitters.  The enzyme monoamine oxidase (MAO) is at least as significant (and possibly more so) that COMT in regulation of dopamine activity.  MAO genes were not assessed in this study, but the contribution of this enzyme cannot be ruled out.

The data lump Val/Val and Val Met genes together in some of the information relating COMT contributions to altruistic behavior.  This combining of gene types does not allow us to assess realistically any influence of dopamine metabolism to altruism.  When the data split out the Val/Val and Val/Met genes separately, subjects with the Val/Met variant (representing an intermediate level of dopamine inactivation) contributed more to charity than the Val/Val or Met/Met individuals.  Therefore, no valid conclusions can be drawn relating the supposed level of dopamine in the brain to altruistic behavior.  In addition, the genes were analyzed from buccal tissue (not brain tissue).  COMT from brain has a different structure than COMT from extra-brain tissues and quite possibly has different kinetics properties (not discussed in this paper).

What can we conclude from all this?  Consider all the possibilities to explain the data.   Other enzymes that would influence dopamine and norepinephrine content in the brain were not explored.  No consideration was given to the possibility that the giving of money by the (presumed) low-dopamine group stimulated the release of more dopamine into the brain, providing a reward reinforcement for the chosen behavior.

But there could be an up-side to this study.  When asked for money (church collection plate, Salvation Army bell-ringer, “homeless” person on the street corner with a sign), just respond that you are a Met/Met COMT variant and are genetically predisposed not to  give.  After all, it’s not your fault that you’re cheap.

Rehabilitation of a Mushroom

Mushroom worship in various parts of the world has existed for centuries.  The ancient Aztecs referred to the hallucinogenic mushrooms as “flesh of the gods”.  The effects of these mushrooms are due to the active indoles psilocin (4-hydroxy-N, N-dimethyl-tryptamine) and psilocybin (4-phosphoryloxy-N, N-dimethyltryptamine).  These two compounds will produce a variety of psychological effects in humans.  Assessing specific effects often has proven difficult since the dosage in users has been variable (there is no “standard” mushroom).  However, recent studies have served to clarify a mass of somewhat confusing information.

In the late 1950s the Sandoz pharmaceutical company produced Indocybin®, a synthetic psilocybin that was widely used at that time for treatment of a variety of psychiatric disorders.  This drug had fewer side effects that the structurally similar LSD. Both drugs produce alterations in perception and mood, increased sensitivity to the world around the subject, and some types of hallucinations.  Psilocybin had a shorter duration of effect than LSD and produced fewer panic attacks and less anxiety.  However, wide-spread problems with the use of LSD and similar drugs led to them being classified as Schedule I materials in about 1970, the sale and distribution of which is very highly restricted.  As a result, interest in the use for psychiatric treatment declined markedly.

In recent years, there has been renewed interest in the use of these psychedelic materials for treatment of obsessive-compulsive disorder and anxiety.  The availability of synthetic psilocybin has allowed standardization of drug administration and better control over dosages and timing.  The ability to control dosage allowed a recent major study (1) to be carried out that evaluated the effects of psilocybin on healthy adults.  The studies reported the following:

“Although psilocybin dose-dependently induced profound changes in mood, perception, thought and self-experience, most subjects described the experience as pleasurable, enriching and non-threatening. Acute adverse drug reactions, characterized by strong dysphoria and/or anxiety/panic, occurred only in the two highest dose conditions in a relatively small proportion of subjects”.

Recent research (2) has shown that psilocybin can be of value in treating the anxiety associated with late-stage cancer.  These patients often have extreme concerns about their health, the pain associated with treatment, and issues related to their families.  Depression and anxiety are common in this group.  Administration of psilocybin under controlled conditions led to significant decreased in anxiety and depression; the improvements were often seen as much as six months after treatment.

Although this study is very preliminary, it suggests that psilocybin and related drugs may prove to be valuable in treatment of the psychiatric side-effects associated with many terminal diseases.  Obviously, further research needs to be carried out to confirm these findings.

References:

1. Acute, subacute and long-term subjective effects of psilocybin in healthy humans: a pooled analysis of experimental studies, Erich Studerus, Michael Kometer, Felix Hasler and Franz X Vollenweider  J Psychopharmacol published online 20 September 2010.

2. Pilot Study of Psilocybin Treatment for Anxiety in Patients With Advanced-Stage    Cancer. Grob CS, Danforth AL, Chopra GS, Hagerty M, McKay CR, Halberstadt AL, Greer GR. Arch Gen Psychiatry. 2010 Sep 6. [Epub ahead of print]

GABA and Schizophrenia – Is There a Connection?

Schizophrenia is a mental disorder that has been misunderstood, misdiagnosed, and often mistreated.  Modern misconceptions about schizophrenia abound, even though major educational efforts have been underway for years. The diagnostic criteria for schizophrenia are ambiguous and unclear (and probably won’t be improved whenever the new Diagnostic and Statistical Manual of the American Psychiatric Association is released).  Treatment protocols have been uniformly unsuccessful, although there are a few medications that can alleviate some of the major symptoms.  One problem with drug treatment is the high rate of non-compliance.  Many patients discontinue drug therapy, often because the side-effects are hard to tolerate.

The prevailing view of the cause(s) of schizophrenia is some sort of chemical imbalance in the brain (a handy catch-all for most mental illness, even though there have been few, if any, chemical abnormalities actually demonstrated).  There also appears to be a genetic component, although the details of this piece of the puzzle are unclear at present.  Two neurotransmitters (serotonin and dopamine) have been implicated as contributing to the problems of schizophrenia.  Both neurotransmitters are believed to be elevated in patients with the disorder.  However, the data are conflicting and there have been few clear studies demonstrating increases of these materials in schizophrenic human brain.

Some interesting clues suggest that gamma-aminobutyric acid (GABA) might be decreased in humans with schizophrenia.  A drug that enhanced the ability of the brain to respond to GABA was shown to raise the cognitive skills in schizophrenic patients (1). A 2009 study (2) indicated that an experimental drug which acted on GABA receptors was effective in improving the cognitive abilities of schizophrenics.  Both studies involved small patient populations, but show promise in developing new treatments for this disorder.  A recent study (3) used high-field magnetic resonance spectroscopy to demonstrate an approximate 10% reduction in GABA levels in the visual cortex of schizophrenics as compared to a normal population.  The authors concluded that this GABA deficit could lead to impaired cortical inhibition and thus explain at least some of the behavioral issues in these individuals.

The search for neurotransmitter abnormalities in schizophrenia continues.  Present information suggests that a decrease in GABA levels in the brain could play a role in the etiology of schizophrenia.

1.  “Subunit-Selective Modulation of GABA Type A Receptor Neurotransmission and Cognition in Schizophrenia”, D.A. Lewis et al., American Journal of Psychiatry 165 (12), 1585-1593, (2008).
2. Psychiatric News, November 20, 2009
3. “GABA Concentration Is Reduced in Visual Cortex in Schizophrenia and Correlates with Orientation-Specific Surround Suppression”, J.H. Yoon et al., Journal of Neuroscience 30 (10), 3777-3781, (2010).

Turn On, Tune In, and Figure It All Out?

In the 1960s, the phrase “Turn on, tune in, and drop out” became associated with the drug culture.  The class of drugs known as hallucinogens (named because they cause extreme distortions in a person’s perception of reality) received special attention because they were considered to open the door to an “expanded” mind and allow people to receive insights that were not possible without the drug. By the mid-60s, because of a number of disastrous results, LSD and related drugs were banned.

But interest in psychiatric use of hallucinogens appears to be on the rise again.  A recent article in the New York Times (April 11, 2010) indicates that some hallucinogens can be helpful in treating some psychiatric disorders.  Psilocybin has been shown to be effective in treating patients with depression, post-traumatic stress disorder, and end-of-life anxiety.

LSD (lysergic acid diethylamide) had is birth as a by-product of research in 1938 into compounds that stimulated the circulation and respiration. Some five years later, Albert Hofman (who originally synthesized the material) accidentally discovered its hallucinogenic properties.  Research on the psychological effects of LSD and its use in treatment of mental disorders began in the late 1940s.  A number of studies were carried out (both legitimate and covert) in the 1950s.  The drug began to appear on the street in the early 1960s and was banned in 1966 after a number of reports began to appear that described the extremely dangerous properties of the drug.

Even though LSD and related hallucinogens (such as psilocybin) received a great deal of negative publicity, there was on-going interest in the psychiatric community.  The hallucinogen aspects of the LSD experience strongly mimicked the hallucinations seen in many schizophrenics.  There were studies that suggested some benefits of LSD use in treating depression.  By 1965, over 2000 papers on the use of psychedelics in the treatment of mental illness had been published.  Unfortunately, many of these studies were anecdotal and seriously flawed in their methodology.  When the drug was banned in 1966, research interest dwindled away.

Present theories revolve around the similarity in structure between the hallucinogens and serotonin, a neurotransmitter.  It is widely believed that depression is accompanied by low serotonin levels in the brain.  Antidepressants are thought to stimulate an increase in brain serotonin, and thus alleviate the symptoms of the disorder.  The hallucinogens have chemical structures similar to that of serotonin and are believed to supplement existing serotonin in the brain, causing levels to rise to normal and alleviating the psychological symptoms.

Currently, research on the use of hallucinogens in treatment of mental disorders is being carried out in a number of facilities.  A world conference on the use of these drugs was recently held in San Jose, California.  Could it be that, some day, the drug that caused many to “drop out” will allow many more to “drop back in” to a more normal way of life?

Gene Modifications and Post-Traumatic Stress Disorder

Neuroscientists and others who study human behavior ask an interesting variation of the old question “which came first, the chicken or the egg?”  In the case of humans, the question comes down to “Do the biochemical changes produce the behavior or does the behavior produce the biochemical changes?”  Recent research tries to deal with aspects of this troublesome question.

Research from Columbia University shows that specific genes can be altered as a result of traumatic events.  The study found in persons with post-traumatic stress disorder (PTSD) that certain genes involved in immune response and other genes that are linked to brain cell development have different levels of modification than genes from a non-affected population.  Both sets of genes had changes in the number of methyl groups attached to the genes.  All genes have a certain number of methyl groups connected to them, with these groups functioning to regulate the gene activity.  Addition of more methyl groups to a gene will slow it down or turn it off, decreasing the amount of protein made by that gene.  Decreasing the number of methyl groups leads to an enhancement of gene activity, causing more protein to be produced.

The research team was led by Sandro Galea, a Columbia University physician and epidemiologist.  The team found that individuals with PTSD had significantly lower levels of methylation on genes associated with the immune system, resulting in a higher level of immune response.  The findings could contribute to a better understanding of PTSD.  These individuals have a much higher risk of physical health problems such as heart disease and diabetes.  Details of the research can be found in the May 3 on-line issue of Proceedings of the National Academy of Sciences.

The research team felt that the traumatic experiences leading to PTSD could alter immune function in these individuals.  There are some well-known links between immune function and emotional behavior (we’ll explore some of these in the future).  Decreased activity of genes associated with brain development was observed, but not discussed to any great extent.  But this research could provide useful clues to causes for the increase in physical health problems associated with PTSD

Genes, Suicide, and What Else?

Science today functions in a very physical environment.  The vast majority of scientists rule out any supernatural or spiritual explanations for phenomena (mainly by saying “we don’t accept these explanations”, not by really sound scientific criteria).  For the most part, this emphasis on the physical works well.  If I want to look at how hemoglobin transports oxygen in the circulation, I am quite happy with an explanation that includes sequential binding of oxygen molecules to specific sites on the hemoglobin molecule, resulting in changes in the three-dimensional conformation of the protein.  This explanation works, it fits the data, and we don’t need to pursue matters further.

However, when we come to explanations of behavior, the simple appeal to the physical does not work any more.   Oh, some scientists try.  They appeal to complex neurochemical processes that supposedly produce the behavior, even though we don’t really understand either the neurochemistry or how the chemical changes are supposed to cause behavior.  Others argue from an evolutionary psychology perspective, making assumptions about our prehistoric ancestors and extrapolating these supposed behaviors to modern day.  All of these explanations are rather simplistic and fall short of the mark.

Increasingly, we are recognizing the complex interplay of environment, social, cultural, psychological, and genetic factors that influence human behavior.  However, I think we still want to find that “magic bullet” cause that will allow us to propose a “magic bullet” cure for behavioral issues.  We have tried for decades with pharmacological treatments for unipolar depression, but have not been overwhelming successful.  Similar attempts to deal with schizophrenia, bipolar depression, and other serious mental disorders have also been shown to be inadequate.

Several recent publications have described gene alterations in the brains of people who commit suicide.  While the interpretations have been cautious (as they should be in this complicated situation), there seems to be some consensus that the alterations in gene structure predispose these individuals to suicidal behavior.  In the next several blogs, I want to look at the research and ask some hard questions about what it all means.



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