Dr. Grossi's Blog
The genus Microtus contains a variety of species of voles who show an extraordinary range of social differences. Male prairie voles form lifelong attachments, share duties in raising offspring and manifest high levels of social interest. The closely related mountain voles do not bond with a mate, do not assist in caring for the offspring, and are socially indifferent. The pattern of vasopressin 1a receptor (V1aR) in the brains of these animals is thought to be largely responsible. The expression is the result of differences in the microsatellite regulatory region with the prosocial prairie vole manifesting several repeating blocks interspersed with non-repetitive blocks while the asocial montane vole has a short version. This results in the brains of prairie voles making more vasopressin receptors than the montane voles do. This connection was strengthened with their work last year in which they added microsatellites in the regulatory region avpr1a in the montane vole and this resulted in behavior more like the prairie vole. This further strengthens the tie between male social behavior in the vole to vasopressin.
Hammock and Young went further in this paper. They paired and then bred voles with long microsatellites and recorded the results, which included the finding that significant genotype difference resulted in significant increased grooming and pup licking in long-allele males when compared to short allele males but no difference in females relative to pup licking and grooming. They also placed males in cages with females for 18 hours and found that those males with longer microsatellites spent more time with their partner than those with shorter microsatellites.
They also compared the microsatellite base length in chimpanzees, bonobos, and humans. The chimps who are more aggressive than the bonobos had a base length that was 360 bases shorter than the bonobo who are more social and form social bonds similar to humans. The bonobo microsatellite has a high homology with the human microsatellite.
Are we more patterned than we usually assume?
While I am not a child psychiatrist, I do see children and I have a number of pre-pubertal bipolar patients in my practice. They often meet criteria for a number of other conditions and almost universally present a formidable treatment challenge. For these reasons I am spending some blog-time talking about the diagnostic questions involved but not the treatment decisions/questions.
All aspects of this diagnostic category are controversial. The diagnosis itself, it's distinction from other diagnoses, especially Attention-Deficit/Hyperactivity Disorder (ADHD) and anxiety disorders, what appears to be an increasing prevalence especially of pre-pubertal forms, and whether the pre-pubertal form becomes the adult form or some other disorder need additional study.
The accurate and timely diagnosis of bipolar disorder is extraordinarily important in order to institute prompt appropriate treatment which will allow the patient to go through the developmental stages that lie ahead and to reduce the family turmoil that results from living in the household with such a patient. I have found that there is a high level of co-morbidity of ADHD in bipolar patients but not the reverse i.e., ADHD patients do not demonstrate a high rate of co-morbid bipolar disorder. DSM-IV sets out reliable criteria for pre-pubertal bipolar disorder. The best symptoms to differentiate bipolar disorder from ADHD are: elation, grandiosity, flight of ideas/racing thoughts, decreased need for sleep, and hypersexuality (when there is no sexual abuse). Some 2009 work done by Luby and colleagues demonstrates that preschool children who meet DSM-IV criteria for bipolar disorder display much more intense emotional response in sadness, joy, and anger when compared to healthy peers. They also demonstrated evidence that bipolar children have trouble regulating these emotions over time. These findings suggest that the emotional reactivity model is a helpful addition to distinguishing bipolar children from healthy peers. So, temper tantrums with little provocation and lasting many hours or even days is suggestive of bipolar disorder. Suicidal ideation or action and psychotic features (auditory hallucinations, delusions, or extreme paranoia) are not consistent with ADHD. Family history of one parent or even better two parents having a bipolar diagnoses is very helpful. Symptoms that overlap ADHD and bipolar disorder are irritability, hyperactivity, accelerated speech, and distractibility. I would like to stress that irritability and aggression can be found in bipolar patients but are also common findings in many other disorders and thus those findings have low specificity.
In a prior blog, Grief/Major Depression, I commented in the final few sentences that ultimately research would draw the dividing line between normal grief and major depressive disorder. When I wrote that, I was thinking about the ideas that follow. Research Domain Criteria (RDoC) is an initiative by National Institute of Mental Health (NIMH) to try to begin bridging the gap between the new findings of neuroscience and the self-reported symptom clusters that are currently used to define psychiatric syndromes. Symptoms are not causes. Symptom complexes are not specific enough for research purposes and thus for finely tailored treatment recommendations which are applied daily to millions of individuals. A good example to clarify this problem is to be found in the aforementioned major depressive disorder. To meet criteria currently, one needs five of nine symptoms. You could have two patients who have the same diagnosis and share only one symptom. It is highly unlikely that they would share the same genetic, molecular, circuit and even behavior but would be in the same diagnostic group for research or treatment purposes. The fact that this Diagnostic and Statistical Manual of Mental Disorders, fourth edition, (DSM-IV) grouping is used by insurance for claim processing, the Food and Drug Administration (FDA) for drug trials, International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10), as a factor in legal proceedings and many other institutional and classification projects makes it now a major impediment because these classifications do not map onto the genetic and neuroscience findings as they are quickly emerging at this time. These DSM diagnoses are heterogeneous, involve multiple brain regions and are, therefore, not suitable for research purposes.
The RDoC is an attempt to start the process of identifying the neural circuits that produce a symptom or disorder and ultimately to produce a diagnostic classification that is based on neuroscience. This is then first and foremost a guide for researchers to classify patients for their studies. There is no intention to try to replace DSM-V any time soon. A detailed and clear presentation can be found at the link above.
The following chart which I have copied from the NIMH site nicely summarizes the type of analysis that is being attempted. RDoC embodies three principles: 1, it is dimensional - normal to abnormal range, and levels of effects - genes cells, molecules, circuits, and behavioral observations; 2. there is no attempt to correlate with current DSM diagnostic categories; 3. all levels of analysis will be used including physiological, behavior, imaging, and self-reporting to choose a unit of analysis that is called a construct and is represented by the entries in rows on the chart. The drafters anticipate that most research investigations in the future will focus on the constructs.
|DRAFT RESEARCH DOMAIN CRITERIA MATRIX|
|– – – – – – – – – – –||UNITS OF ANALYSIS||– – – – – – – – – – –|
|Cognitive (effortful) control|
|Imitation, theory of mind|
|Facial expression identification|
|Arousal & regulation (multiple)|
|Resting state activity|
While it is true that this proposal does not take into account developmental issues or interpersonal or environmental impact, I believe this is a tremendous leap forward and should be supported by all. I encourage all readers to click on the RDoC link at the beginning of this blog for a more complete description and discussion of the project and especially of the Constructs.