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Showing entries tagged depression.  Show all entries

December 4, 2011

Neuropsychiatric Disorder Models: Improvement Needed!


Neuropsychiatric disorders such as schizophrenia, depression and bipolar disorder are serious health problems. They have substantial negative affects on a significant subset of the population and are still largely not understood. While the molecular targets of many psychotherapeutic drugs have been successfully reverse engineered, this was done in the 1960's. Despite ongoing efforts to further understand these disorders, little progress has been made since then. This raises the question: why? Two scientists, Eric J Nestler and Steven E Hyman have published an article in the journal Nature Neuroscience seeking to find a solution to this. In their paper, Animal models of neuropsychiatric disorders, they claim that the primary thing holding back research in the field is the difficulty of creating animal models of human psychiatric diagnoses. The authors then seek to contribute to the field by doing an analysis of the currently used models and discussing which ones are most likely to be valid and productive.

It can be very difficult to translate between animal and human thoughts and feelings. Whenever one does so they risk unfairly anthropomorphizing. Since animals are incapable of reporting their feelings researchers need to find round-about ways to determine what is actually going on within an animal's head. The typical methodology then used to study animal behavior and use it as a proxy for mental activity. However for most of the neuropsychiatric disorders that are professionally addressed what constitutes a legitimate disorder is not clearly separated from what constitutes normal variation. Furthermore, the same neuropsychiatric diagnose can be proscribed to two completely different sets of symptoms. This leaves researchers in a position where they must decide for themselves what constitutes a legitimate disorder, how to define it, and the subsequently how it can be represented in behavioral models.

In order to usefully discuss the efficacy of studies relating to these neuropsychiatric disorders, the authors of the article referred to a framework for validating studies with the components construct, face and predictive validity. Construct validity is a measure of how well a model's construction is relevant to a disease. Face validity is a measure of how well a model reiterates the physical and behavioral features of a human disease. Predictive validity is a measure of how well a model's response to treatments compares to patients actual responses to these same treatments.

The article then discusses different things that can be modeled in schizophrenia, depression and bipolar disorder and the validities of potential models. For schizophrenia, it is stated that blunted affect, asocial behavior, diminished motivation and deficits in working memory and/or conscious control of behavior are all symptoms that a behavioral model should seek to measure. The article claims that a good way to creat constructively valid models is to use genetic animal models with highly penetrant human mutations, although it doesn't consider these models to be perfect. It also states that a good (but not sufficient on its own) measure of face validity is a deficit in prepulse inhibition (PPI) of a phenomenon where weak starting stimuli reduce a startle response produced by a following more intense stimulus.

For depression it's stated that neurovegetative symptoms such as abnormalities in sleep, appetite, weight and energy along with psychomotor agitation or retardation are all potential indicators. With the caveat that no abnormality has proven sufficiently robust or consistent enough to validate an animal model the paper claims that chornic social defeat stresses along with chronic mild and chronic unpredictable stress are all capable of inducing states of depression which have some face value. These methodologies are criticized however as potentially setting off an anxiety disorder with similar symptoms instead of modeling depression. The authors suggest that measures of other homeostatic symptoms such as alterations in sleep, circadian rhythms and feeding with attendant metabolic parameters would strengthen claims of depression in animal models.

For bipolar disorder it's stated that the diagnosis comes from periods of mania with or without depression. The article states that transgenic mice have exhibited manic-like behavior when they were programmed to over express glycogen synthase kinase-3beta. These mutants are assesd to meet partial criteria for face validity along with predictive validity. However they failed to meet requirements for contruct validity. The article suggests that mania investigative studies use a broad range of behavioral tests and interpret their data cautiously.

Finally, the article listed some generalized recommendations towards researchers. These recommendations included listing the specific aspects of the illness meant to be model and stating the types of validators applied to the model. The researcher also noted that construct validity is most compelling of the different validities and that it's best to use a broad range of behavioral assays.

It's clear that research into these neuropsychiatric disorders still faces a great deal of hurdles, especially when it comes to assessing bipolar disorder. However, as this paper shows, there is constructive focus being brought to the forefront of this area. With genetic and technological advances combined applied to models with clearly stated rationales and sober discussion of validity significant progress can potentially be made in the field.
Posted by      Michael A. at 11:54 PM MST
  Michael Asnes  says:
Nestler, Eric J., and Steven E. Hyman. "Animal Models of Neuropsychiatric Disorders." Nature Neuroscience 13.10 (2010): 1161-169. Print.
Posted on Sun, 4 Dec 2011 11:54 PM MST by Michael A.

October 23, 2011

Depressed due to stress? Blame your genes...


Everyone experiences stress on a daily basis, whether it be due to misplaced car keys or the impending doom of taking Intro to Neuroscience quizzes online, knowing that Teamviewer will crash at least 3 times. There are many ways to deal with everyday stress; some combat the stressor head on, and others try finding ways around it. Us college students seem to combat the never-ending stress during the week with shots (usually one too many) on weekend nights. Most of us can find ways to effectively relieve this everyday stress and continue on our merry ways, ready for the next stressor that rears its ugly head. But for some, stress can cause a detour from this merry path, instead leading to a path of anhedonia, a defining symptom of depression characterized by an inability to find pleasure in activities once found pleasurable. So why can most people cope with stress, while others seem to fall apart at the seams? Ryan Bogdan and his affiliates may have found a simple answer as to why some follow this crippling detour.

Before I go any further, let me give some background into the neurobiology of stress response. Corticotropin-releasing hormone (CRH) is a hormone released by the paraventricular nucleus of the hypothalamus in response to stressful stimuli. CRH binds to the corticotropin-releasing hormone type 1 receptor (CRHR1) to exert its critical role in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis, a complex neuronal network responsible for a wide variety of processes, including mood and reactions to stress. Got all that? Good.

Recently discovered is a genetic variation in the DNA encoding CRHR1, coined the CRHR1 A allele, that contains a single point mutation. This small mutation has big consequences, most notably an attenuated response to positive feedback in the ventral striatal region under stress. So what the hell does this all mean? Simply put, it means that the A allele of this receptor have disrupts processing rewarding stimuli under stress. When an individual cannot process something as rewarding, such as activities and hobbies that they used to find pleasurable (anhedonia), the inevitable result is clinical depression.

Ryan Bogdan used this information collected on the A allele to design a study focused on reward learning, an important behavioral aspect of anhedonia. In this study, control subjects and subjects homozygous for the A allele were subjected to two separate tasks involving reward; one task was stress-free, the other under the stressful possibility of electric shock should one fail the task. Under the stress condition, subjects homozygous for the A allele performed far more poorly than the control subjects, confirming that this genetic mutation produced stress-induced behavioral deficits in reward learning. Surprisingly, these same A allele subjects performed better than control under the no-stress condition.

This unfortunate genotype sheds more light on the high cormobidity between stress, anxiety, and depression. However, it could also possibly lead to effective treatments for families carrying this A allele. Stress sucks for everyone, but for certain individuals, it sucks way, way worse. Keep this in mind while studying for your next midterm, and remember, the weekend (and shots) are coming soon.

http://www.jneurosci.org/content/31/37/13246.full
Posted by      Kevin K. at 11:27 PM MDT

Seasonal Depression: Connecting Immunology and Neuroscience


In the United States, depression has quickly become one of the most well known and most common mood disorders. The notoriety of this disease has certainly come about due its prevalence in society and how it affects the afflicted. Depression can have devastating effects on a person, so it naturally has become a hot area in research. Seasonal affective disorder is a subset of major depression that afflicts people in different seasons due to a change in the amount of light in a day. A large number of residents in Alaska, for example, suffer from this disorder due to the few hours of light they receive during certain times of the years. Perhaps this seasonal depression risk, along with the burden of listening to a certain political figure, is a reason Alaskan residents receive an annual stipend for living where they do. In order to understand this form of depression further, a group at the Medical University of Vienna studied the relationship between immune system proteins and seasonal depression.

Depression has been linked to altered circadian rhythms, and, subsequently, altered levels of immune system elements like cytokines, specifically interleukin 6 (IL-6). In the immune system, cytokines promote inflammation in areas where they are produced. To observe the affects of light deprivation the researchers deprived mice of light and determined their depression and cytokine levels. The light deprived mice showed depression-like behaviors when subjected to depression distinguishing tests. Furthermore, these mice with traits relating to depression showed elevated levels of IL-6 in circulation and in hippocampal cells. To further understand this increase in the pro-inflammatory cytokine IL-6, the researchers observed the effect of NF-kB, which is a transcription factor for IL-6. Discovered in these mice were elevated levels of DNA binding by NF-kB which supports the evidence that there are higher levels of IL-6. In order to further implicate the role of IL-6 in seasonal depression, IL-6 knock out mice were exposed to the same light deprivation as the control mice. These IL-6 knock out mice showed lower levels of depression-like behavior, which tells us more firmly that IL-6 cytokines play some sort of role in seasonal depression.

These studies could potentially provided huge implications in the world of seasonal affective disorders. Since light deprivation was shown to activate NF-kB and therefore production of IL-6, one may think we could simply inhibit this pathway. The problem with this would be the severe negative implications on the immune system. These cytokines that NF-kB activate are crucial for fighting infection and maintaining a healthy individual. Without them, an organism would quickly be riddled with infections that they could not control. Although the study does not provide an immediate treatment for seasonal depression, we are provided beneficial knowledge that takes us a step closer to finding a better form of treatment. This link between immunology and neuroscience also provides more incentive to study this relationship in other neurological diseases and provide more treatments for diseases that affect so many people.

Source: Constant Darkness Induces IL-6-Dependent Depression-Like Behavior through the NF-╬║B Signaling Pathway

http://www.jneurosci.org/content/31/25/9075.full
Posted by      Kyle D. at 9:21 PM MDT
Tags: depression

July 31, 2011

Your Brain on Yoga: Better than an Antidepressant?


Depression [1] is a disease that afflicts millions of people and costs billions of dollars every year, and it is getting worse. One has to ask: besides the obesity epidemic, is our sedentary lifestyle contributing to a depression epidemic? Is exercise necessary for a healthy psyche? Can physical activity 'cure' depression?

In the last decade, a new kind of brain chemical has been discovered that plays a pivotal role in the healthy balance of the other chemicals in our brain. This chemical is called brain-derived neurotrophic factor (BDNF) [2] and is discussed by Rassmusen, et al. in the article 'Evidence for a release of brain-derived neurotrophic factor from the brain during exercise.' BDNF has been found to regulate the maintenance, growth and survival of neurons; to influence learning and memory; is low in patients with Alzheimer's Disease and clinical depression; and affects body weight, energy homeostasis, and blood glucose levels. In addition, genetic mutations of the BDNF gene are associated, in both mice and humans, with the entire laundry list of metabolic syndrome problems. Where does BDNF come from in our brain? Why does it affect so many aspects of a healthy self? What can we do to 'balance' our brain chemicals without resorting to Prozac« or Abilify«, which we are beginning to find out are more like temporary bandaids for a much deeper problem of brain chemical imbalance and are only slightly better than a placebo [3]?

Recent studies have shown that exercise raises circulating BDNF levels. Exercise has been found to enhance BDNF transcription [4] in the brain and to effectuate brain uptake [5] of insulin-like growth factor 1, which is a necessary ingredient for increasing mRNA expression of BDNF. BDNF has also been shown to promote [6] the health of serotonin-responsive neurons and to interact with serotonin-producing genes. Instead of a prescription for an antidepressant, should doctors be prescribing 30 minutes a day at the gym? And what if the exercise had the added benefit of reducing stress? What if doctors prescribed yoga classes instead of Prozac«? Could we expect to see even more benefits than exercise alone: reduced stress, improved mood, thinner waistlines, less Type II diabetes, and better sex lives? If I was depressed and yoga could do any of those things, it would be enough to undepress me, BDNF levels aside.

Recent studies show that there is a positive correlation between yoga and circulating BDNF levels. In his master's thesis [7], NL Pan discovered that a form of yoga called Sudarshan Kriya yoga (SKY) increased serum BDNF level in patients that had high initial depression indices, and as an added bonus, reduced cortisol. This effect was determined to be independent of circadian rhythm levels. Other researchers have investigated the effect of yoga on depression with positive results (Pilkington, et al. [8], Javnbakht, et al. [9], Janakiramaiah, et al. [10]) but linking yoga to BDNF levels is a more recent finding.

As controversial as the idea sounds, maybe it is time for doctors to stop doing the easy thing by prescribing a pill and just tell patients to get off the couch and go to yoga class. And if patients don't believe their own doctor, while they are sitting on the couch they can just tune into Dr. Oz, our new national guru of all things health, who promotes exercise as a cure for many ills. I don't mean to trivialize the problem of depression, but the idea that it is we ourselves who are responsible for our health, even our mental health, should not be revolutionary or controversial. But depression is like a lot of things these days: someone else or something else is supposed to provide an easy fix.

[1] http://www.huffingtonpost.com/robert-leahy-phd/the-cost-of-depression_b_770805.html
[2] http://onlinelibrary.wiley.com/doi/10.1113/expphysiol.2009.048512/full
[3] http://www.thedailybeast.com/newsweek/2010/01/28/the-depressing-news-about-antidepressants.html
[4] http://www.ncbi.nlm.nih.gov/pubmed/9795193
[5] http://www.ncbi.nlm.nih.gov/pubmed/10751445
[6] http://www.nature.com/npp/journal/v33/n1/full/1301571a.html
[7] http://ethesys.lib.ncku.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0808107-104238
[8] http://www.sciencedirect.com/science/article/pii/S0165032705002570
[9] http://www.sciencedirect.com/science/article/pii/S1744388109000048
[10] http://www.sciencedirect.com/science/article/pii/S0165032799000798
Posted by      Anne H. at 12:07 PM MDT
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