Message Board

"Lower N-Acetyl-Aspartate Levels in Prefrontal Cortices in Pediatric Bipolar Disorder: A 'H Magnetic Resonance Spectroscopy Study"
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1. Why might lowered NAA, glycerophosphocholine plus phosphocholine (GPC+PC) and PCr+Cr neurochemical levels in the brain be indicative of neurodevelopment alterations?
a.http://en.wikipedia.org/wiki/N-Acetylaspartic_acid (NAA)

2. Why did the researchers choose to evaluate the MPFC, DLPFC, cingulate and occipital cortex? Why grey and white matter? For mood disorders (like BD) what other neuroanatomical regions might scientists examine?

3. In terms of the levels of the neurochemicals evaluated, we found no differences between the following subgroups: BD patients with ADHD or anxiety disorders versus BD patients without such disorders; BD type I patients versus BD type II or BD NOS (not otherwise specified) patients? What do you think could account for these variations in co-morbidities/symptoms?

4. Researching psychopathologies can be tricky, especially in pediatric populations. Do you see any problems with this study (would you do anything differently?) Where can the research go from here? Do these results provide insight into new treatment options?

Use the questions to guide your discussion, you don't have to answer them all. Please comment on anything you found exciting, unusual, confusing ect...

In the described experiment, the medial prefrontal cortex, dorsolateral prefrontal cortex, and anterior cingulate were studied in pediatric patients diagnosed with bipolar disorder. The reason these specific areas were chosen is because they ?are involved in mood regulation.? All of these parts of the brain, however, exist in the frontal lobe, which, to me (being an undergraduate intro to neuroscience student), is more involved in cognition, decision making, and reasoning. Bipolar disorder, on the other hand, involves oscillations in the extremes of mood, ranging from mania to depression, and I associate this more with the limbic system. It has more ?control? over memory, sexual arousal, emotions, and pleasure experienced by the person, and I would think bipolar disorder, being primarily a mood disorder, would show more differences between affected and unaffected individuals in this area. However, upon further research, I have found that the cingulate gyrus is part of both the limbic system and the frontal lobe and that the limbic system and the prefrontal cortex are very closely associated. This being said, I still believe that more of the limbic system could have been studied in this experiment, seeing as it seems to be one of the most prominent brain areas involved with bipolar disorder. It should also have been given more consideration since the study was done on children. In my opinion, after my experience with young kids, their cognition and ability to reason is not fully developed until they reach a more advanced age (say the early teens), so they tend to be more emotional and ?think? more with their emotions rather than logic. This being said, it would make more sense to focus on the limbic system in kids affected by bipolar disorder because they use their emotions more to make sense of their world and thus may show more pronounced differences in a part of the brain more involved in producing and modifying emotions. This may also be an explanation for the lack of differences between BD patients with ADHD or anxiety disorders and those solely with BD: the frontal lobe and prefrontal cortex may be what is more affected by the ADHD and anxiety disorders, whereas the areas studied in this experiment are affected by BD, so the absent difference between the two groups could stem from the fact that the scientists were only looking at a few specific areas that happen to be similar or the same in the two groups. Maybe if they'd probed other areas more in the frontal lobe, they may have found other differences between those with ADHD and anxiety disorders and those without. As with any part of the brain, though, specific functions are very difficult to ascribe to one particular area, and, as cited by the study, ?decision making? and ?executive functions? are also abnormal in pediatric BD patients, meaning a study involving the prefrontal cortex was appropriate for their purposes. After reading this, though, I am curious as to what might be discovered if the limbic system was tested in a similar manner in similar patients. I also believe that this research has proved fruitful and that new forms of treatment may be created and tested in light of this new information.

This paper did a good job showing that there is a certain level of underdevelopment in the prefrontal cortical regions of children diagnosed with BD. I think they did a good job making sure that the method to which they obtained the images and measurements were accurate.

However, I am a bit unconvinced about the quality of their sample. There were several factors that I think could be eliminated to ensure better results. First, although the mean age of children tested came to be about 12 years old, the range was from 8 to 17. There are significant developmental differences between the brain of the individuals on both end of the spectrum, which contributes to the level of the NAA, PCr+Cr, and GPc+Pc expressed in the brain due to developmental stages. If they had limited the age range down to a more reasonable size, then the data would be more convincing. Second, there were some unmatched sociodemographic characteristics between the experimental group and the control. While there were 27 white and 12 Hispanic test subjects in the experimental group, there were 6 white and 26 Hispanic test subjects in the control group. Although Parental socioeconomic status were evaluated using Hollingshead Two-factor Index, the unparallel testing samples cannot rule out the possibility that genetics, cultural environment, and specific diet that might lead to different expression levels cell products in the brain. If the experimental group and the control group could contain subjects of similar backgrounds, then that could rule out those doubts. Lastly and perhaps most importantly, the subjects were in different stages of their BD at the time of the scan, the experiment assumed that chemical levels in those regions of the brain would show similar under-expression or over-expression regardless of their mental state, which there is a reasonable doubt to whether that?s a valid assumption, because episodes of mania and depression show very different symptoms. I would also think that it would be difficult to draw any valid conclusion when the test subjects are still going through neurodevelopment. Their brains are still changing and making new connections, the chemical levels in the brain aren?t going to be the same for every individual.

Since there seems to be similar results with ADHD & anxiety patients, this means that the areas tested is not specific to BD patients, and therefore, cannot explain exactly what is abnormal about BD. Both ADHD and BD show decreased cortical thickness, exhibiting underdevelopment, some of their symptoms are very similar. But there are differences, one of these is in the hippocampus. The hippocampus is compromised in ADHD patients, leading to their inability to focus their attention for a normal period of time, it also explains their comprised learning ability. Those who have BD do not show similar symptoms, but rather, they show a wide range of mood disorder, so maybe there are other areas, such as the limbic system that is more specific to Bipolar Disorder. If this experiment could be repeated for abnormalities in BD specific areas, then combine it to this study, that would provide a better explanation for exactly what are the abnormalities of BD.

There are a lot of studies done on BD by assessing the differences in diffuse modulatory system. Since BD is an affective disorder, I wonder if there is any correlation between the level of monoamine (e.g. dopamine and 5-HT) and the expression of NAA, PCr+Cr, and GPc+Pc levels in the prefrontal cortex, after all, monoamines are present in all the areas that the experiment tested for. Perhaps one is a precursor to the expression of another? Or maybe there is a feedback system. The HPA system is also a huge area of study for in relation to BD, what is the correlation there?

In regards as to why the researchers chose to study NAA levels, it is because NAA is associated with myelin formation and the branching of dendrites during development in order to establish new synapses, thus if low levels were observed, it could be indicative of abnormal neurodevelopment. GPC and PC were likewise chosen as they are involved in forming the phospholipid bilayer as well as in various processes that help to modulate cell growth. Finally, PCr and Cr were measured as they are key in enhancing the synthesis of ATP, so decreased PCr and Cr indicates a lower metabolism which in turn could suggest less synaptogenesis or otherwise altered development.

As has been mentioned, a more uniform sample would have been ideal in limiting variations outside of experimental control, however, I do not think that the study is invalid and it has certainly opened up a number of questions. I find it interesting that the researchers observed identical results in patients with both BD and ADHD and those who only had BD. To me, this implies that BD and ADHD may have some similar alteration present during their developmental period. I would be interested in additional studies to flesh out what it is exactly that accounts for the different behaviors associated with the two disorders given that they seem to share some characteristics of abnormal neurodevelopment with one another. Since there was no difference observed between BD type I, type II and NOS, their different behavioral effects must be due to something else outside the realm of the study such as altered circadian rhythm or differences in the neurons? abilities to sustain normal firing, causing either excitatory or inhibitory periods.

As drew said, the role of NAA and GPC is important for establishing the amount of myelination of axons, indicative of neurodevelopment and neuronal connection strengthening. I though an important aspect of the article was that they mentioned that studies on adult bi-polar disorder have shown that mitochondrial dysfunction has been shown to decrease the total levels of energy production and phospholipid metabolism. This presents a novel mechanisim by which bipolar disorder develops, perhaps allowing us to see the underlying cause of bi-polar disorder. I do not know much about genetic predisposition to bipolar disorder. If mitochondrial defects are a target for further research, then perhaps establishing a maternal genetic predisposition may lead to identification of who is at risk for the disorder.

I do not want to repeat what Nick already said, so I will add other issues with the experiment. My initial issue with the sample group of people was that compared to the control group, the BD group had too many pre-pubertal children. However the results showed that the the BD group had lower levels of NAA. This should correspond with higher amounts of NAA due to it?s role in myelination of axons for younger patients. Since levels of NAA naturally decrease with age, if the result was that these patients had higher levels of NAA then this result would not be significant.

As the paper said, one of the limitations they had with the study is the varying mood states of the patients that came in. Some data from previous experiments focused on patients suffering either a manic or depressed state, producing differing results. Because of these varying results, further research is required to see the affect of mood on the measured levels and the effect of treatment. I think observing the correlations between a developmental unipolar disorder and a developmental bipolar disorder would provide insight into the differences between a manic or depressed state, or the effects of drugs on development.

There?s been a bit of discussion already on the validity of this study?s results. While I definitely also feel that the percentage of Hispanic and Caucasian subjects between the control and the experimental groups could have been much more equal, honestly, there is no such thing as the perfect subject pool. True, there was a wide age range for subjects, which likely affected the data. More importantly though the control group and BD group both have that same age range, allowing comparisons to still theoretically be accurate. Overall, I don?t feel the sociodemographic characteristics of the chosen subjects significantly reduced the validity of their results.
I feel the most prevalent limitations, as Caetano et al. mentioned, were the differing moods of subjects during testing and the researchers? mode of statistical analysis. Studying psychopathologies can truly be ?tricky? because a new variable is added in, the subject?s current emotional state. Making that a constant throughout the testing pool is incredibly difficult. Moreover, in this study Caetano et al. stated that they used less conservative statistical methods, which is saying quite a bit (a good statistian can make a given data set say anything).
After reading this article I must say, I was rather surprised that the levels of neurochemicals in the cingulate cortex were statistically equivalent between the BD patients and the control. Yes, this didn?t seem to confound researchers as previous studies showed the same results, yet as a lowly undergrad I had this thought process: the anterior cingulate cortex is highly involved in reward-anticipation, empathy and emotion (as the above diagram so kindly points out). Thus, a mood disorder such as BP would highly affect this area of the brain. I anticipate future studies that will address why the cingulate and occipital cortices of BD patients are able to produce and utilize these neurochemicals to their normal degree, while the prefrontal cortex seems less than proficient.

After reading this article and the wikipedia article about NAA it is understood that NAA is a heavily concentrated molecule throughout the brain. This means that NAA must contribute to the connections between synapses. If there are problems in connections of synapses then it can lead to problems in development, which was being studied throughout this essay.

Agreeing with many other people, I think it is difficult to have a study pool that would produce perfect, accurate results. Though these differences cannot cause too much of a discrepancy, they still have an affect on the study. It is noticable that the healthy clients primarily consisted of those who were in the "advanced puberty degree". These clients have obviously had a longer time to build connections within the brain; they are more developed in many aspects. We know that BD is a developmental disorder and this therefore causes a slight uncertainty in the data. While the number is very similar to that of the patients with BD, it still shows the the percentage of results in the study pool primarily come from the developed patients. I think that if they had gotten more clients with the same level of development, the conclusions could have been more accurate.