About PFC maturation

[Popelus]

Hello everyone!
I'm currently working on the final project of my Psychology's degree, and the topic I've chosen is the relation between the maturation of the PFC and the development of executive functions. As you will see, my work is quite simplistic, as I'm mainly focusing on brain morphology.

Although I'm finding very nice papers to work with, there's something that particularly bothers me about the different methods to measure PFC maturation.
On the one hand, several studies show that synaptic density peaks at around 4-5 years of age in the PFC.
On the other hand, it's widely known that the volume of gray matter peaks at around 11-12 years of age in the PFC.

So, I know these two measures are compatible. I know that gray matter volume is only partially related to synaptic density. Gogtay et al. (2004) say:

The GM density on MRI is an indirect measure of a complex architecture of glia, vasculature, and neurons with dendritic and synaptic processes.

Selemon (2013) also says:

Synaptic elimination in adolescence is widely thought to account for the decline in gray matter volume detected via longitudinal magnetic resonance imaging (MRI) of human subjects. Although reduction of synaptic connectivity might be accompanied by retraction of glial and neuronal processes, elimination of neuronal cell bodies occurs much earlier in development.

Okay, so it seems like the synaptic pruning in the PFC becomes noticeable at around 4-5 years, and at 11-12 years this process speeds up, so much that it leads to a decrease in gray matter volume.

However, as I said at the beginning of this post, something about this really bothers me. My question is: What's making the gray matter volume of the PFC steadily increase from 5 to 11 years of age, if synaptic density is decreasing during this period? I couldn't find any papers researching this, although it seems intuitive that it's due to the growth of glial cells and other non-neuronal cells. Most papers either focus on gray matter volume, or on synaptic density, and they hardly ever analyze the factors that account for the differences between these two measures. There must be something that I am missing...

Thank you very much!

 

EDIT: found this very interesting article ( http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2762785/ ) that answers my question. Seems like indeed scientists may be overestimating the relation between synaptic density and gray matter volume.

Edited June 9, 2016 by Popelus

[DrmDoc]

Have you read this paper: Mapping brain maturation...? This is a link to an abstract of an 2005 paper that appears to explore a topic in brain maturation similar to yours. Although I could not find a link to this article outside of university, perhaps you may through your institution. From the abstract:

 

"Non-invasive mapping of brain structure and function with magnetic resonance imaging (MRI) has opened up unprecedented opportunities for studying the neural substrates underlying cognitive development. There is an emerging consensus of a continuous increase throughout adolescence in the volume of white matter, both global and local. There is less agreement on the meaning of asynchronous age-related decreases in the volume of grey matter in different cortical regions; these might equally represent loss ("pruning") or gain (intra-cortical myelination) of tissue. Functional MRI studies have so far focused mostly on executive functions, such as working memory and behavioural inhibition, with very few addressing questions regarding the maturation of social cognition. Future directions for research in this area are discussed in the context of processing biological motion and matching perceptions and actions."

 

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Edited June 11, 2016 by DrmDoc

[Popelus]

Hello DrmDoc!

Thanks for your reply. I do have access to that article and I had it already in my Mendeley database. I've been researching non-stop since I published my original post, and all I have to say is I am disappointed by scientists. Several papers say in their abstracts that they've researched the synaptic pruning process, when actually all they've measured is gray matter volume. Likewise, several papers say that they've researched the myelination process, but all they've measured is white matter volume.

 

As the paper that you quoted states, there are many factors that can alter the white and gray matter volumes. One of the most obvious is intra-cortical myelination, which leads to (when measured) more white matter volume and less gray matter volume.

 

Although white matter volume does keep increasing even into adulthood, several articles disagree on whether myelination is what causes this increase. Check this and this to see opposite results using different indirect techniques to measure myelination separatedly from white matter volume. The first paper finds that myelination does increase and decrease more or less at the same rate as white matter volume. The second paper states that "The MTR results suggest that this growth [in white matter volume of male adolescents] is not related to myelination".

 

Whatever factors underlie growth and decay of white and gray matter volumes, we should clearly stop carelessly assuming that these are the same as myelination/demyelination and synaptogenese/synaptic pruning respectively.

Edited June 12, 2016 by Popelus

[DrmDoc]

I thought about your question regarding what factors underlie the growth and decay of brain matter volume. In considering a referenced link between myelination and neurodegenerative diseases, I am reminded of this article regarding relatively recent study of the glymphatic system, which is a function of sleep that appears to removes extracellular toxins from the brain such as the Amyloid-B peptide plaques associated with Alzheimer. Perhaps the processes of sleep are not relevant to your project but it may merit some consideration regarding what factors may contribute to synaptogenese/synaptic pruning. We know that sleep patterns change with age and synaptic pruning occurs in sleep, wherein, brain volume can decrease by as much as 6%. I'll try to find the specific reference for you and post a link here, if that is your interest.

[Popelus]

That would be very nice if you could find the link. I haven't found any refererence saying that synaptic pruning occurs in sleep. The glymphatic system looks really interesting, and it makes sense that it could be related to synaptic pruning (many authors question themselves what happens to the gray matter that decays during synaptic pruning, and perhaps it is removed by the glymphatic system).

 

I'm currently having a new doubt... as I've ran into some papers that state that during adolescence a new "second wave" of synaptogenesis occurs. For instance, in this paper they mention a second surge of synaptogenesis in adolescence. And in this paper (the link will let you download it) it is stated that a "second wave" of synaptogenesis occurs. I've checked all the papers they citate, and none of them seems to say so. I think these two papers I linked are misunderstanding the synaptic rewiring or remodeling that takes place in adolescence, thinking that it's actually a new synaptogenesis. What do you think?

Edited June 12, 2016 by Popelus

[DrmDoc]

I reviewed the links you provided and found in the first paper what may be the basis for its second synaptogenesis surge conclusion. In the introduction, the authors conclude:

 

"Brain maturation during adolescence (ages 10–24 years) could be governed by several factors, as illustrated in Figure 1. It may be influenced by heredity and environment, prenatal and postnatal insult, nutritional status, sleep patterns, pharmacotherapy, and surgical interventions during early childhood. Furthermore, physical, mental, economical, and psychological stress; drug abuse (caffeine, nicotine, and alcohol); and sex hormones including estrogen, progesterone, and testosterone can influence the development and maturation of the adolescent brain. MRI studies have suggested that neurocircuitry and myelinogenesis remain under construction during adolescence because these events in the central nervous system (CNS) are transcriptionally regulated by sex hormones that are specifically increased during puberty"

 

Under the following Adolescent brain heading of the paper, the authors cited:

 

" Longitudinal MRI studies have confirmed that a second surge of neuronal growth occurs just before puberty.1,7 This surge is similar to that noticed during infancy and consists of a thickening of the grey matter."

 

I think what your looking for here are the longitudinal MRI studies the authors cited. According to one of those studies, regionally specific "linear decreases in cortical gray matter" were identified post-adolescence; whereas, pre-adolescence increases were observed. I think the author of the first link inferred a second surge of synaptic growth from the pre-adolescent increases that continue, "regionally specific", through puberty. They appear to view pre-adolescence as one phase and puberty as a second citing hormonal influences as a basis. A general overview of the second paper you provided appear to suggests a similar reliance on MRI studies involving continuing pubescent increases in white and regional gray matter.

 

Perhaps worth a mention, I found this article referencing GABA receptors as a probable initiate of synaptic pruning at puberty. In reference to my comments on the nature of synaptic pruning in sleep, this article appears to regard similar. Again, you may have access to the full text through your institution. I hope it helps.

 

 

EDIT: After a another look, that second wave or surge referenced in the paper described an occurrence prepubescence rather than concurrent with puberty. Therefore, only continued increases rather than a second surge during adolescence appear to be suggested.

Edited June 12, 2016 by DrmDoc

[Popelus]

(I am going to sleep now, but tomorrow I'll write a bigger post.)

 

Everytime I follow the citations' chain from articles which talk about the "second wave of synaptogenesis", I see that they end up citating the 1999 seminal paper by Giedd et al., which has been citated almost 4000 times. It was one of the first MRI studies to notice that gray matter volume in the Prefrontal Cortex increases until 12 years of age and then starts decreasing. Here is what Giedd et al. say in that article:

Whether this gray-matter increase is related to changes in neuropil, neuronal size or dendritic or axonal arborization will be best addressed by methods other than MRI. If the increase is related to a second wave of overproduction of synapses, it may herald a critical stage of development when the environment or activities of the teenager may guide selective synapse elimination during adolescence.

I feel like this has been taken too literally by most authors. After this Giedd paper, most papers simply assume that changes in gray matter volume are changes in synaptic density, and therefore they say that there is a second synaptogenesis... because they see that there is a peak of gray matter volume several years after the synaptic density peak that Huttenbacher found histologically (4-5 years).

Edited June 13, 2016 by Popelus

[DrmDoc]

I think your right. As I read his quote, Giedd made no reference to a second wave occuring during puberty. Instead, he appears to be discussing prepubescent increases continuing into puberty and how they might relate to subsequent selective synaptic pruning in adolescence. This appears to coincide with linked longitudinal MRI studies confirming "a second surge of neuronal growth" occurring "just before puberty." Papers suggesting a second pubescent wave based on Giedd's paper and the linked MRI studies I reviewed have misinterpreted their findings. According to the links you've provided, there is no second wave of synaptic growth proven, merely a continuation of selective prepubescence increases.

Edited June 13, 2016 by DrmDoc