By Tom Wasiuta as part of the Neurodevelopment Neurowiki

One of the most crucial periods in human neurodevelopment occurs during adolescence. The teenage brain is subject to extensive structural and chemical changes that result in important modifications of both behavior and cognitive ability. Throughout adolescence, the brain undergoes a significant structural re-modeling process which includes a substantial increase in white matter, and an overall decrease in grey matter attributable to the activity-dependent process of synaptic pruning.1 These changes directly influence the levels and distributions of several neurotransmitters in the brain, having a particularly strong effect on dopamine and serotonin. These changes are seen in many areas of the brain, but they are particularly widespread in the prefrontal cortex and the limbic system; areas known to be involved in emotion and high-order cognitive processes, including planning, executive control and decision-making. Specifically, there is an evident balance-shift between mesolimbic and mesocortical dopamine reward systems, which is thought to underlie many of the unique behaviors exhibited during adolescence.2
Adolescence - A time of extensive neuronal re-organization

1 Grey Matter Changes
2 White Matter Changes
3 Changes in Neurotransmitter Systems
4 References

Grey matter changes


During adolescence, neuronal cell bodies in the central nervous system collectively known as grey matter, experience substantial changes in volume and organization. These changes are characterized by the formation of new connections (synaptogenesis), and the elimination of old ones via synaptic pruning. There is an agreement among neuroscientists that the overall grey matter volume experiences a significant decrease during adolescence, however these changes are very dynamic and differ substantially from one brain area to the next1.

Synaptic Pruning Mechanism

Synaptic pruning is a neuronal regulatory process necessary for normal brain development that results in the elimination of approximately half of the neurons originally present at birth3. It is through this mechanism that excess neurons and synapses in the immature central nervous system are eliminated throughout development, leaving more efficient synaptic circuitry in the adult brain. As the brain develops and more complex associations are introduced into the neuronal circuitry, certain connections become obsolete and get pruned away4. Although the cellular mechanisms of synaptic pruning remain somewhat of a mystery in the mammalian nervous system, the process has been shown to be experience/activity dependent in many areas, including the visual cortex5 and auditory brainstem6. It has also recently been discovered that microglia play a crucial role in the developing mouse brain by engulfing synaptic material7, however this role has not yet been confirmed in the human CNS. This activity-dependent process of synaptic elimination is thought to play a role in learning and memory by indirectly selecting which synapses become strengthened and survive as the brain develops4.

Grey Matter Changes in Adolescence

In human subjects, cortical thickness (indicator of grey matter volume) experiences a period of decline during adolescence, and also during the transition to young adulthood. Different areas of the brain, however, follow variable developmental patterns ranging from simple linear decreases to more complicated trajectories. Linear decreases in cortical thickness have been observed in areas of the limbic system, specifically the frontal and posterior orbitofrontal operculum, the medial temporal cortex, medial occipitotemporal cortex, subgenual cingulate cortex, and parts of the piriform cortex8. Patterns of quadratic and cubic nature were observed in higher association areas8. In a more recent longitudinal study observing changes in cortical thickness during adolescence, significant thinning (decrease in GM volume) was observed in multiple areas, ranging from the medial parieto-occipital cortex to lateral parietal areas1.

White matter changes

Overview and Mechanisms

Oligodendrocyte - Insulates multiple axons of the CNS with myelin

The myelinated axons comprising the white matter of the CNS also experience extensive changes during adolescence. In contrast with the neuronal cell bodies, white matter volume and density both increase dramatically in the teenage brain1. White matter volume is determined by three factors9; the caliber of axons, the number of axons, and the thickness of the myelin sheath that surrounds these axons (determined by oligodendrocyte activity in the CNS10). Changes in these three variables lead to visible differences in white matter volume and density that can be measured using magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), and fractional anisotropy (FA).

White Matter Changes in Adolescence

There have been a great number of studies investigating white matter changes during adolescent development, both cross-sectional and longitudinal in design. The general consensus among neuroscientists is that during this crucial developmental period, white matter volume increases significantly throughout multiple regions of the CNS. Specifically, white matter expansions have been observed (using structural MRI analysis) in the corticospinal tract11, corpus callosum1,11 (especially the body and splenium), arcuate fasciculus, and interthalamic pathways11. In addition, increases in FA indicative of greater white matter volume/density have been shown in the superior longitudinal fasiculus12, the inferior fronto-occipital fasiculus13, the anterior limb of the internal capsule14, and the cingulum12.

Sexual Dimorphism

There is some debate as to whether or not the development of white matter throughout adolescence is sexually dimorphic. Some studies have found no difference in male and female white matter progression, while others have found dramatic inconsistencies between the sexes. A recent longitudinal study following 24 subjects through their adolescent development found no significant difference in white matter changes between the 10 male and 14 female participants1. The authors did, however, acknowledge the fact that the development of white matter microstructure may be sexually dimorphic, citing two recent publications15, 16 in which certain brain areas showed clear FA value differences between the sexes. Another recent publication emphasizes the importance of testosterone levels on white matter volume increases during adolescence17. In this study, the authors found a striking dimorphism between males and females, with males showing a markedly steeper increase in white matter volume during adolescence.

Changes in Neurotransmitter Systems

Dopamine Overview

The extensive remodeling process that shapes the CNS during adolescence has both structural and functional implications. Although all neurotransmitters experience changes in concentration during this period, the shifts in dopamine levels appear to have the most functional and behavioral significance. In both non-human primates and rats, it has been shown that during adolescence, dopamine input to the pre-frontal cortex is much higher than normal. These increases have been observed in the dorsomedial cortex, primary motor cortex, principal sulcus, and most of all in the projections to cortical layer 318.

Visual Representation of Dopamine and Serotonin Pathways in the Brain (Adapted from National Institute on Drug Abuse)

Mesocortical/Mesolimbic Reward Pathways

Because of the mesocortical peak in dopamine during adolescence, there is an apparent balance shift between mesocortical and mesolimbic dopamine pathways in the brain. Increased dopamine activation in the prefrontal cortex inhibits excitatory cortical input via direct inhibition of pyramidal cells or by indirect inhibition through GABA-ergic interneurons19. This activation pattern in the prefrontal cortex is consistent with certain characteristic adolescent behaviours, including heightened incentive-seeking, increased risk-taking (e.g. gambling), and poor decision making23. Incentive-seeking and risk-taking are thought to be over-compensatory behaviours for the decrease in excitatory cortical input, while poor decision making is often attributed to the deficient executive control functions in the prefrontal cortex when dopamine levels are high20.

Serotonin Changes

Serotonergic alterations during adolescence are not as well characterized as their dopaminergic counterparts; however rat studies have provided some insight as to what goes on in this neurotransmitter system throughout the teenage developmental period. Serotonin turnover rates have been estimated to be up to 4 times lower in the anterior cingulate cortex (ACC) during adolescence relative to childhood and adulthood21. Low serotonin activity has been linked to several symptoms and behaviours in humans, including anxiety, depression, increased alcohol consumption, and hyper-responsivity to stressors. Since these characteristics are often attributed to adolescents, low serotonin turnover could be involved in their onset/emergence, however this hypothesis has yet to be tested.

Neurotransmitter measurement issues

Measuring neurotransmission in human subjects is a difficult process. Until now, most estimates of neurotransmitter levels and activity have been obtained using non-invasive imaging techniques, such as functional magnetic resonance imaging (fMRI). Other imaging techniques, such as positron emission tomography (PET), provide a more direct manner of measuring neurochemical activity; however these techniques use radioactive ligands which are harmful in high concentrations22. Some researchers have investigated alternative study designs, using molecular genetic techniques to gauge neurotransmitter function20, however direct measurements would be more ideal.


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