Introduction:

Human’s life as we know, goes through quite distinct stages. But these stages are not as simple as infancy, childhood, adolescence, adulthood and old age as most of us even medical fields recognize. That is why many medical studies including those in neuropsychiatry or neuropsychology plan their studies based on the above commonly known life stages. Even in many instances children including infants are mixed up with adolescents in studies or adults with elderly. As we know for example pediatrics cover the medical care of infancy, childhood and adolescents, while as we will read here with clear evidence by probing into the brain development that any of these stages are quite distinct. Here by probing into the brain development, a new classification and definition of different stages of life is presented that is vital to understand for medical, psychological and behavioural, even medical intervention of diseases and in a near future their preventions.

 Psychological, behavioural and cognitive classification of life stages:

Long time ego, Freud (1) the father of psychology and psychoanalysis divided early stages of life into: 1) Oral stage in the first year of life or infancy; 2) Anal stage in the second year of life; 3) Phallic stage in the 3-5 years of life; 4) Latency stage of 6-11, and 5) sexual stage from 12 to 18 years of age. Due to the sexual nature of his psychology, Freud’s classification of life stages was based on sexual development and the pressure on ego by id and superego and all speculative and not experimental and scientific.

 After Freud, Erik Erickson (2) tried to classify all stages of life from infancy up to old age as: 1) Birth-2 years (Infancy), that he believed the stage of learning Trust; 2) 2-4 years (Toddlers), when the child moves toward Autonomy; 3) 3-5 years (Preschoolers), when the child becomes Initiative; 4) 6-12 years (school age), when the child starts to become Industrious, more aware of themselves as individuals and responsible; 5) 13-19 years (Adolescents), when the teenager starts the process of Identity and role identification and self-confidence; 6) 20-40 (young adulthood), when the young adult enters Intimacy and serious and life long relationships; 7) 40-65 (middle adulthood) when the middle aged adults are at the stage of generativity vs. stagnation; 8) Late adulthood (65-death) when the individual facing integrity or despair.

 

Later on Jean Piaget (3) classified the stages of life from a cognitive developmental perspective into: 1) Sensorimotor Stage: Birth-2 years, when the infant perceives the world around only through his senses and discovers the surroundings by his motor movements; 2) Preoperational stage: 2-7 years, when the child masters the language, expressing himself and controls surrounding somewhat by speech without yet having any sense of abstracts, logic and no mental power to operate well enough in the environment; 3) Concrete operational stage: 7-11 years, when the child is more logical, though still in a concrete manner without understating the abstracts; 4) Formal operational stage: 11-18 years, when the teen masters the abstract logic, hypothetical and deductive reasoning. Like Freud, Piaget did not go beyond adolescence and did not cover the cognitive development beyond age 18, even into adulthood.

 

None of the above classifications of the stages of life that were proposed in the first half of 20^th century, based on the different stages of brain development and were strictly observational, though from quite distinct perspectives. The second half of the past century and the advent of neuroimaging and neurochemical studies brought to medical specially the filed of neuroscience, that the brain goes through different stages of development and that would not stop after the stall of the growth of the brain in size by age five. The neuroscientists cruising in the field of the brain development soon discovered not increasing in the number and sizes of neurons, but increasing in the surface of the brain by folding and making the convolutions and gyries, and specification in the development of the brain for different purposes throughout the different stages of life. Here I will present some of these discoveries as we walk through different years of life in an attempt to re-define the stages of life based on the development of the brain.    

The brain development during the fetal stage of life:

The brain cells are born in embryo from about 6 weeks of gestation. First the Neuron cells (the main brain cells that make the gray matter of the brain) then the glia cells (that glue the neurons together, and are the highways of the brain to connect different gray matter regions and make the white matter of the brain) are born. Neuronal progenitor cells are born, differentiate, and laid down in an inside-out pattern. Larger cells, like pyramidal cells, typically arrive earlier than smaller cells (i.e. granule cells). Proper innervation patterns are guided by radial glia or target-derived neurotrophic factors. Once neurons reach their final destination at about the 16th fetal week, they arborize and branch in an attempt to establish appropriate connections. From about 15 weeks of gestation, the axons and dendrites start to outgrow to form the highways of the brain for connection and communication that continues until about 18 months of life. Brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), glia-derived GF (GDNF), and other neurotrophic factors influence the migration or retraction of neurons. (4)

Growth factors continue to play an integral role in dendritic branching once neurons reach their target. The expression of growth factors reaches its highest level during the prenatal period as neurons first establish synaptic contacts. Around the same time synapses, that are the crossroads of brain cells are formed so the cells can communicate, take nutrients, chemicals and hormones through their receptors. Growth factors continue to play a role in synaptic plasticity throughout the lifespan, and are integral for neuronal changes associated with learning. But interesting that the brain like an expert gardener while planting, starts pruning and removing the weeds as well by “Programmed cell death”. This happens almost at the same time that Myelination (a cover sheath of axons that is actually an outgrowth of glia cells) happens. The myelination is essential for conducting signals and impulses between the neurons not just in the brain but all across the body through peripheral nerves and that is how the brain coordinates the entire body. Myelin layers are also vital for regeneration of the whole nervous system that makes it the only body organ to regenerate and comes to life after insults, cuts and injuries. Myelination is so important that continues until mid-adolescence. (4-5)

The brain development during infancy stage of life:

Dopamine as the brain fertilizer neurotransmitter is apparent even at the embryonic stage, but after birth increases first with an increase in D1 and D2 receptor density in a linear fashion during the first 4 weeks of life and reach their adult-like density at this stage. The timing of synaptic production and elimination of the postnatal human brain is different across different regions of the cortex. For example the density of synapses in the primary visual cortex peaks at 6 months of age, but peaks at 2 years of age in the prefrontal cortex. Also cortical changes occur later than subcortical changes in overproduction and elimination. (6-7) These anatomical changes parallel the functional development of each region, with marked differences in time course for cortical and subcortical regions. For example, functionally, motor development occurs earlier than cognitive development and parallels the ontogeny of the striatum and cortex, respectively. (7)

In addition to the structure-function relationships described above, age-dependent changes in intrinsic factors such as neurotransmitters and neurotrophic factors are integral for determining set points in synaptic activity that further define a developmental trajectory. (8) Changes in neurotransmitter levels produce regional- selective changes indirectly via their trophic actions during development. Appropriate stimulation during a critical period of development is necessary for normal maturation, while inappropriate stimulation during these transitions causes abnormal development. For example, dopamine and serotonin have trophic roles early in development (including neuroblast division, cell migration, and synapse formation). Dopamine increases neuronal branching and outgrowth via the D2 receptor family, while activation of D1 dopamine receptors inhibits growth cone motility. (9) Transient expression of receptors and/or function during early postnatal life is believed to play a guiding/trophic role for innervation. These receptors/functions are expressed for a discrete period developmentally and then become virtually absent from the adult brain. For example, the serotonergic 5-HT7 receptor is transiently expressed in striatum before 15 days and is virtually absent by 21 days and adulthood. (10)

The brain development during childhood:

Through the process of pruning for the purpose of self-regulation and specification of the different brain regions and levels, there is a non- linear decrease in cortical gray matter, but linear increase in the white matter that starts around age 4. The increase in the white matter volume is for the purpose of connection and communication of different regions of the brain from bottom-up (subcortical to cortical) and posteri-anterior or occipito-frontal. The nonlinear decrease in the cortical gray matter in longitudinal MRI studies across ages from childhood to adolescence has demonstrated a preadolescent increase followed by another post-adolescent decrease. These changes in cortical gray matter were regionally specific, with developmental curves for the frontal and parietal lobe peaking at about age 12 and for the temporal lobe at about age 16, whereas cortical gray matter continued to increase in the occipital lobe through age 20. (11) While it is hard to pinpoint any specific changes in the development of the brain across any age groups or stages of life, as the development is ongoing and longitudinal, there are specific differentiations at any point in time that makes the function of the brain or the individual different across ages.

Cortical white matter increases from childhood (~9 years) to adolescence (~14 years), most notably in the frontal and parietal cortices. (12) This increase in the white matter reflects the continued axonal myelination and/or axonal calibre. (13) Through Diffusion tensor imaging (DTI) that is a magnetic resonance imaging technique that measures the diffusion of water in the white matter and tracts of the brain, it has been shown that more rapid increase of the white matter occurs at earlier age and lowers during the adolescence until it levels off in by young adulthood. (14) The volume of grey matter in the frontal and parietal lobes increase during late childhood and early adolescence with a peak occurring at around 12 years, followed by a decline during adolescence. Grey matter development in the temporal lobes reach the peak later at about age 17 years. In terms of cortical grey matter density, sensory and motor brain regions mature earliest, followed by the remainder of the cortex, with a direction from posterior to anterior regions, as shown by the loss of grey matter, occurring last in the superior temporal cortex. (15)

Developmental functional imaging, using fMRI (Functional MRI), over the past couple of decades has rapidly expanded our knowledge of the developmental function of the brain across life span, including the development of our social brain. While this process begins in childhood, even in the first five years of life, it reaches a rapid peak in adolescence. The social brain is defined as the network of brain regions involved in understanding other people, including the network that is involved in the theory of mind, or mentalising, the process that enables us to understand other people’s actions and intentions in terms of the underlying mental states that drive them. (16) Adolescence, a transitional stage between childhood and adulthood, that is characterized by the attainment of a stability and independence in society, psychological changes in terms of identity, self-consciousness and relationships, more sensitivity to acceptance and rejection by peers and others, is associated with more robust development of the social brain. A growing number of fMRI studies in this regard and in comparison with even adult brains, have found more active social brain, specially at the dorso-medial prefrontal cortex (dMPFC) and left inferior frontal gyrus in adolescence than in adults during mentalising tasks. Also the relative roles of the different areas change with age, with activity moving from anterior (dMPFC) regions to posterior (pSTS) regions. (17)

Other than age differences in the brain development, there are sex differences in the general and specific regional development of the brain. For example, the frontal and parietal lobes attain peak grey matter volume at around age 11 in girls and 12 in boys. The ages at which these peaks occur approximately correspond to the sexually dimorphic ages of gonadarche onset, which suggests possible interactions between puberty hormones and grey matter development. There are also differences in regional brain development such as the increase in amygdala volume during puberty in males only, and increases in hippocampus volume in females only. (15, 18) Moreover females show a positive relationship between oestrogen levels and limbic grey matter volume, and males show a negative relationship between testosterone and parietal cortex grey matter. Also adolescent structural MRI studies have showed evidence for a positive association between testosterone levels and global grey matter density in males (and not in females), while females showed a negative association between oestradiol levels and both global and regional grey matter density. (19)

The brain development during pre-adolescence and adolescence:

As discussed above, while the brain’s development is a continuous process from foetal life onward and there is no demarcating line to separate one stage from the next, there are differences in every step of this development that manifest as different stages of life on the surface. While the differences in some stages of life behaviourally and psychologically or even cognitively are evident on the surface, some others are not much such as the difference between pre-adolescence and adolescence unless through the brain development.

 

The human brain is not fully developed by the time a person reaches puberty. Between the ages of 10 and 25, the brain undergoes changes that have important implications for behavior. The brain reaches 90% of its adult size by the time a person is six years of age and since it cannot increase in size (the we would have giant heads!), but still develops, the brain starts to fold during adolescence to increase its coverage and surface area. The biggest folding and increase in the area of brain occurs during late adolescence into mid 20’s especially in the parts of the cortex that process cognitive and emotional functions. (11-12,14-15)

Some of the most developmentally significant changes in the brain occur in the prefrontal cortex, which is involved in decision making and cognitive control, as well as other higher cognitive functions. During adolescence, myelination and synaptic pruning in the prefrontal cortex increases, improving the efficiency of information processing, and neural connections between the prefrontal cortex and other regions of the brain are strengthened. This leads to better evaluation of risks and rewards, as well as improved control over impulses. Specifically, developments in the dorsolateral prefrontal cortex are important for controlling impulses and planning ahead, while development in the ventromedial prefrontal cortex is important for decision making. Changes in the orbitofrontal cortex are important for evaluating rewards and risks. (12, 14-15)

As shown earlier, cortical white matter increases from about age of 9 to 14 years, most notably in the frontal and parietal cortices. (12) The volume of grey matter also in the frontal and parietal lobes increase during this period of pre-adolescence with a peak occurring at around 12 years of age, followed by a later decline during adolescence. But the grey matter in the temporal lobes continue to grow until a later age of 17 years. (15) These important developments of the brain like the body physical and physiological changes during pubescence are also to certain degree under the influence of sex hormones so having somewhat different timelines of growth between the sexes. At the same time neurotransmissions such as glutamate and dopamine as the excitatory growth factors of the brain that play the major roles until puberty, slow down and give the way to other neurotransmitters such as GABA and Serotonin. These latter neurotransmitters are more regulatory, inhibiting and maturing (along still with dopamine that now functions on the frontal and prefrontal cortices). (19-21)      

Another aspect of brain development from childhood towards adolescence and adulthood, anatomically is pruning and clearing up excess neurons and synapses so to make the brain function more efficient. In other word, the brain of adults more than adolescents and that more than children’s while losing and thinning the cortical grey matter and its synapses, it will become more effective and productive for having more efficient and less redundant substrates. (20) Neurochemical evidence suggests that glutamatergic neurotransmission is accomplished during prenatal and immediate postnatal life for stimulation of neurogenesis. But gamma-aminobutyric acid (GABA)ergic neurotransmission that is inhibitory, particularly in the prefrontal cortex, commences working for maturation of the brain, specially in the higher cortical areas such as prefrontal cortex from mid-adolescence into adulthood until mid-20’s. (21)

The subcortical grey matter, such as basal ganglia consisting of the caudate, putamen, globus pallidus, subthalamic nucleus, and substantia nigra, that control the body movements and muscle tones primarily are developed at earlier ages and peaking at about 7.5 years in girls and 10.0 years in boys. But these subcortical regions, the home of the neurotransmitter Dopamine, in late adolescence through adulthood are further developed through projection and connection with the higher cortical areas such as the frontal and prefrontal, to serve sophisticated brain functions such as higher cognitive functions, attention, and affective states. (11) Also other subcortical regions such as Amygdala and Hippocampus, sub-serving emotions, aggression, language, cognition and memory develop at earlier ages and differentially between sexes. Depending on the needed functions of the system, these subcortical areas of the brain start developing from age 4 for basic primary functions and as the individual ages and in need of higher functional levels, the corresponding anatomical developments occur. Other than age differential in the growth and development, there is a gender differential as well, as amygdala influenced by the male sex hormone of androgen, develops earlier in the boys, while hippocampus under the effect of the female sex hormone of estrogen is developed earlier in girls.

While the development and growth of the grey matter of the brain is very regional, age and sexual specific, the white matter has more a linear steady growth and development all the way from childhood to adulthood. (23) But despite this difference in the grey and white matters developmental trajectories, there is an inseparable connection among neurons, glial cells, and myelin, which are components of the same neural circuits and share lifelong reciprocal relationships. Neuron activity influences myelin production and the proliferation and survival of oligodendrocytes, while oligodendrocytes influence neurons via secretion of neuronal growth factors and influence axonal growth. Also proximal pathways tend to be myelinated before distal, sensory before motor, and projection before association. (24)

The most prominent white matter structure is the corpus callosum, consisting of approximately 200 million myelinated fibers, most of which connect homologous areas of the left and right cortex. The functions of the corpus callosum can generally be thought of as integrating the activities of the left and right cerebral hemispheres, including functions related to the unification of sensory, memory storage and retrieval, attention and arousal, enhancing language and auditory functions. Corpus callosum development like the rest of the brain white matter continues to develop from age 4 up to mid 20’s, and though no significant differences between the sexes, there is a marginal more growth volume in males than females. (25)

The brain development during Adulthood:

The developmental trajectory of cortical gray matter follows a regionally specific pattern with areas subserving primary functions, such as motor and sensory systems, maturing earliest and higher order association areas, which integrate those primary functions, maturing later. For example, in the temporal lobes the latest part to reach adult levels is the superior temporal gyrus/sulcus which integrates memory, audio-visual input, and object recognition functions (along with prefrontal and inferior parietal cortices). (22) The general brain development that has been very active all the way from foetal life towards childhood, then adolescence and young adulthood, slows down and stops by mid-20’s. From here on, like the body muscles, “use it or lose it” as the further development of the brain and slow down of its atrophy is conditional and dependent on its activity and stimulation, through working actively, learning, problem solving, invention and more.

 Brain imaging studies like post-mortem and cognitive studies have shown an overall decrease in the weight and volume of the brain with age, a trend that begins earlier and results in a larger total brain loss in men than in women. For both male and female subjects, the subarachnoid CSF volume is a strong indicator of brain loss and correlated more highly with age than any other measure. In male subjects, brain loss with aging is also reflected by ventricular expansion, with third ventricular volume correlating most highly. In comparison, for female subjects, increases in the volume of the lateral ventricles and third ventricle are delayed, reaching statistical significance only in the age 56 to 65. (26)

Studies have shown that there are correlations of brain structural measures with IQ on both whole-brain and regional levels. Since intelligence is multifaceted, related to different regional functions of the higher cortex, each region has a correlation with a specific cognitive or intellectual function. For example, memory has been correlated in animal models and humans to the size, growth and development, hence the function of hippocampus. A study of taxi drivers in London found that they had larger posterior hippocampi than controls, thought to be related to their extensive amount of navigational memory required for their work. (27-28)

The plasticity of the brain, even present and developing in the adult brain has made clear that the relationship between factors affecting brain development and the resultant brain structures is staggeringly complex and interactive, not solely genetic, but epigenetic and influenced by the environmental factors and learning. The more the individual’s brain is active and nourished by the environment, learning, problem solving, invention, etc. will all expand the plasticity and the growth and development of the brain. This may not translate simply to regional volume increase of any part of the brain, but increase in myelination, communication pathways and more in the developed brain. Stress and a mismatch between the individual’s capacities and demands placed by the environment may result in hindering the brain development out of normal and potential development. Although mapping all these possible functional anatomical correlations is a huge task that has not yet been fully achieved, there are minute clues to such correlations, that could open the venue to the practical applications that we could extract to benefit the most of out of our brains. (29)

In addition to the age differences in the brain development, there are sex differences in general and regional development of the brain. Since women have smaller cranium than men, they seem to have proportionally more volume of the grey matter and less of white matter than men. (30) Also the grey matter showing reduced volume with age more than white matter and this is more so in men than in women. (31) The smaller volume of white matter in women due to their smaller cranium seems to be an         evolutionary adaptive strategy because smaller crania require shorter distances for information transfer. While women have almost equal volume of grey matter bilaterally in both of brain hemispheres, there is laterality effect in men as there is a higher left hemispheric volume of the grey matter than the right. This is consistent with some behavioral and neurobiological data suggesting less hemispheric asymmetry in women (32) For example, it has been shown in functional MRI studies that for phonological tasks men show more left lateralized inferior frontal gyrus activation, whereas women show more bilateral activation in this region, consistent with the hypothesis that men are more highly lateralized for language functions. (33)

On the other side, men for having a relatively larger volume of the grey matter in the left hemisphere, outperform women in spatial performance that also require more volume of white matter for information transference. (34) This also shows that verbal tasks require less intrahemispheric transfer than spatial tasks. Anatomical-behavioral correlations studies have also shown that task conditions requiring sensory interhemispheric integration or transfer, are less related with the participation of the corpus callosum, that connects both brain hemisphere than higher cortical and cognitive functions. (35)

The brain development upon aging:

As alluded earlier, while brain is the only organ of the body to continue with its growth and development until mid-20’s, it is the only body tissue that starts its general retrogenesis or atrophy if it is not actively used and stimulated. This age timeline that is too early for the individual and the whole body system is an evolutionary and adaptive manifestation of the brain as the most evolved and developed body tissue. The brain has evolved per necessity and adaptation to the external and internal environment of coping, learning, language and cognitive development and more. So the nature and this genetic evolutionary programming provides the general basics of development until mid-20’s, but from then on it is up to the individual efforts of stimulation of this tissue for further regional development needed for specific tasks. In summary as Hensch and Bilimora (36) have shown in the diagram below, the developing brain has a timing window in its maturation.

The functional neuroimaging studies such as fMRI has well shown a shift in brain activity from the posterior to the anterior regions with aging, as well as a decrease in cortical thickness, which is more pronounced in the frontal lobe followed by the parietal, occipital, and temporal lobes (retrogenesis model). (37) This is in the opposite direction of brain development in earlier age when the frontal lobe and the prefrontal cortex is developed the latest, but it is lost and atrophied the earliest if it is not activated and stimulated. This anatomical retrogenesis or atrophy of the brain in normal aging has also been shown in their correlated cognitive functional tasks such as visual perceptions and attention, visuospatial memory, working memory, and episodic encoding and retrieval tasks. (38-41)

 Another fact of early brain aging observed in fMRI studies is the Hemispheric Asymmetry Reduction of Old (HAROLD). This means that during higher cognitive or cortical functions, the brain of older adults is less lateralized in tasks such as episodic memory, semantic memory, working memory, perception, and inhibitory control. Therefore as we age, we need more resources from both hemispheres, or in a better word more efforts to perform a task than when younger or compared to the younger people. This factual difference of aging in cognitive function is evident in many tasks even language, speech, visual and auditory processing, etc. that are highly lateralized in the brain, with the left hemisphere being the dominant anatomical substrate needed for such tasks. (42)

 The brain atrophy by aging is generic and across all regions and sub-regions of the brain, though with some differentials in anatomical regions or their corresponding functions. For example, the primary area, which is composed of the motor and visual cortices, shows more marked increase in heterogeneity indicating deterioration in these regions and the corresponding functions, that has been supported by studies showing age-related decline in fine motor functions, and in structural MRI studies showing decreases in the cortical thickness of the primary motor and somatosensory areas with age, even under age of 55. (37,40, 43) Further, fMRI studies have shown over-recruitment of bilateral motor cortices by older adults while performing unimanual movements indicating inefficient use of the brain resources. (44) In addition, there are significant differences in the brain neurochemistry between young and older adults. (45)

 Despite the reduction in the volume of primary areas of the brain, the limbic and paralimbic regions of the brain in charge of emotional regulation are less and late affected by aging. (46) In contrast, the hippocampus contributing to higher cognitive functions such as memory showing a very high increase in heterogeneity with age, while sub-cortical structures such as, putamen and globus pallidus involved in involuntary motor function are spared of such significant change. (37, 47) As outlined earlier, the first cortices to atrophy are the ones that were developed the last, so the frontal lobe, then the parietal and lastly occipital and temporal lobes are lost in atrophy, opposite the direction that they were developed, so the “first-in last-out” (retrogenesis) hypothesis of brain atrophy. (43)

 In addition to the gross cortical volume loss and thinning, there are age related losses inside the brain tissue, for example loss of dendrites, connecting the neurons due to increased pruning by aging, as they have been shown in animal and human post-mortem studies. (48) The loss of neurons in the grey matter, the astrocytes of the white matter and the loss of dendrites, are replaced by gliosis or weeds of the brain as the process of aging, the same as happening in traumatic brain injuries. (49) There is also a significant increase in the amount of extracellular free-water throughout the brain with increasing age. This could be due to a combined effect of brain atrophy and increased inflammation during aging, as has been reported by several studies on neurochemical analysis of the brain. (50-51)

Potentiation of the brain development upon aging:

This alchemic or million dollars question of how to slow down the process of aging brain, while looks hard or impossible, it is in fact simple and straightforward. Typically, the neurodevelopmental processes can be broadly divided into two classes: “activity-independent mechanisms” and “activity-dependent mechanisms”. Activity-independent mechanisms are generally believed to occur as hardwired processes determined by genetic programs played out within individual neurons. These include differentiation, migration and axon guidance  to their initial target areas. These processes are thought of as being independent of neural activity and sensory experience. Once axons reach their target areas, activity-dependent mechanisms come into play. Although synapse formation is an activity-independent event, modification of synapses and synapse elimination requires neural activity. (52) Therefore past adolescence and in adult life when there will not be any neurodevelopmental activities, any brain development depends all on the activity of the subject to stimulate further growth, development and differentiation of the brain.

The concept of activity dependent brain development, learning or plasticity could be traced back to the neural plasticity at the cellular level discussed first in 1913 by Ramon y Cajal, who proposed that modification of synaptic connections could serve as a substrate for memory. (53) Donald Hebb in 1949 more clearly hypothesized that, correlated pre- and postsynaptic neuronal activity may trigger long-term synaptic potentiation or learning. (54) At the level of neural circuits, Hubel and Wiesel in 1998 discovered a striking example of developmental plasticity of visual circuits through their studies of monocular deprivation (55), which led to the discovery of the critical period of the environmental input or stimulation of a specific part of the brain or neuronal region for further development and plasticity. (56) Subsequent demonstrations of remodeling of topographic maps in sensory and motor cortices in response to experiences or injury further indicated that the mature brain is also highly plastic, capable of modification, further development or reconstruction after insult. (57-58).

The discovery of the critical period plasticity or activity-dependent development of the brain soon was studied at the different brain regions and functional levels and their astonishing results were published world-wide. At the visual level, the development of visual systems was shown to require interplay between sensory experiences, spontaneous neural activity, and genetically encoded innate programs. Prior to eye opening, early development and the formation of the topographic map in the primary visual cortex occurs in the absence of visual experience, through both molecular cues and spontaneous, internal or physiological activity. (58) But later on after birth, environmental visual input is required for further development, during which the left/right ocular preference of neurons of the visual cortex (i.e., ocular dominance) is established and the orientation preference of binocular neurons for the left and right eyes are matched (56). During a postnatal critical period, however, monocular deprivation could lead to a permanent loss of the response to the deprived eye (55).

At the motor level, while the primary motor cortex or “motor map” has been developed prenatally, after birth it needs to go under a period of refinement by environmental stimulation during a critical period analogous to that of the visual system (59). This further maturation leads to an increase in excitable zones, reduction in thresholds and more stereotyped evoked movements (60). The descending corticospinal tract (CST) is also refined through an activity-dependent process similar to the sensory systems, so that silencing the CST during the postnatal period results in permanent alteration in the topographical distribution and axon terminal morphology as well as long-term motor impairments (59).

While early plasticity studies focused on the growing brains of infants and children, later on the adult nervous system was also shown to possess plasticity, capacity of changing, learning, further development at least regionally or reconstructing after deprivation of stimulation or activity and injuries. (61) For example, the capability of the adult brain for declarative learning and memory implicates functional and structural plasticity of the adult brain (62). Activity-dependent plasticity is also essential for learning and memory in the amygdala (63), the basal ganglia (64), and almost any other parts of the brain, even the spinal cord (65).

The optimization of any motor skill by repeatedly performing the task, was first demonstrated in 1995 in learning of sequences of finger movements in piano playing using transcranial magnetic stimulation (TMS). (66) It was shown then that any finger movement would activate the corresponding corticospinal projections in the primary motor cortex of the brain, where it will be stored through long-term potentiation for consolidation of that specific skill. Expansions of the cortical representation in corticomotor excitability of specific muscles has since then been demonstrated in relation to the acquisition of a number of different motor skills. (67)

MRI studies have also shown that musicians have a larger volume of the sensorimotor cortex than other subjects which may be related to a larger representation of the fingers in the sensory cortex and a higher excitability of the corticospinal projections to the fingers. (68-69) Of direct relevance to sports, it has also been reported that the cortical representation of the hand used for playing is larger in elite racquet players as compared with control subjects. It is also of interest that the acquisition of a motor skill as, for example, when learning to generate motor sequences, results not only in performance improvements in the practicing hand but also in the other resting hand, a process referred to as an inter-manual transfer of skill learning. This process results in characteristic changes in intra-cortical inhibitory (predominantly GABAergic) mechanisms and also in inter-hemispheric (predominantly transcallosal) interactions. (70-71)

Considering the brain higher cognitive functions, intelligence, logic and reasoning, these have been divided into “Crystallized” that is genetic and inherent in the individual, and “Fluid” that is the by-product of stimulation of the brain by the environment of learning, experience and practice. The fluid intelligence or ability that starts from early childhood, advances rapidly until early adolescence, and reaches the highest level in the mid-to-late adolescence, after which it begins to decline (72) The development of the fluid intelligence that adds to inherent crystallized intelligence or higher cognitive abilities is depending on the plasticity of multiple cortical regions, from the frontal, prefrontal, parietal and other cortices in a synergistic manner. For example while the prefrontal cortex is critical for relational integration during relational reasoning, the parietal cortex is essential for the identification and representation of visual–spatial relations that are fundamental to overall relational reasoning. It has been shown that individuals with superior IQ scores rely more heavily on parietal cortex during relational integration tasks, compared to individuals with average IQ scores. (73-75)  

Therefore what has been acquired through stimulation by internal or external environment, through education, experience and practice, need to be maintained and develop in an ongoing basis, if one is willing to improve his skills and not to lose their mental capacity. This is true not only in the case of higher cognitive functions and intellectual tasks, but in the case of motor and sensory skills, and even simple daily tasks such as attention, working memory, problem solving, and decision making. If the brain is not active, whatever skills and knowledge has learnt over years through the process of plasticity and generating fluid intelligence, it will lose down to the level of crystallized intelligence that has been inherited biologically and genetically.

A new classification of Life Stages based on the Brain Development:

1.The foetal stage of Life:

No classification of life stages, at least psychologically or behaviourally has counted the first stage of life that is fetal and life in formation, internally though not externally. But this is a vital and the first stage of life, significant to the mother and the medicine, as any defect at this stage will have irreparable consequences not just on the individual but on the family and the society at large. From the brain development perspective that will coordinate the rest of the body, if there is any fault, the whole individual will be affected though physically looking normal. While after birth and the first 5 years of life, the major stages of brain development occurs every year or a few, the fetal brain developmental stages are week by week, if not day by day! Therefore any minute delay or interruption in the brain development day to day, or at least week by week, could result in multifold irreversible consequences. The earlier the delay, interruption by insults (physical, microbial, chemical or psychological) the greater damage to the brain development, hence to the development of the infant as an individual for the rest of his or her life. These could be neurodevelopmental delay in the formation of neurons (the principal brain cells, making the grey matter) in general all over the brain or regional in specific parts of the brain; delay or interception in the development and formation of glia cells (that form the white matter or the highways of the brain for communication between the different parts); delay or interruption of the formation of myelin sheaths, dendrites and axons, then synapses and else, so while all the ingredients of the primal brain is available, there is no integration and connection so to function; delay or interception in the production of the brain growth factors, the ingredient of the brain plasticity, so that later on while the brain has all the primal elements and even connections, does not possess the plasticity, meaning the flexibility and the capacity of learning, adaptation, and more; and finally delay or interruption in the process of pruning of brain cells or weeding could result in a huge volumetric brain, but inefficient in function. Any of these delays or interception in the earliest fetal stage of brain development could result in many neurodevelopmental delay disorders that on a gross level we know them as mental retardation, autism spectrum disorders, learning disorders, schizophrenia, and so on. But at a finer level, unrecognizable to the naked eyes, any minimal delay or interruption, for example by drugs and alcohol, infections, and stress could cause minimal brain dysfunctions later on in life, that could or could not be recognized by the individual and her surrounding. This could be at the least not letting the brain reaching its utmost potential that could otherwise.

2. The infancy stage of Life:

While the fetus is mainly dependent on the womb of the mother and the innate and programmed growth and development including of the brain, it is still influenced and could be affected negatively or positively by the environment provided by the mother through nutrition, healthy life style and so on, and her environment that could include assaults, stress, etc. After birth as the infant is more influenced and stimulated negatively or positively by his or her environment for further development of the brain, though the brain general development is still programmed to continue until late adolescence. But since the brain from now on is more activity or stimulation dependent, there will be more and more difference between the stimulated or active than non-stimulated or inactive brain from infancy on. During the infancy, the further synaptic formation to connect neurons of different regions continues. For example,      there is an increase of D1 and D2 receptor density during the first 4 weeks and the density of synapses in the primary visual cortex peaks at 6 months of age, although continues to peak at 2 years of age in the prefrontal cortex. Infancy in the brain development is the stage of most growth and development of sensory and motor cortices. Neurotrophic factors for further growth of the brain and certain neurotransimtters, such as dopamine and glutamate that are more excitatory and stimulating in the first year of life are more in action than GABA and norepinephrine that are more inhibitory, emotional and attention regulatory. Some neurotransmitters such as serotonin, while in later age has emotional regulatory role, in infancy takes on trophic roles along with dopamine for cell migration and synapse formation. Dopamine increases neuronal branching and outgrowth via the D2 receptor family, while activation of D1 dopamine receptors inhibits growth cone motility. (9) Transient expression of receptors and/or function during early postnatal life is believed to play a guiding/trophic role for innervation. Further some receptors of neurotransmitters such as the serotonergic 5-HT7 receptor presents transiently in striatum between 2-3 weeks of life and then will be virtually absent. As psychologists and behaviourist such as Freud, Erickson and Piaget believed that delay or interruption in any stages of life could be detrimental and the next stages will be affected, that is true in the process of brain development. So if there is a deficiency in any of the neurotrophic factors or neurotransmitters in any stage of life the following stages would be affected and the brain will not reach its ultimate maturity. The earliest the neurodevelopmental delay, the worse the outcome will be.

3. The childhood stage of Life:

This stage that covers from age 2 to 11-12 is the longest in the brain development, though these years of childhood on the surface seem to be all the same to the naked eyes, and even medical and professional eyes or society at large that consider adolescence due to its tumultuous characteristic as the most important. But childhood at the level of the brain is building a foundation for adolescence as a transitional stage to adulthood. Attentional failure to this fact leads to facing many issues in adolescence that the teenagers and the world of grownups facing in any society. Further increase in the cortical gray matter continues throughout childhood, though the increase in the white matter or highways of the brain, for connection and communication of different regions of the brain starts around age 4. While in the early years of the childhood, there is a general such increase, in late childhood there will be specific increase for specific increase in the substrates of the brain and its highways. For example the frontal and parietal lobes peaking growth at about age 12, while the temporal lobe peaks its growth at about age 16, the occipital lobe continues its growth through age 20. In regard with the white matter growth, first corpus callosum, the white matter bridge between the two hemispheres grows, then temporal and occipital lobes and finally from about age 9 years until age 14 in adolescence, the frontal and parietal white matter develop, until levels off in young adulthood. Furthermore during childhood, the sensory and motor cortices, subcortical regions of limbic system and the posterior regions of the brain develop before other anterior and higher cortical regions. For example the logical, reality testing, and the social parts of the brain, specially prefrontal cortex and inferior frontal and cingulate gyri accomplish development in later childhood and peaking in adolescence. Also the full development of the brain in need of sexual hormones for facilitating maturation and differentiation between genders, starts in late childhood, going through pre-adolescence and finishing by the end of teens and young adulthood. For example, amygdala in charge of assertive or aggressive emotions and defense develops more and earlier in males at puberty, while hippocampus has similar growth pattern in females. Moreover the limbic grey matter develops more and earlier in girls under the influence of oestradiol levels, boys show a more global grey matter growth under the impact of testosterone. Therefore what it seems as a drastic change in pre-adolescence and adolescence in every aspects, from biological, physiological, psychological, behavioural and social, all have started years before in the seemingly quiet childhood period. Failure to take care of the precious years of childhood in every aspects of nourishing by the proper environment, in a fair balance manner, not enforcing or neglecting will be too late to repair and reverse in adolescence, lest in adulthood.

 4.The pre-adolescence stage of Life:

While there is no such a stage in any other life stage classifications, from the brain development perspective, there is such a stage that cannot be ignored. This is a short period of transition between the long years of childhood and short years of adolescence. The brief years of late childhood from age 10-11 to 12-13, is the stage of preadolescence that only the pre-teen and the brain are aware of. This is the final stage of growth across the whole brain with peak in certain regions of the brain, before the very specification and full maturity of region by region throughout adolescence and young adulthood. On the surface, this is a short period of farewell with the sweet years of childhood and beginning of the teen years, full of changes and surprises, issues to deal with and preparation to face an adult life. In this stage, the grey matter in the frontal and parietal lobes reaches its peaks in volume before starting their specializations during adolescence and young adulthood. The total cortical white matter also reach its peak by age 14. At the same time the excitatory neurotransmitters of glutamate and dopamine give way to inhibitory GABA and Serotonin for mood and behavioural regulations. While most of the brain substrates development has occurred in the long years of childhood, there is a tiny chance of redemption in the pre-adolescence to make things righter, on the surface between the care-givers, society and the pre-teen, and at a brain level through proper environmental stimulation and containment.

 5.The adolescence stage of Life:

During adolescence, the brain achieves all its volume growth and folding to increase its surface further, for the future farther development and specifications. Significant anatomical or substrate development occurs in the higher cortical regions of frontal, prefrontal and else with the expansion of communication pathways between the subcortical or lower regions such as limbic system and the higher regions, for emotional regulation and logical and reality testing maturations. Along the way, further myelination and synaptic pruning happens in the corresponding areas of the brain to improve the efficiency of information processing and achievement of the higher efficiency of the brain. So there will be better evaluation of risks and rewards, improved control over impulses, more reasoning and logical thinking, more social brain, etc. Also during this stage, there is a start of more action of the inhibitory neurotransmission, so more behavioural control and mature conducts. During childhood, when boys and girls behaved almost similarly, but perceived each other as two quite separate beings and detracted in some ways from each other, in adolescence, they start to get attracted to each other basically due to the influence of their sexual hormones on their brain development. The white matter of the brain, specifically the corpus callosum or the bridge of the brain, reaches its highest development for communication between the left logical hemisphere and the right emotional brain. Any delay or interruption in the brain development of the adolescence that is more of “maturation”, there will not be any further chance of redemption or recuperation. This is the stage that due to the full growth of different parts of the brain, specially the higher cortices, and the white matter or finishing the building of the highways of the brain to communicate globally across all the regions, the mature teen close to adulthood, has the capacity of reasoning and judgement. The brain of the adolescence, specially at the later years of teens, is not only developed across life span and in comparison to his or her previous years of childhood, it has reached an evolutionary development, separating him or her from the old generation. The generational gap between the teens and adults is in fact due to this revolutionary process that is often has been misunderstood, ignored or opposed to by the older generation.

 6.The Adult stage of Life:

It takes about 25 years for humans to reach a fully developed brain. But unfortunately while as adult on the surface, he or she starts to enjoy the fruits of his or her life by mid-20’s, his or her brain as soon as completed its general growth and development, it will begin to shrink and lose its capacity if not used actively. This fact while it is surprising, shocking and unbelievable to many, it is a testimony to what our brain is really for. Our brain that is the reason of our distinction from other animals, is a product of evolution, that is adaptation and survival, through its tremendous and incomparable plasticity. Without the plasticity, our brain is like other animals’ is a nervous system for day to day survival without any advancement in our beings. It is only through the plasticity of our brain, that we have evolved and will still evolve, that we have learnt, invented and came to control our environment to a certain degree. If we do not use the plasticity of our brain for further learning, inventing, problem solving and active thinking, the neurons, the glia cells, the synapses, the neurotrophic factors and the neurotransmitters all take a down spiral and we lose all the development of the brain achieved since birth. So if the brain is taken passively, the stage of life as early as young adulthood is ended, and the rest of the life we live like a robot, performing our daily routines. That is why people who do not use their brains actively, start to lose their potentials and they live a passive life. Since we are in majority consumers and not producers and do not learn beyond high school, a college diploma or university degree and as soon as having a job, we stop using our brains actively, we may not notice the loss or lack of reaching our potentials. That is why forgetfulness, memory loss, dementias such as Alzheimer’s have become common and we are easily sheer subjects of brainwash! The plasticity of the brain as discussed above is still ongoing even in adult life, meaning the brain if not globally, regionally could still develop and grow with no limitation. This simply means, the individual can always learn a new skill and knowledge, create things or being active in problem solving, decision making and changing his, her and others’ environment for a better active life, not a worse passive living.        

Dr.Mostafa Showraki, MD, FRCPC                                                                  Lecturer, School of Medicine, University of Toronto                                  Author: “ADHD:Revisited” Book/ “adhdrevisited.com”/”medicinerevisited.com”

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