Hallmarks of Brain Plasticity

1. Introduction

Numerous studies showed that experience and lesions of the peripheral or central nervous system can modulate functional cortical organization [2]. Hence, the brain is a dynamic organ, which implies the ability of the network of neural connections for self-modification in response to experience [22]. Brain plasticity (BP) refers to its ability to optimize the functioning of brain networks through reorganization of neuronosynaptic maps [1,2]. BP is a continuous process and remodeling of the maps can be short-, middle- and long-term [23]. The capacity of the brain to change structurally and/or functionally allows the individual to learn, remember, forget and recover from injury [1,24]. Therefore, BP is a compensatory phenomenon [2]. BP changes across life: it is enhanced in children and reduced in adults [25]. Herein, we summarize views on pathophysiology of cerebral plasticity at sub-cellular, cellular, and synaptic map level.

1.1. Concept of Brain Plasticity

Neuroplasticity is the ability of the brain to change structurally and functionally [24]. Experience may produce multiple dissociable modifications to the neural system (see Figure 1). These refer to an increase in dendric length and glial activity, change in spine density, synapse formation, and altered metabolic activity. These variations change brain weight, cortical thickness, acetylcholine levels and dendric structures. The structural modulation impacts behavior. Age, hormonal profile, trophic factors, stress, and brain pathology also affect the functional outcomes.

The key principle of behavioral neuroscience is that experience can modify brain structure long after brain development is complete [24]. In response to behavioral demands, the mammalian brain can form new synapses, grow dendrites, and create new elements of supportive tissue: astrocytes, blood vessels [13,26]. Environmental enrichment studies showed large changes in various measures of cortical morphology. In these studies, a control group of animals is kept in laboratory cages and the experimental group is placed in large enclosures with visually stimulating objects and an opportunity to interact with the environment. The studies reported an increase in the dendritic fields of neurons by 20% relative to cage-reared animals. Dendric space correlates closely with synaptic numbers [27,28,29].

Besides, experience (environmental enrichment) modulates synapses by modifying the excitatory-inhibitory equilibrium. Specifically, the number of excitatory synapses per neuron increases and the number of inhibitory ones decreases. Changes in neuronal morphology require more active metabolism, blood supply and support from glial cells, especially from astrocytes [24].

Merely having exercise is not sufficient to induce neuronal changes. A more complex task increases neuronal processing, which results in a more active synapse formation [24]. Environmental enrichment increases both dendritic length and density of synaptic spines on the dendrites. Some authors found an association between the extent of dendritic arborization in a cortical language area and the amount of education [30]. In another experiment, children with developmental delay had spindly dendrites with a reduced spine density compared to average intelligence children [31].

1.2. Different Types of Plasticity

BP can be classified in different ways. For example, scientists mention ’activity-dependent plasticity’, and it talks to itself [1]. The brain’s ability to alter the structural and functional properties of neurons refers to structural and functional plasticity, respectively [32]. Researchers presume that synapse is the most likely place to identify neural changes associated with behavior [24]. Synaptic plasticity is the ability of a synapse to change over time through use or disuse. Meanwhile, dendritic plasticity occurs at postsynaptic sites, the dendrites, and spines of excitatory neurons [5].

In the glossary section, we listed a broader classification of BP into subtypes. Still, physicians mainly focus on post-lesional plasticity, which is the ability to adapt after damage to the peripheral or central nervous system, with functional reshaping underlying a partial or complete clinical recovery [2] Although BP is a dynamic construct, it should be stabilized through the mechanisms called homeostatic plasticity, otherwise, the system will not be functional [2].

2. Neuroanatomic and Neurophysiologic Bases of Brain Plasticity

2.1. Plasticity in the Periphery and at the Centrum of the Brain

In local anesthesia, amputation, and peripheral neuropathy, sensory deprivation is the major reason for cerebral reorganization. The adjacent regions of the cortex expand at the expense of the deprived cortex. The suggested mechanism of the expansion is as follows. Within certain minutes after the trauma, the acute reorganization happens due to the unveiling of latent intracortical connections. In the following months, additional remodeling occurs. In the primary motor cortex, a peripheral lesion also results in the expansion of the cortical areas in the vicinity of the representation of the body part that is injured [2].

After lesions of the primary somatosensory area, the damaged representations are redistributed both in remote regions and in the areas adjacent to the injury [2]. For the motor function, animal studies have also demonstrated a similar experience-dependent plasticity after the central lesions. The researchers showed a potential of rehabilitative training to shape remodelling in the adjacent undamaged cortex [2]. Hence, the recruitment of the intact motor cortex is a mechanism of motor recovery [33].

2.2. Natural Plasticity in Different Functional Areas

Plastic changes differ among functional areas. The primary motor cortex controls the kinetic and dynamic parameters of voluntary movements [34], and the cortical representations of muscles and movements have a mosaic structure [35]. Motor training reshapes the primary motor cortex, and the acquisition of new motor skills necessitates an extension of activation, which is reached by temporal or durable recruitment of adjacent sites [36].

The primary sensorimotor cortex integrates sensory and motor signals necessary for skilled movement, namely involved in cognitive functions: motor skill learning [37], calculation [38], and mental imagery [39]. Hence, the role of the sensorimotor cortex is more complex than the control of movements. Learning a skill modifies the activity of isolated neurons and brain regions. The synchronous activity of many neurons in the same cortical region may quickly change the time-course of the ensemble of neurons executing the movement [40,41]. The non-primary parts of the somatosensory network also undergo plasticity-related changes, and the effective connectivity within the whole functional network rises [42,43].

The functional areas of language and cognition are cortico-cortical and cortico-subcortical networks which function parallel. The areas have a hierarchy with both simultaneous and successive activation of the networks. Some of them are essential while others are compensative [44,45,46]. Plasticity implies the modification of spatio-temporal parameters of the functioning of the networks.

3. Pathophysiological Mechanisms Underlying Cerebral Plasticity

3.1. Plasticity Mechanisms at Microlevel

At the microscopic level, many ultrastructural and synaptic changes may take place. During neurodevelopment, these are cyto- and histogenesis, with proliferation and elaboration of dendritic and axonal branches; cell migration, formation of synapses, and cellular differentiation; precise organization of the circuitry, apoptosis, regression of axons, elimination of cells and synapses. At this stage, radial glia controls neuronal migration from the subventricular zone to the cortex, thus also contributing to developmental plasticity [47]. After the period of neurodevelopment, structural and functional reorganization of the brain may proceed with the major changes taking place at the synaptic level. The plasticity mechanisms include changes in the activity of isolated neurons, in synaptic efficacy, and in the temporal relations between ensembles of neurons in specific oscillation bands [48]. In a combination, these mechanisms can modulate the behavior [2,49].

The synapse is a dynamic rather than a static contract. Beyond its increase in size and number due to learning [50], one can see modulation of synaptic strength, which evidences the presence of plastic properties in these dynamic connections [51]. Once appear at the microscopic level, these modulations account for functional map reshaping observed at the macroscopic level [52]. The examples are the activity-dependent synaptic plasticity, auto-regulation of synapses which is called ‘metaplasticity‘.

The activity-dependent synaptic plasticity is a leading mechanism of memory formation. Repeated nerve impulses change synaptic transmission: frequent stimuli coming to the presynaptic membrane may increase or decrease the induced excitation of the postsynaptic neuron. The activity-dependent synaptic plasticity establishes a real-time control over the flow of information within neuronal networks [2]. This type of plasticity explains both long-term potentiation and long-term depression – the two opposite phenomena. The first one is a durable enlargement of the synaptic strength which is followed by a brief high-frequency stimulation. Otherwise, such stimulation might lead only to a short-term potentiation. The mechanism was demonstrated in the hippocampus and motor cortex, and it may underly functional plasticity in motor cortex [53]. The second phenomenon plays an important role in learning and memory [54].

Metaplasticity is an ability of synapses to auto-regulate themselves [55,56]. Different hypotheses were proposed to describe the mechanisms of memory formation through modulation of synapses. According to the synaptic plasticity and memory hypothesis, the induction of activity-dependent synaptic plasticity at appropriate synapses forms the memory [57]. However, little evidence supports the sufficiency of activity-dependent synaptic plasticity for storing memory [2]. According to Hebbian’s rule, the physiological bases for learning and memory are modifications of synaptic strength among neurons that are activated simultaneously when the task is repeated [11]. The rule is widely accepted in neuroscience [58]. Moreover, scientists have discovered a mechanism essential for balancing the processes of Hebbian learning. It is synaptic stabilization through a regulation of the AMPA receptors mediating fast synaptic transmission [59]. This self-regulation of neuronal excitability relative to network activity is called ’homeostatic’ plasticity - the term derives from two opposing concepts, and it means "staying the same through change".

Synchronization of episodic electrostimulation of cerebral ganglia is necessary for a massive reorganization of the cortex [60]. ’Effective’ connectivity refers to influences among brain regions. Biomathematical modeling is used to determine how a constrained set of brain regions influence each other in a specific task. Knowledge of these regions comes from neuroanatomy [12]. A study showed a synchronization of activity among different areas involved in a sensorimotor function due to training [61]. Hence, plasticity may appear as a modification in ’effective’ connectivity within the whole functional network [42].

Another major mechanism of short-term plasticity is a decrease in the inhibitory activity of the GABA interneurons that block horizontal connections in regular settings [62]. However, sensory deprivation or learning suppresses the GABA inhibition, which unmasks latent connections and transforms silent synapses to functional ones [11,63]. Thalamo-cortical networks facilitate the described process [64].

Glia can also affect synaptic transmission, coordinate activity across neuronal networks, and modulate neuronal activity in different ways. These include a release of neurotransmitters and other signaling molecules, neuro-vascular coupling which regulates energy metabolism [65]. Besides, glial cells can communicate with each other thus forming a glial network which is able to both listen and talk to neuronosynaptic circuits [66].

At the neuronal level, structural modifications include sprouting of the dendritic spine, growing of the axon and formation of new synapses (neosynaptogenesis). Experience or brain damage may initiate these modifications. The experience-dependent plasticity is based on the increased synapse turnover which denotes the accelerated formation and elimination of synapses. This mechanism underlies adaptive remodeling of neural circuits [67].

The post-injury plasticity is based on a rapid induction of changes in the number, size and shape of dendritic spines [68,69]. The suggested molecular mechanisms for this are protein synthesis [69], secretion of growth factors and neurotrophins [70]. AMPA receptors and integrins stabilize morphological changes through the mechanism of ’homeostatic’ plasticity [50,71]. Axons may also regenerate spontaneously and elongate [72]. Glia controls the number of synapses [73] and adjusts to meet modifications in the brain environment [74]. Both in physiologic conditions and after injury, the changes in the glia size and phenotype is quick (hours) [67,75], and it can be conveyed to other glial cells via connexin [76].

Researchers began to question the old dogma that the adult mammalian brain cannot develop new neurons. The olfactory bulb, the dentatus gyrus, and even the neocortex of adult primates are exceptions to this rule which turned out to be not absolute [26,77,78]. In vitro, multipotential progenitor cells of adult humans underwent neurogenesis. The cells were isolated from the temporal neocortex, hippocampus, and subcortical white matter [79,80,81]. Studies suggest that these newly created neurons may store memories and contribute to learning via changes in neuronosynaptic circuits, formation of new connections and networks [82]. The post-lesional plasticity can also be arranged in the way of the neurogenesis, as this was shown in adult rats. The animals generated endogenous neural precursor cells in situ and then to differentiate then into mature neurons replacing the damaged ones [83]. This fact favors the idea of neuronal replacement therapies.

3.2. Plasticity Mechanisms at Macrolevel

At the macroscopic level, functional reorganization is carried out through the mechanisms of diaschisis, functional reorganization of cortex within eloquent areas and networks, cross-modal plasticity, compensatory strategies, and macroscopic morphological changes. Diaschisis is a general term describing functional alteration outside of focal brain damage. These are electrophysiological, metabolical, and hemodynamic changes. Although diaschisis underlines initial functional impairment, the same mechanism accounts for spontaneous functional recovery after injury [84,85].

Another mechanism of functional reorganization after brain injury affects eloquent cortex. The eloquent areas have redundant representation of the same function within the same region, Within the eloquent areas, functions have multiple cortical representations within the same region. So, the eloquent site is discrete, and once partially destroyed, it is compensated by the adjacent redundant sites that are unmasked post injury [86,87]. However, in wide lesions, this mechanism does not provide sufficient compensation, therefore other cortical parts are recruited to restore the function [88]. These are regions of the same functional networks, remote ipsi-hemispheric structures and functional homologous structures in the contralateral hemisphere. The suppression of the regions is released step by step with the unmasking of each next region if the functional compensation is insufficient [89].

’Cross-modal plasticity’ refers to the compensation of functional alterations through the recruitment of the structures that did not belong to the eloquent circuit which was altered [8,9,10]. For example, deaf patients may activate auditory cortex during somatosensory tasks, and in this way, they get better tactile discrimination [90]. For the same reason, these individuals can benefit less from cochlear implants due to extensive cross-modal plasticity [91]. If the unimodal areas cannot be recruited after massive damage, heteromodal association areas are activated. Although the activation does not allow for a complete functional restoration, this mechanism can be considered as an elaboration of compensatory cognitive strategies [92].

Although happening mainly at the ultrastructural level, neurogenesis may result in the macrostructural changes that can be detected with the voxel-based morphometry [93]. With this technique, scientists showed that cortical regions, cerebellum hippocampus, and density of the white matter tracts in the predominant hemisphere can be enlarged to meet professional or educational demands [94,95,96,97,98,99]. In the grey matter, training can induce transient morphological changes [100].

4. Modulation of Experience-Dependent Change

4.1. Sex Hormones

Studies reported that the brain is more sensitive to experience in females than in males [101,102,103,104]. Same studies showed that hippocampus has the same gender disproportion: it is more sensitive to experience in females. However, these changes can be manipulated with hormonal replacement therapy [24]. A failure of dendric growth is a supposed pathophysiologic mechanism of developing dementia [105].

4.2. Neurodevelopment and Brain Plasticity in Childhood

A superior ability of children to learn a language and to recover from brain trauma demonstrate enhanced brain plasticity in comparison to adults [1]. During early years, several mechanisms account for enhanced brain plasticity. First, neurogenesis does not stop right after birth, although adult neurogenesis is missing in humans [106]. Second, programmed cell death (apoptosis) may eliminate neurons [107]. Third, the number of synapses may either increase or decrease and synaptic functioning can be refined by activity-dependent mechanisms [5,25].

In children, plasticity of the brain is maximal, and it can be classified into the following categories: adaptive, impaired, excessive plasticity, and plasticity that makes the brain vulnerable to injury [1]. The first category refers to adjustments in neuronal circuitry that allow the individual to compensate for injuries to the brain or develop a special skill with practice. The second one is linked with cognitive impairment when genetic or acquired disorders disrupt molecular plasticity pathways. In contrast to this, excessive plasticity leads to disability through the reorganization of maladaptive neuronal circuits in the developing brain. These new maladaptive brain circuits cause neurologic disorders such as partial seizures following mesial temporal sclerosis or focal dystonia. Finally, brain plasticity can become its ’Achilles’ heel’ and increase the vulnerability of the brain to injury. In energy failure or status epilepticus, the mechanisms regulating plasticity are over-stimulated, which leads to excitotoxic neuronal damage.

4.3. Brain Plasticity in Adulthood

The brain holds the potential for functional and structural rearrangement throughout life, which has been underestimated recently [108]. In adults, learning induces the elaboration of new circuits and the maintenance of neural networks. In elderly people, natural plasticity may resist negative outcomes of brain aging which typically results in neurocognitive slowing [22,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126]. In normal aging, the number of synapses increases in the cortex, which allows middle-aged people to compensate for the loss of neurons with age and to maintain the number of synapses across life [24].

5. Non-Coding RNAs in Brain Plasticity

This section reveals the molecular alterations that may serve as biomarkers of plastic changes in the brain. These comprise non-coding RNAs, microRNAs, circular RNAs, long intergenic non-coding RNAs, Y RNAs. The recently discovered world of non-coding RNAs (ncRNAs) is continuously expanding to all areas of biomolecular interactions and variety of cellular processes including control of metabolism, gene regulation and protein turnover. Expectedly, multiple ncRNA players were found to be involved in brain plasticity (for several examples, see Table 1). Furthermore, interactions between different types of ncRNAs create multidimensional networks that respond to a range of endogenous and exogenous stimuli. Noncoding RNAs (ncRNAs) represent the major part of the transcriptome. Various classes of ncRNAs have emerged as critical regulators of transcription, epigenetic processes, gene silencing and play important roles in neural brain plasticity and cognitive processes [127]. ncRNAs regulate diverse intracellular and neuronal functions: modulate chromatin structure, act as chaperones, and contribute to synaptic remodeling and behavior [128].

Neurons are highly compartmentalized due to their morphological and functional complexity. This happens due to the transport of messenger RNA (mRNA) transcripts to specific subcellular areas, e.g. synaptic regions, for the local translation. Increasing evidence shows that highly expressed cerebral ncRNAs participate in the spatial and temporal control of the mRNA translation, therefore, in synaptic plasticity [129].

ncRNAs may contribute to the development of a variety of neuropsychiatric disorders, including schizophrenia, addiction, and fear-related anxiety disorders [127,128]. Moreover, the diversity of ncRNAs and their association with neurodegenerative diseases render them particularly interesting as putative targets of brain disease [130]. New RNA-based therapeutics can be developed due to the new knowledge on the ncRNA regulation and the downstream effects of their interactions in different pathologies.

Long non-coding RNAs (lncRNAs) act as scaffolds for biomolecule binding and mediate different RNA-protein interactions. LncRNAs are increasingly recognized for their involvement in neurodevelopmental processes including cell proliferation, neurite outgrowth, synaptogenesis, and neuroplasticity [159]. Neuronal lncRNAs are crucial for orchestrating neurogenesis, for tuning neuronal differentiation, and for the exact calibration of neuronal excitability [130]. Particularly, Malat1 is an lncRNA which is abundant in the nuclei of neurons. It promotes synapse formation by recruiting the serine/arginine splicing factors to the transcription sites of genes involved in synaptogenesis. Overexpression of Malat1 enhances the number of synapses in hippocampal neurons in vitro while its deficiency reduces number of synapses between dendrites and axons [160,161]. Gomafu is another lncRNA involved in ES cell, neuronal cell and retinal cell differentiation. The lack of Gomafu led to hyperactive phenotype and increased sensitivity to the psychostimulant MAP in Gomafu KO mice [131]. lncRNA Gas5 promotes neuronal differentiation of hippocampal NSCs and restores learning and memory in rats with cholinergic injury [132]. Furthermore, synapse-specific Gas5 KO led to impaired fear extinction memory [162].

MicroRNAs (miRNAs) are small endogenous RNAs about 20–25 nucleotides in length that regulate gene expression posttranscriptionally [163,164]. They are commonly expressed in specific brain regions and affect nervous system development, plasticity, and function [165]. For example, miR-9 has a critical role in hippocampal synaptic plasticity and memory [136], miR-34 regulates synaptogenesis [137], miR-132 participates in axon growth, neural migration, and plasticity [138]. In the temperament-character molecular integration network (TCMIN), only three miRNAs (hsa-miR-1-3p, hsa-miR-335-5p, hsa-miR-34a-5p) are sufficient to coordinate interactions between two gene networks in brain involved in self-regulation of emotional reactivity to extracellular stimuli (e.g., self-regulation of anxiety) and interpretations of meaning (e.g., production of concepts and language) [144].

Potential targeting or therapeutic use was demonstrated for several miRNAs [166]. Particularly, miR-17-92 cluster shown to enhace neuroplasticity [139] and regulate adult hippocampal neurogenesis, anxiety, and depression [140]. miR-144-5p is currently considered as a key target in major depressive disorder [141] and miRNA-145 was recently shown to enhance neural repair after spinal cord injury [142]. One of the highly conserved miRNAs in mice and humans, miRNA-153 stabilizes the neurogenesis of neural stem cells and enhances cognitive ability through the Notch signaling pathway [143].

Circular RNAs (circRNAs) are closed structural isoforms of linear mRNA. They are abundant in the brain and play a significant role in the development of the nervous system [167]. Cerebral circRNAs are linked with neurotransmitter function, synaptic activities, and neuronal maturation. Levels of ciRS-7, circRMST, and circFAT3 increased during the differentiation of human embryonic stem cells into rostral and caudal neural progenitor cells [145]. The level of a recently discovered circular RNAs - circIgfbp2 - is significantly increased in injured brain tissue. It is involved in neural plasticity and might be a future therapeutic target for anxiety and sleep disorders after traumatic brain injury [146]. At least four circRNAs (cirC_0000400, cirC_0000331, cirC_0000406, cirC_0000798) are involved in postoperative neurocognitive disorders [147]. In a rat model, a large number of circRNAs including 1167 cerebral circRNAs displayed a developmental-dependent expression pattern and may have important biological function in differentiation, development, and aging [148]. Enhancer RNAs (eRNAs) are long non-coding RNAs, bidirectionally transcribed by RNA polymerase II from enhancer regions of the genome. Generally, eRNAs are not spliced or polyadenylated [168,169,170]. Bdnf-Enhg1 and Bdnf-Enhg2 were characterised as novel enhancers that regulates Bdnf expression in developing neurons [149]. Conserved enhancer Evf2 was shown to functionally and spatially organizes megabase distant genes in the developing forebrain [150].

Long intergenic non-coding RNAs (lincRNAs) are biochemically identical to other lncRNAs but differ in their genomic organization as they reside in the space between genes [171]. Knockout of linc-Brn1b showed a reduced number of intermediate progenitor cells in the subventricular zone. This suggests that linc-Brn1b can be involved in the development of cortex [151]. Long non-coding RNA X-inactive specific transcript (XIST) was mentioned as a promising molecular target for SCI therapy [172] and may have a significant role in AD [152].

Piwi-interacting RNAs (piRNAs) are a class of Piwi-associated, 26–32 nucleotide small non-coding RNAs that, unlike other small RNAs, are generated from long genomic clusters [173,174,175]. piRNAs are part of a gene regulatory mechanism responsible for establishing stable long-term changes in neurons and the persistence of memory in brain synaptic plasticity [153]. The main molecular function of piRNAs is to regulate transposons. The co-existence of piRNA and retrotransposons might play important roles in the brain development and the adult brains [154]. A number of piRNAs across brain transcriptome are associated with Alzheimer’s disease [155].

Y RNAs (yRNAs) are a class of non-coding RNA often found abundantly expressed in brain and neuronal tissues. Y RNAs are linked to neuronal stress and very often associated with neuronal ELAV-like proteins in Alzheimer’s disease [156] and could serve as biomarkers in glioma [157]. Recent study suggested that the strong tendency of Y RNAs to bind nELAVL proteins to in response to stress conditions might prevent these proteins from associating with their normal messenger RNA targets [156].

6. Implications for Medical Practice

6.1. Pharmacology

In a study, the administration of piracetam potentiated post-lesional plasticity, thus playing a neuroprotective role [176]. Transgenic mice models enabled modulation of plasticity. In humans, different drugs can improve brain reshaping after stroke or brain trauma [177]. The beneficial effect was observed in different functional areas. Norepinephrine, fluoxetine, paroxetine, scopolamine, and lorazepam improve cortical motor plasticity [178,179,180,181,182]. Meanwhile, amphetamine, bromocriptine, and piracetam reactivate brain parts in the left hemisphere and facilitate recovery after aphasia by modulating activity in language centers [183,184,185].

6.2. Transcranial Magnetic Stimulation

In post-stroke rehabilitation, transcranial magnetic stimulation (TMS) can potentiate motor learning [186]. It can rapidly elevate the excitability of primary motor cortex with a long-lasting effect [187]. The same technique modulates sensory maps: it can eliminate the deficit of spatial awareness for the contralesional space [188,189]. TMS can facilitate cognitive rehabilitation by improving memory and performance in picture-naming, analogic reasoning, and decision-making tasks [186,190,191,192,193]. Its mechanism of action is based on a modulation of the effective connectivity [194]. A combination of TMS, pharmacological intervention and rehabilitation is suggested.

6.3. Surgery

Cortical stimulation is an intervention performed for different indications. High-frequency chronic cortical stimulation efficiently modulates functional networks in movement disorders and chronic pain [195,196,197] This technique improves the functioning of the subcortico-cortical loops, which relieves motor, cognitive, and behavioral symptoms in Parkinson’s disease [198,199].

Surgical resection redistributes functional activity throughout latent networks. Hence, an incomplete removal of a tumor in eloquent areas reshapes the eloquent maps and extends functional sites. In a few years, the extended resection during the second surgery will not induce sequelae due to recruiting latent networks, unmasked after the first resection [200,201,202,203,204,205,206]. This approach allows to extend indications for surgeries in ’non-operable’ eloquent regions (sensory motor and language). Still, cortical plasticity may manifest only if subcotrical connectivity is not altered. Therefore, a stroke can cause permanent deficit due to the damage to the white matter [207]. For the same reason, resection of subcortical pathways may display sequelae despite a plastic potential of the cortex [208,209,210].

6.4. Transplantation

Observation of neural grafts explains how environment and experience can modulate brain function [211]. For example, the transplantation of neuroblasts from the fetal striatum to the same brain region may treat Huntington’s disease. The graft enhances cognitive performance and motor functioning by strengthening connections of the striato-cortical loop [212]. In Parkinson’s disease, the transfer of dopaminergic neural cells to putamen showed promising results [213]. After the basal ganglia infarction, the graft comprising cultured human neuronal cells can reduce motor deficit [214].