Abstract
Adaptive plasticity, the brain's ability to reorganize and form new neural connections after injury, is crucial for recovery following acquired brain injury (ABI). This process involves axonal sprouting, dendritic remodeling, and neurogenesis, which restore neural connections and compensate for lost functions. While neuroinflammation and reactive astrocytes aid tissue repair, optimizing these responses to minimize secondary damage remains a challenge. Brain‐derived neurotrophic factor (BDNF) plays a vital role in neurogenesis and dendritic growth, positioning it as a potential therapeutic target for brain repair. Rehabilitation strategies that stimulate these adaptive changes can enhance neuroplasticity and functional recovery. The complexity of ABI recovery is influenced by factors such as injury severity, age, and genetic and epigenetic factors, which regulate neuronal repair and synaptic plasticity. Maladaptive plasticity refers to compensatory mechanisms that initially aid recovery but ultimately become harmful. Severe injuries like traumatic brain injury (TBI) and stroke can trigger adaptive responses, such as axonal sprouting, but excessive reliance on these processes may become maladaptive. In contrast, mild TBIs offer greater recovery potential. Age‐related differences in plasticity complicate recovery, with younger individuals exhibiting greater plasticity and older adults experiencing reduced plasticity and increased likelihood of maladaptive changes. Genetic factors, such as BDNF gene polymorphisms and DNA methylation, influence recovery outcomes. Neuroinflammation plays a dual role: acute inflammation supports recovery, while chronic inflammation can exacerbate damage. Precision medicine, tailored to an individual's genetic and epigenetic profile, offers promising strategies to optimize recovery. Growth factors like BDNF and insulin‐like growth factor 1 (IGF‐1) are essential for neurogenesis, synaptic plasticity, and neural network reorganization, supporting both structural and functional recovery. However, maladaptive plasticity must be managed carefully for effective recovery. Targeted rehabilitation therapies, along with pharmacological agents and neuromodulation techniques, offer insights into personalized treatment strategies to enhance adaptive plasticity and optimize ABI recovery outcomes. This review explores the mechanisms of adaptive plasticity following ABI and discusses therapeutic interventions to support and optimize recovery, offering promising avenues for improving patient outcomes.
Keywords: acquired brain injury, adaptive plasticity, axonal sprouting, BDNF, neuroinflammation, synaptic plasticity, traumatic brain injury
This figure illustrates the dynamic process of neurogenesis following brain injury, focusing on the roles of neural stem and progenitor cells at the injury site. Key mechanisms include axonal sprouting, synaptogenesis, dendritic remodeling, and brain‐derived neurotrophic factor signaling via TrkB receptors. These processes underscore the brain's capacity for regeneration and adaptation, offering valuable insights into potential therapeutic strategies to enhance recovery following injury. NMDA, N‐methyl‐d‐aspartate; TrkB, tropomyosin receptor kinase B.
Highlights
Significant findings of the study
Neurogenesis in the hippocampus supports cognitive flexibility, memory formation, and resilience against stress, while synaptogenesis enhances neural circuit strength.
Experience‐driven synaptic plasticity, including long‐term potentiation and long‐term depression, regulates synaptic strength through α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor trafficking, with enriched environments increasing synapse density by up to 25%.
Axonal sprouting, classified as reactive, reparative, or unbounded, plays a crucial role in neural recovery, influenced by growth‐promoting and inhibitory molecular factors.
Neuroinflammation has a dual role, aiding early repair but impairing recovery when chronic, while glial scars act as both protective and inhibitory elements in neuroplasticity.
Growth factors like brain‐derived neurotrophic factor and insulin‐like growth factor 1 facilitate synaptic plasticity, neurogenesis, and cognitive function, with their levels influencing neural recovery and aging‐related decline.
What this study adds to the advances in the areas of basic, translational or clinical neuroscience
Highlights the interplay of neurogenesis, synaptogenesis, and dendritic remodeling in brain recovery and adaptation.
Demonstrates how metaplasticity and synaptic strength regulation contribute to cognitive functions and neurological disorders.
Provides insights into therapeutic interventions, such as rehabilitation strategies and targeted molecular therapies, to enhance neural recovery.
Identifies compensatory versus maladaptive plasticity mechanisms, emphasizing their clinical implications in stroke, traumatic brain injury, and neurodegenerative diseases.
Explores neuromodulation techniques and pharmacological agents that optimize adaptive plasticity while minimizing maladaptive effects.
1. INTRODUCTION
Acquired brain injury (ABI) refers to any damage to the brain occurring after birth, differentiating it from congenital or hereditary conditions. ABI encompasses a wide range of causes, broadly categorized into traumatic brain injury (TBI) and non‐TBI (nTBI). TBI results from external forces, such as falls, motor vehicle accidents, assaults, or sports injuries, and may involve penetrating or non‐penetrating mechanisms. It can cause physical, cognitive, and emotional impairments, with symptoms including headaches, memory deficits, mood disturbances, and coordination challenges. Treatment often requires emergency care, rehabilitation, and, in some cases, surgical intervention to relieve intracranial pressure. In contrast, nTBI arises from internal factors, such as cerebral ischemia‐reperfusion (I/R) injury, brain tumors, infections, oxygen deprivation, metabolic disorders, or prolonged seizures. Cerebral I/R injury—encompassing conditions such as ischemic stroke, transient ischemic attacks, and global cerebral ischemia—results in neuronal damage due to impaired blood supply and subsequent reperfusion injury. These conditions can lead to cognitive deficits, physical disabilities, and emotional or behavioral changes, significantly impacting an individual's quality of life. 1 , 2
TBI involves primary and secondary damage phases. The primary phase occurs instantly from mechanical forces, causing direct damage to neurons, axons, glial cells, and blood vessels, often leading to diffuse axonal injury. The secondary phase develops over hours to days, involving biochemical and cellular cascades like blood‐brain barrier (BBB) disruption, neuroinflammation, excitotoxicity, oxidative stress, and mitochondrial dysfunction. Excess extracellular glutamate and N‐methyl‐d‐aspartate receptors (NMDARs) overactivation cause ionic imbalance, calcium influx, and activation of proteases, triggering oxidative damage, mitochondrial failure, and neuronal death. BBB breakdown exacerbates neuroinflammation, while reactive gliosis can impair recovery. TBI increases neurodegenerative risk, including Alzheimer's via β‐amyloid accumulation. These interconnected processes—excitotoxicity, oxidative damage, inflammation, and impaired repair—undermine cognitive and neurological recovery, underscoring the need for targeted therapies to mitigate secondary injury and promote healing. 1 , 2 , 3
An nTBI is brain damage caused by internal factors rather than external trauma, occurring after birth due to various physiological conditions such as vascular disruptions (stroke, hemorrhage, and aneurysm), oxygen deprivation (cardiac arrest, near‐drowning, and respiratory failure), infections (meningitis, encephalitis, viral infections), metabolic disorders (kidney or liver failure), toxic exposures (lead poisoning and substance abuse), tumors and related treatments, or other conditions like seizures and diabetes complications. The pathological mechanisms of nTBI are complex and multifactorial. Vascular disruptions impair blood flow, leading to ischemia and secondary injury cascades. Oxygen deprivation results in hypoxic or anoxic injuries, causing neuronal energy failure. Neuroinflammation, triggered by activated microglia and inflammatory mediators, disrupts neurotransmission and hormonal balance. Metabolic and toxic disturbances alter systemic homeostasis, leading to neuronal damage. Additionally, direct cellular damage can occur due to infections, autoimmune responses, or tumor‐induced pressure on brain structures. These diverse mechanisms highlight the need for a comprehensive understanding of nTBI causes and potential treatment strategies. 1 , 4 , 5
This review offers a comprehensive and integrative perspective on adaptive plasticity following ABI. It highlights key mechanisms such as neurogenesis, synaptogenesis, axonal sprouting, and synaptic modulation while considering various influencing factors, including injury severity, genetic and epigenetic modifications, and neuroinflammation. Unlike previous reviews, it connects fundamental neurobiological processes with clinical relevance by examining recent pharmacological interventions, their mechanisms, and experimental validations. This approach provides valuable insights into targeted therapeutic strategies for optimizing neural recovery.
2. OVERVIEW OF ADAPTIVE PLASTICITY
Adaptive plasticity refers to the brain's ability to reorganize itself functionally and structurally in response to experiences, learning, or injury. This phenomenon is a subset of neuroplasticity, which encompasses both functional and structural changes that enable the brain to adapt to new information, recover from damage, and optimize performance. Functional neuroplasticity involves changes in neural network properties, such as shifting cognitive functions to homologous regions in the opposite hemisphere, expanding cortical maps through frequent stimulation, and enabling one sensory modality to compensate for another. Structural neuroplasticity involves physical changes, including dendritic remodeling and axonal sprouting, to establish new neural connections. Synaptic plasticity, which is crucial for learning and memory, includes long‐term potentiation (LTP), which strengthens synaptic connections, and long‐term depression (LTD), which weakens them. Adaptive plasticity plays a vital role in recovery from brain injuries, such as strokes or traumatic brain injuries, by enhancing synaptic connectivity, promoting structural changes, and facilitating recovery through cognitive rehabilitation techniques. Effective rehabilitation strategies capitalize on neuroplasticity through task‐specific training, cognitive exercises, and pharmacological interventions. Understanding adaptive plasticity not only advances neuroscience but also informs therapeutic approaches for individuals recovering from neurological impairments, offering promising avenues for improving recovery and enhancing quality of life. 6 , 7 , 8 A comprehensive understanding of the causes, mechanisms, and effects of ABI is crucial for prompt diagnosis, effective management, and the development of individualized rehabilitation strategies aimed at improving outcomes and restoring functionality.
Studying adaptive plasticity in ABI is critical for understanding recovery, rehabilitation, and brain function, as it reveals how the brain reorganizes itself following damage. After ABI, such as stroke or TBI, the brain initiates regenerative processes that can continue for weeks or months. 8 , 9 An initial neuroinflammatory response occurs, involving immune cells and central nervous system (CNS) cells like microglia and astrocytes. These cells respond to injury by clearing cellular debris and protecting neural tissue; however, prolonged inflammation may exacerbate secondary damage. Reactive astrocytes play a dual role: they form a glial scar that limits further damage and remodel the extracellular matrix (ECM) to support neuronal survival and regeneration. 6 , 8 , 9 , 10 , 11 Neurons near the injury site can exhibit axonal sprouting and form additional synaptic connections, which help restore functional circuits and compensate for lost functions. Although endogenous neurogenesis—the mobilization of neural stem cells (NSCs) to the injury site—is limited in the adult brain, these cells have the potential to contribute to recovery. However, their integration into existing neural circuits remains a significant challenge. 6 , 8 , 9 , 11 The brain compensates for damage through neural pathway reorganization, rerouting functions from injured areas to healthier regions via compensatory mechanisms. Rehabilitation techniques and targeted therapies enhance these adaptive changes, stimulating activity in specific brain regions and promoting functional recovery. 6 , 8 , 9 Understanding these processes not only provides insights into brain resilience but also informs the development of effective interventions to optimize recovery and improve outcomes for individuals with ABI.
3. MECHANISMS OF NEURAL PLASTICITY
3.1. Neurogenesis and synaptogenesis
Neurogenesis, the process of generating new neurons from neural stem or progenitor cells, occurs predominantly in specific brain regions such as the hippocampus. This process is crucial for maintaining cognitive flexibility, supporting memory formation, and enhancing resilience against stress‐related disorders. It is regulated by multiple factors, including growth molecules, environmental stimuli, and physiological conditions. Among these, brain‐derived neurotrophic factor (BDNF) stands out as a key neurotrophin that orchestrates both the formation of new neurons and the growth of dendritic structures essential for neuronal communication. 12 , 13 A more detailed discussion of BDNF can be found in the Section 5 titled “Neurobiological Processes Facilitating Recovery.”
Synaptogenesis, the formation of new synapses between neurons, is fundamental to establishing and strengthening communication pathways in the brain. This dynamic process is driven by a combination of environmental stimuli, learning experiences, and molecular mechanisms that fine‐tune neural circuits for optimal function. It plays a critical role in cognitive processes such as learning, memory, and adaptive behavior. 12
Mechanisms of experience‐driven synaptogenesis are crucial for shaping neural circuits. Environmental enrichment, for example, significantly promotes synaptic growth. Studies indicate that animals raised in enriched environments show increased dendritic branching and higher synapse density compared to those in standard or isolated conditions, with enriched environments leading to a 20%–25% increase in synapse number per neuron in the visual cortex. Similarly, engaging in learning tasks, such as motor skill training, directly stimulates synapse formation. Research demonstrates that animals trained on specific tasks develop significantly more synapses in relevant brain regions, highlighting that the learning process itself, rather than physical activity alone, drives synaptogenesis. Notably, the changes induced by learning are long‐lasting, persisting even after exposure to less stimulating environments. 14 , 15
Cognitive activities directly influence synaptogenesis through processes like LTP and LTD, which modulate synaptic strength. LTP strengthens synaptic connections through repeated stimulation, whereas LTD weakens them to allow for plasticity and refinement. 16 , 17 , 18 The insertion and removal of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptors (AMPARs) at the synapse are central to these mechanisms. AMPARs are critical ion channel proteins that play a fundamental role in neurological function. During LTP, additional AMPARs are recruited to the postsynaptic membrane, enhancing synaptic efficacy. Conversely, LTD involves the removal of these receptors, reducing synaptic strength. This activity‐dependent regulation of AMPA receptor trafficking is vital for maintaining a balance between synaptic strengthening and pruning, essential for learning and memory. 17 , 18 , 19
During synaptogenesis, both presynaptic and postsynaptic neurons undergo functional changes. The presynaptic neuron becomes more proficient at releasing neurotransmitters, thereby strengthening synaptic connections and enhancing inter‐neuronal communication. Upon activation, the presynaptic neuron releases neurotransmitters stored in vesicles into the synaptic cleft, converting electrical signals into chemical signals that can be detected by the postsynaptic neuron. The postsynaptic response is further enhanced through an increase in receptor availability or heightened receptor sensitivity, often via processes such as LTP. LTP strengthens synaptic connections by promoting receptor phosphorylation and increasing receptor density on the postsynaptic membrane. 20 , 21
Synaptogenesis involves the growth of dendritic spines, small protrusions on dendrites where synapses form. Neural activity stimulates spine growth, expanding the surface area for synaptic connections by generating new spines and enlarging existing ones. This process requires interactions between presynaptic and postsynaptic components, including scaffold proteins and cell adhesion molecules (CAMs), which stabilize the synaptic structure. Synaptic pruning further refines neural circuits by eliminating inefficient or inactive synapses. Dendritic spines enhance neuronal communication by increasing the surface area for synaptic inputs. As spines grow, they accommodate more postsynaptic receptors, such as AMPARs and NMDARs, improving the neuron's response to neurotransmitters and strengthening synaptic transmission. Larger spines with more receptors also integrate multiple inputs more effectively, supporting complex brain functions. Structural changes in spines are linked to enhanced synaptic strength. During LTP, spines enlarge, increasing their receptor density and improving postsynaptic responses. Dendritic spines also act as independent compartments, concentrating signaling molecules like calcium ions, which strengthen synapses locally. Experience‐dependent plasticity, crucial for learning, induces changes in spine density and morphology, promoting cognitive function. Learning tasks lead to the formation of new spines and the enlargement of existing ones, stabilizing synapses through cytoskeletal reorganization and gene expression. Finally, dendritic spines mature from thin, motile structures to stable forms, increasing neurotransmitter receptors and scaffold proteins, which enhances synaptic stability. Learning experiences also promote clustering of spines along dendrites, improving signal processing and computational efficiency. 22 , 23 , 24 , 25
Dendritic remodeling is a vital process in recovery after ABI, such as TBI or stroke. This process involves structural and functional changes in dendritic spines, the small protrusions on neurons where synapses form, facilitating synaptic communication. 26 , 27 Dendritic spine remodeling specifically refers to the dynamic reorganization of these structures, enabling the nervous system to adapt to injury and restore disrupted functions. Following brain injury, the formation of new dendritic spines, known as spinogenesis, increases, typically peaking within one to two weeks and persisting for several weeks. This spinogenesis is crucial for re‐establishing lost synaptic connections. During this phase, dendritic filopodia, precursors to mature spines, play a key role by exploring the local synaptic environment and initiating contact with presynaptic axons. These contacts often stabilize into functional spines, fostering the formation of new synaptic connections and aiding neuronal adaptation to altered connectivity. 9 , 28
Molecular modulators such as matrix metalloproteinase‐9 (MMP‐9) and neurotransmitter signaling play a central role in dendritic spine remodeling. MMP‐9, an enzyme involved in regulating spine density and morphology, exhibits a dual role; its heightened activity after TBI can initially cause spine shrinkage but later support recovery and remodeling. Neurotransmitter release from presynaptic axons promotes the formation and stabilization of spines, emphasizing the critical role of synaptic activity in this process. 28 , 29 Inflammatory responses also influence dendritic plasticity, with inflammation induced by surgical or traumatic interventions temporarily increasing spine turnover rates, creating a favorable environment for remodeling. However, prolonged or chronic inflammation can result in maladaptive changes, underscoring the need for a balanced inflammatory response during recovery. 28
Behavioral experiences and rehabilitation play a significant role in dendritic remodeling through experience‐dependent plasticity. Engaging in specific tasks and rehabilitation programs stimulates structural changes in dendrites, increasing the formation and stabilization of spines and reorganizing neural circuits to compensate for lost functions. This process is closely tied to LTP, which strengthens synaptic connections and supports learning and memory. Motor learning tasks, for instance, can induce the rapid formation of new dendritic spines within hours, with practice stabilizing these changes to support functional recovery. These dynamics highlight the importance of dendritic remodeling in neural adaptation and the efficacy of targeted rehabilitation in promoting recovery. 9
Dendritic spine remodeling is a key process in recovery from brain injuries and neurological conditions, driving neuroplasticity to establish new synaptic connections. This remodeling is particularly significant in conditions such as stroke, where increased spine formation in peri‐infarct regions contributes to functional recovery. Conversely, maladaptive remodeling, as seen in diabetic neuropathic pain, can result in chronic dysfunction. Emerging targeted therapies, such as inhibitors of signaling pathways like Ras‐related C3 botulinum toxin substrate 1 (Rac1), hold promise for correcting these pathological changes. Rehabilitation strategies designed to enhance neural plasticity play a crucial role in promoting adaptive spine remodeling, thereby improving recovery outcomes. Dendritic spine dynamics also underpin cognitive processes like memory and learning, with disruptions in remodeling adversely affecting these functions. Supporting healthy dendritic spine remodeling is therefore essential not only for functional recovery but also for preserving and restoring cognitive abilities, highlighting its potential for transformative clinical applications 28 , 30 , 31 , 32 (Figure 1).
Figure 1.
Neurogenesis and synaptogenesis. Neurogenesis, the process of generating new neurons from neural stem cells (NSCs) and progenitor cells, is crucial during embryonic development and continues in specific brain regions, such as the hippocampus, into adulthood. This process is modulated by various factors, including physical exercise, environmental stimuli and growth factors like insulin‐like growth factor 1, which promotes NSCs proliferation and their differentiation into neurons and glial cells. Synaptogenesis, the formation of synapses between neurons, occurs predominantly during early brain development but persists throughout life as a critical aspect of neuroplasticity. This process facilitates neuronal communication, playing a fundamental role in learning, memory, and recovery from brain injuries. 33 Neurotropic factors such as brain‐derived neurotrophic factor (BDNF) is crucial for neurogenesis in the hippocampus, promoting neural progenitor cell differentiation, dendritic morphogenesis, and synaptic plasticity. Its absence impairs connectivity without significantly reducing neuron numbers. BDNF supports NSCs survival by activating protective pathways and inhibiting apoptosis. It enhances synaptogenesis, glutamate release, α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA), and N‐methyl‐d‐aspartate (NMDA) receptor activity, key for memory formation. Additionally, BDNF increases dendritic spine complexity, stabilizes synapses, and promotes synaptic plasticity by upregulating cell adhesion molecules (CAMs) like the neural cell adhesion molecule (NCAM), cadherins, and integrins. 34 , 35 , 36 , 37
3.2. Understanding axonal sprouting in neural recovery
Axonal sprouting is the process by which nerve fibers, or axons, develop new branches or connections, often as a response to injury or disease. This phenomenon is a vital component of neural plasticity, allowing the nervous system to adapt and recover from damage. 38 , 39 Two main types of sprouting are recognized—collateral sprouting and regenerative sprouting. Collateral sprouting occurs when intact axons generate new branches to innervate denervated target areas after nearby axons are damaged, a process commonly observed in the peripheral nervous system (PNS) that can partially restore function even before severed fibers regenerate, however, it may also occur in CNS. 38 , 40 , 41 Regenerative sprouting, in contrast, involves injured axons attempting to reconnect with their original targets or establish new connections. While more prevalent in the PNS, regenerative sprouting can also occur in the CNS under specific conditions. 38 , 41
Axonal sprouting can also be categorized as—reactive, reparative, and unbounded axonal sprouting. Reactive axonal sprouting occurs in response to local injury, where axons extend new branches into areas surrounding the damaged tissue. This automatic response helps restore function by establishing new synaptic connections within the perilesional cortex. In contrast, reparative axonal sprouting involves the development of longer‐distance connections that integrate functionally related brain areas. This form of sprouting can be enhanced by inhibiting suppressive signals or introducing growth‐promoting factors, thereby supporting more substantial functional recovery. Unbounded axonal sprouting represents a more extensive but less organized process, often leading to less effective connections. 42 , 43 The impact of axonal sprouting on functional recovery is well‐established. Research indicates that sprouting within peri‐infarct regions is closely associated with improved motor function following ABI. In animal models, axonal sprouting near infarction sites correlates with motor recovery after stroke. Behavioral interventions post‐injury can further influence the extent and pattern of sprouting, underscoring the importance of rehabilitation in enhancing neural plasticity and optimizing recovery outcomes. 9 , 42 Molecular mechanisms underpinning axonal sprouting include substances like inosine, which promote axon outgrowth and functional recovery by activating specific neuronal signaling pathways. The interplay between excitatory and inhibitory signals also plays a pivotal role. For instance, reduced gamma‐aminobutyric acid (GABAergic) signaling increases neuronal excitability, facilitating axonal remodeling and aiding recovery. These insights provide critical targets for developing therapeutic strategies to enhance axonal sprouting and promote functional restoration. 9 , 43
Several biological factors regulate axonal sprouting. Growth‐promoting molecules, such as growth differentiation factor‐10 and alpha‐thalassemia mental retardation X‐linked, are essential for enhancing axonal growth and sprouting following neural injuries like stroke. These molecules activate a growth program within neurons, improving their ability to establish new connections. In contrast, inhibitory molecules, including Nogo receptor 1 and Ephrin‐A5, suppress axonal growth, and their blockade has been shown to facilitate sprouting and improve recovery outcomes. Age significantly influences the capacity for axonal sprouting, as molecular changes in the neuronal environment over time reduce the ability to respond effectively to injury. 38 , 39 , 44
The clinical implications of axonal sprouting are substantial. In disorders such as amyotrophic lateral sclerosis, compensatory motor axon sprouting occurs but is often insufficient to halt disease progression. Enhancing this process pharmacologically could slow symptom progression and extend muscle function preservation. Similarly, after a stroke, axonal sprouting near the infarct site is strongly linked to motor function recovery, and therapeutic strategies targeting this process offer promising avenues for improving rehabilitation outcomes in stroke patients 38 , 39 , 44 (Figure 2).
Figure 2.
Axonal sprouting. Axonal sprouting is a critical neurobiological process in which intact neurons extend new axons to reinnervate denervated target cells, promoting functional recovery following neural injuries. This process encompasses two primary forms: collateral sprouting and regenerative sprouting. Collateral sprouting occurs when uninjured neurons extend new branches into denervated regions, influenced by factors such as the Wallerian degeneration environment and the upregulation of sprouting‐associated genes, thereby enabling functional compensation without direct involvement of the injured neuron. In contrast, regenerative sprouting involves axon growth from the transected stump or proximal regions of the injured neuron, aiming to reconnect with original targets via intrinsic and extrinsic growth‐related pathways; however, this is often constrained in the central nervous system (CNS) by inhibitory myelin‐associated proteins. 38 , 40 , 41 Glial cells, particularly microglia, play an essential role in facilitating axonal sprouting after CNS injuries by phagocytosing myelin debris and damaged tissue, thereby clearing inhibitory molecules, modulating local inflammation, and restoring tissue homeostasis to create a permissive environment for axonal outgrowth and guiding sprouting fibers toward viable targets. 45 , 46 PNS, peripheral nervous system.
3.3. Changes in synaptic strength (LTP and LTD)
LTP and LTD are fundamental synaptic processes that exemplify the ability of synapses to strengthen or weaken over time. These mechanisms are critical for learning and memory, enabling dynamic adjustments in synaptic efficacy in response to neuronal activity. LTP is characterized by a persistent increase in synaptic strength following high‐frequency stimulation of a synapse. First observed in the hippocampus, LTP involves repeated synaptic activation that enhances synaptic transmission. The underlying mechanisms include calcium influx, AMPA receptor trafficking, and protein kinase activation. 47 , 48 , 49
The initiation of LTP is heavily dependent on NMDARs activation, a key subtype of glutamate receptors. During high‐frequency stimulation, glutamate released from the presynaptic neuron binds to NMDARs and AMPARs on the postsynaptic membrane. AMPA receptor activation permits sodium influx, causing depolarization. This depolarization removes the magnesium block from NMDARs, allowing calcium ions (Ca²⁺) to enter the postsynaptic neuron and initiate intracellular signaling critical for LTP. 47 , 48 , 50 Calcium influx serves as a second messenger, activating calmodulin‐dependent protein kinase II (CaMKII). Activated CaMKII phosphorylates proteins involved in AMPA receptor trafficking, increasing their insertion into the synapse. This enhances the postsynaptic neuron's sensitivity to glutamate and strengthens synaptic transmission. These changes, lasting minutes to hours, represent early‐phase LTP. 47 , 48 , 51 , 52 Protein kinase activation underpins both immediate and sustained changes in synaptic efficacy. CaMKII plays a central role by promoting AMPA receptor insertion and structural synaptic modifications. Additionally, mitogen‐activated protein kinases (MAPKs) are involved in late‐phase LTP, regulating gene expression necessary for the synthesis of proteins that maintain LTP over hours to days. The late phase of LTP requires transcription factors such as cyclic adenosine monophosphate (cAMP) response element‐binding protein (CREB), which is activated by calcium‐dependent kinase signaling. CREB‐mediated gene expression drives structural and functional synaptic changes essential for consolidating long‐term memory. 47 , 48 , 51 , 52 , 53
LTD is a process that results in a sustained decrease in synaptic strength, playing a crucial role in synaptic plasticity, learning, and memory. This mechanism is primarily governed by calcium signaling, AMPA receptor endocytosis, and distinctions between homosynaptic and heterosynaptic LTD. 47 , 48 , 49 , 50 Ca²⁺ are central to the induction of LTD. The process typically begins with a transient rise in postsynaptic calcium concentration. Unlike LTP, which requires high‐frequency stimulation and substantial calcium influx, LTD is typically induced by low‐frequency stimulation or prolonged, low‐intensity stimuli. Calcium enters the postsynaptic neuron primarily through NMDARs, but the magnitude and temporal pattern of calcium elevation are critical in determining whether synaptic plasticity leads to potentiation or depression. Sustained low‐frequency stimulation results in a modest yet prolonged increase in intracellular calcium, favoring the induction of LTD. 49 , 54 , 55
A major mechanism underlying LTD is the endocytosis of AMPARs from the postsynaptic membrane. Following LTD induction, AMPARs are internalized via clathrin‐mediated endocytosis, decreasing the number of functional receptors at the synapse and thereby reducing synaptic efficacy. This receptor internalization is regulated by calcium‐dependent signaling pathways. For example, protein phosphatases such as calcineurin, activated by elevated calcium levels, mediate AMPAR endocytosis. The removal of AMPARs not only diminishes synaptic strength but also alters synaptic architecture, potentially reshaping synaptic responses to future stimuli. 55 , 56 , 57 LTD can be categorized into two types based on spatial specificity– homosynaptic LTD and heterosynaptic LTD. Homosynaptic LTD occurs at the synapse directly activated by low‐frequency stimulation, leading to a localized decrease in synaptic strength through AMPAR internalization at that specific synapse. In contrast, heterosynaptic LTD affects neighboring, unstimulated synapses. This broader reduction in synaptic strength may involve modulatory signals or the action of interneurons, leading to a widespread decrease in synaptic efficacy across interconnected pathways. 47 , 48 , 49 , 56 , 58
The interplay between LTP and LTD is fundamental to synaptic plasticity, facilitating the activity‐dependent strengthening or weakening of synaptic connections. This dynamic is primarily governed by calcium signaling and distinct downstream pathways. High calcium levels, resulting from high‐frequency stimulation, promote LTP by activating protein kinases such as CaMKII, which enhance AMPA receptor insertion into the postsynaptic membrane, thereby increasing synaptic efficacy. In contrast, lower calcium levels, typically triggered by low‐frequency stimulation, induce LTD through the activation of protein phosphatases and AMPA receptor endocytosis, leading to a reduction in synaptic strength. Both processes are input‐specific, enabling precise neural tuning at individual synapses. The balance between LTP and LTD prevents circuit saturation, maintaining neural homeostasis while supporting learning, memory formation, and adaptability. The dynamic reversibility of these processes—where synapses can transition between potentiation and depression in response to changes in neuronal activity—underscores the brain's remarkable flexibility. This balance has significant clinical implications. For instance, in conditions such as depression, therapeutic interventions like electroconvulsive therapy (ECT) may leverage LTD‐like mechanisms to restore synaptic equilibrium, highlighting the relevance of these processes to neuroplasticity‐based treatments. 47 , 48 , 49 , 59
Metaplasticity is a higher‐order form of synaptic plasticity that involves activity‐dependent changes in neural functions, influencing future synaptic plasticity. Often called the “plasticity of synaptic plasticity”, it refers to alterations in the physiological or biochemical state of neurons or synapses, which impact their ability to generate plasticity. Metaplasticity regulates key processes like LTP and LTD, affecting how subsequent plasticity is induced. This process is triggered by synaptic or cellular activity and depends on the synapse's prior activity history. It allows synapses to integrate relevant signals over time. By adjusting the thresholds for LTP and LTD, metaplasticity keeps synaptic strengths within a functional range, preventing both overactivation and underactivation of postsynaptic cells. NMDARs are central to metaplasticity, controlling how AMPA and NMDARs are rearranged. Some evidence suggests that G protein‐coupled receptors modulate NMDARs activity, influencing synaptic strength through NMDARs mechanisms. Unlike conventional neuromodulation, where molecules present during plasticity induction regulate LTP or LTD, metaplasticity involves changes in neurons triggered by “priming” activity at a specific time. Metaplasticity helps integrate responses across spaced episodes of synaptic activity, maintaining synapses within a dynamic range, and preparing neuronal networks to encode specific information. 60 , 61 , 62
3.4. Genetic and epigenetic regulation of neural plasticity
Epigenetic mechanisms, including DNA methylation, histone modifications, and noncoding RNAs, dynamically regulate gene expression and play a crucial role in neural plasticity. They influence synaptic connectivity, neurogenesis, and adaptive responses to environmental stimuli. 63 , 64 , 65
DNA methylation, a key epigenetic mark, affects synaptic plasticity by regulating activity‐dependent gene expression in neurons. Synaptic signals influence promoter methylation in neuronal nuclei, impacting gene expression. The regulation of de novo DNA methyltransferase DNMT3A1 in neurons is controlled by the activation of NMDARs containing the GluN2A subunit. Synaptic NMDARs promote DNMT3A1 degradation through a neddylation‐dependent process. Inhibiting neddylation disrupts this degradation, leading to deficits in promoter methylation of activity‐dependent genes, ultimately impairing synaptic plasticity and memory formation. Additionally, synaptic activity itself induces DNA methylation changes, as seen in tetanic stimulation, which alters methylation patterns and phosphorylates methyl‐CpG‐binding protein 2. The methylation of the reelin (RLN) gene is particularly critical for synaptic plasticity and memory formation, while sleep deprivation has been shown to modify DNA methylation in genes related to neuritogenesis and synaptic plasticity. Furthermore, synaptic transmission in inhibitory interneurons is regulated by DNA methylation‐dependent control of endocytosis. 64 , 65 , 66 , 67
Histone modifications—such as acetylation, methylation, phosphorylation, and ubiquitination—shape synaptic plasticity by altering chromatin structure and regulating gene expression. These modifications influence the affinity of histones for gene promoters, either activating or repressing transcription and modulating neuroplasticity. Histone acetylation and deacetylation regulate synaptic connectivity and memory‐related gene expression, while histone methylation plays a crucial role in neurogenesis by determining neural lineage specification and neuronal differentiation. Additionally, histone modifications influence BDNF gene expression, which is essential for synaptic plasticity, cognition, and memory functions. Histone deacetylase (HDAC) inhibitors can enhance BDNF transcription by increasing the acetylation of RNA polymerase II and histone H4 at the BDNF promoter. Moreover, histone variants such as H2AZ and H3.3 contribute to plasticity regulation, with neuronal activation inducing H3.3 expression to support dendritic spine density and memory formation. 68 , 69 , 70 , 71 , 72 Histone modifications regulate synaptic plasticity, particularly LTP and LTD, key mechanisms in learning and memory. These modifications reshape chromatin, aiding excitatory synapse formation and hippocampal‐dependent memory. Histone acetylation is linked to LTP, with increased H3 and H4 acetylation during LTP induction. Inhibition of suppressor of variegation 3–9 homologue 1 (SUV39H1) reduces H3K9me3, boosting BDNF expression and enhancing synaptic plasticity. HDACs, such as HDAC1, HDAC2, HDAC3, and HDAC4, are found at neuroplasticity‐related gene promoters, while impairment of histone acetyltransferase (HAT) CREB‐binding protein (CBP) disrupts LTP by reducing H2B acetylation. Histone modifications also regulate BDNF expression, which is crucial for synaptic plasticity and memory consolidation. Acetylation and methylation influence dendritic spine morphology and density. CBP, a HAT, strengthens synapses by acetylating histones, promoting long‐term synaptic plasticity. FMRFamide, a neuropeptide, recruits HDAC5, decreasing histone acetylation and shifting plasticity toward LTD by suppressing CCAAT/enhancer‐binding protein (C/EBP) gene expression. Altered LTP‐like plasticity is associated with increased depressive symptoms and stress. LTP, a sustained increase in excitatory synaptic transmission, underlies memory and learning. 68 , 73 , 74
Noncoding RNAs, particularly microRNAs (miRNAs), play a crucial role in regulating gene expression by targeting mRNAs, thereby influencing synaptic transmission, neurogenesis, and cognitive functions. These epigenetic mechanisms allow the brain to undergo structural and functional reorganization in response to environmental stimuli and experiences. Disruptions in miRNA regulation have been linked to neurodegenerative and neuropsychiatric disorders, highlighting their essential role in maintaining brain health. These are small, noncoding RNAs about 22 nucleotides long that regulate synaptic plasticity by modulating gene expression within synaptic compartments. They control gene expression at the posttranscriptional level by directing mRNA degradation and inhibiting translation, thereby coordinating a wide range of physiological and pathological signaling pathways. Specific miRNAs are involved in synapse formation, structural remodeling, and functional modifications critical for synaptic plasticity. Research has shown that miRNAs influence plasticity‐related proteins within the postsynaptic density, thereby shaping synaptic function. For example, miRNA‐132 interacts with fragile X mental retardation protein to regulate synaptic plasticity by controlling mRNA translation and protein synthesis at the synapse. Additionally, miRNA‐132 and miRNA‐125b contribute to the regulation of dendritic spine morphology, further refining synaptic connectivity. Neuronal activity dynamically influences miRNA expression, affecting their role in synaptic modifications. Dysregulated miRNA expression has been associated with pathological conditions such as chronic pain, where long‐term gene expression changes contribute to maladaptive plasticity. For instance, miR‐134 modulates dendritic spine size by negatively regulating LIM kinase 1 (LIMK1) in an activity‐dependent manner. Meanwhile, miR‐132 plays a key role in experience‐dependent plasticity, where its expression levels determine dendritic spine stability. Beyond synaptic regulation, miRNAs are essential for higher‐order brain functions, including cognition and mood regulation. Their ability to fine‐tune gene expression within neuronal circuits underscores their significance in brain homeostasis and their potential as therapeutic targets for neurological disorders. 75 , 76 , 77 , 78
3.5. Molecular signaling pathways in neurogenesis
Adult neurogenesis, the process of generating new neurons in the adult brain, is carefully regulated by various molecular signaling pathways. These pathways involve complex interactions between internal and external factors, such as growth factors, neurotransmitters, and genes, which together influence the proliferation, differentiation, migration, and integration of NSCs and neuroblasts. Among the key regulators, the wingless‐related integration site (Wnt) signaling pathway plays an important role in hippocampal neurogenesis, especially in the adult brain. NSCs in the adult hippocampus express multiple Wnt proteins and their corresponding receptors. Wnt signaling impacts NSC proliferation and differentiation during early development. In particular, autocrine signaling through the canonical Wnt pathway promotes NSC proliferation and maintains their multipotency by involving glycogen synthase kinase 3β (GSK3β) and β‐catenin. Canonical Wnt/β‐catenin signaling specifically regulates NSC proliferation and fate commitment, while noncanonical Wnt signaling contributes to the differentiation and development of new neurons. Notably, activation of the Wnt/β‐catenin pathway boosts the expression of NeuroD1, a critical factor that supports neuronal differentiation in NSCs. 79 , 80 , 81
Notch signaling is crucial for neurogenesis as it regulates the proliferation, survival, self‐renewal, and differentiation of NSCs. It plays a key role in stem cell activity and maintenance in the nervous system. In the developing brain, Notch signaling is essential for maintaining neural progenitor cells (NPCs). Activating this pathway keeps NPCs in a proliferating state, while mutations that affect key components of the pathway can cause premature neuronal differentiation and depletion of NPCs. Additionally, Notch signaling helps regulate cell fate decisions by controlling NSC self‐renewal and the specification of cell fate. It prevents premature differentiation of progenitor cells (P2 cells) into neurons and, once differentiation signals begin, directs glial precursors toward developing into astrocytes. Notch signaling also influences neurite outgrowth, which is important for structural and functional plasticity involved in processes like learning and memory. When Notch signaling is activated, neurite outgrowth is inhibited or retracted, while inhibiting Notch‐1 signaling promotes neurite extension. Furthermore, Notch signaling controls the cell cycle, particularly at the G1/S transition, to regulate cell fate identity and differentiation. Lastly, Notch signaling is necessary for determining oligodendrocyte fate, but excessive Notch signaling can prevent oligodendrogenesis and maintain progenitor cells in an undifferentiated state. 81 , 82 , 83 , 84
The Notch signaling pathway works in coordination with Wnt/β‐catenin, bone morphogenetic proteins (BMPs), and sonic hedgehog (Shh) signaling pathways to regulate stem cell behavior in the hippocampal region. These signaling cascades influence the plasticity of NSCs and NPCs, playing a key role in neurogenesis. BMPs are essential regulators of stem cells in both the central and PNSs, helping establish tissue structure and influencing neural development at various stages. BMP signaling not only affects the maturation and fate of NSCs but also helps maintain the balance between NSC proliferation and quiescence during the postnatal period and adulthood. Moreover, BMPs regulate the stem‐cell niche in the dentate gyrus (DG) and interact with other signaling pathways, including fibroblast growth factor (FGF), cytokines, Notch, Shh, and Wnt, to control neural differentiation. 81 , 85 , 86 , 87 , 88
Shh signaling, a critical player in development, is essential for maintaining stem cell lineages and neurogenesis in the postnatal and adult brain. Shh regulates the self‐renewal of neurosphere‐forming stem cells and promotes the proliferation of subventricular zone lineages by acting as a mitogen in collaboration with epidermal growth factor. Additionally, Shh and BMP signaling work together to preserve cells with stem cell properties. BMP‐2 modulates the proliferative effects of Shh signaling by phosphorylating Smad5, which initiates differentiation and helps cells exit the cell cycle. 81 , 85 , 87 , 89
4. FACTORS INFLUENCING ADAPTIVE PLASTICITY POST‐ABI
4.1. Injury type and severity
The nature and severity of brain injury significantly influence the extent and pattern of neuroplastic changes, with injuries such as TBI or stroke triggering distinct adaptive responses. Severe injuries often lead to pronounced neuronal remodeling, including axonal sprouting and dendritic restructuring, which support compensatory mechanisms crucial for recovery. However, these changes can become maladaptive if alternative pathways are overly relied upon, potentially disrupting neural network functionality. 8 , 9 Most studies on neural remodeling after TBI are conducted in animal models, with only a few focused on the human brain. One such study shows that the human motor cortex network, particularly the interaction between the supplementary motor area (SMA) and the primary motor cortex (M1), displays sophisticated neuronal plasticity that depends on precise stimulation timing. The amplitude of the motor evoked potential varies based on the timing between SMA and M1 stimulation: it increases when SMA stimulation occurs 6 ms before M1, but decreases when SMA stimulation lags behind M1 by 15 ms. This bidirectional associative plasticity requires highly specific and temporally coordinated neuronal interactions. The research provides evidence of system‐level adaptability in brain networks, bridging our understanding of cellular and network‐level plasticity, and offering potential insights for neurological rehabilitation. These findings have wide applications, including advancing our understanding of brain network dynamics, developing targeted neurological interventions, and exploring the mechanisms of neural communication and learning. 90
Mild TBIs typically cause transient disruptions with a higher potential for recovery through neuroplasticity. In contrast, moderate to severe injuries often result in long‐term neurodegenerative changes that diminish the brain's ability to repair itself. Traumatic injuries are characterized by immediate mechanical damage and secondary effects such as inflammation and oxidative stress, which can impair recovery. On the other hand, acquired injuries like stroke may initiate different adaptive responses, influenced by ischemia and reperfusion dynamics. 91 , 92 The location of the injury is also critical, as certain brain regions, such as the hippocampus and motor cortex, exhibit greater receptivity to plastic changes. This receptivity influences recovery dynamics and functional outcomes. 9 , 93 Additionally, the role of neuroinflammation is dual‐faceted– while acute inflammation helps clear debris and initiate repair processes, excessive or chronic inflammation, mediated by reactive microglia and astrocytes, can release pro‐inflammatory cytokines that exacerbate tissue damage and inhibit axonal regeneration. This complex interplay between injury severity, inflammation, and neuroplasticity underscores the challenges in managing brain injuries. Therapeutic strategies must balance promoting adaptive plasticity while mitigating maladaptive changes and chronic inflammatory responses to optimize recovery. 91 , 92
4.2. Age and developmental stage
Neuroplasticity, the brain's ability to adapt and reorganize, changes significantly across the lifespan. Age and developmental stage are crucial factors influencing the brain's capacity to adapt, particularly following an ABI. Neuroplasticity varies across different life stages, which has profound implications for recovery and rehabilitation strategies. While younger individuals generally exhibit greater plasticity, often referred to as the “young age plasticity privilege”, older adults rely on compensatory mechanisms to maintain cognitive function. 94 Although plasticity declines with aging, it does not stop entirely, as new neurons can still be generated throughout life. 95 , 96 , 97
One of the key differences between younger and older individuals is the pattern of brain activation and neural recruitment. Younger individuals demonstrate more pronounced neuroplastic changes, such as functional reorganization and synaptic strengthening, allowing for more effective compensation for lost functions. In contrast, older adults tend to over‐recruit additional brain regions during cognitive tasks, likely as a compensatory response to age‐related decline. However, this compensation is not always effective, as older individuals may experience maladaptive plasticity, where neural adaptations fail to restore function and may even exacerbate deficits. 94 , 98
Older adults also exhibit reduced gray matter volume and increased functional connectivity between certain brain areas, which suggests an adaptive mechanism to counteract structural and functional deterioration. This decline is linked to structural changes such as diminished synaptic connections, neuronal loss, and atrophy, particularly in regions crucial for memory and learning, like the hippocampus. 98 The timing of brain injury relative to developmental stages further influences neuroplasticity. Certain critical periods of heightened plasticity offer better recovery prospects, but early injuries do not always guarantee optimal outcomes, as factors like injury type, location, and overall health play a role. 94
Several theories attempt to explain how neuroplasticity changes with aging. The compensation hypothesis suggests that older adults engage alternative neural pathways to maintain cognitive function. As neural efficiency declines, the brain compensates by recruiting additional networks to sustain performance. This compensation can occur through two primary mechanisms: adjusting for internal neural decline and adapting to degraded input from other brain regions. 99 , 100 In contrast, the dedifferentiation hypothesis presents a less optimistic perspective, arguing that the spread of neural activity in older brains is not always beneficial. According to this theory, age‐related changes in the brain lead to a general loss of neural specialization due to deficits in neurotransmission, a reduced signal‐to‐noise ratio in neural firing, and inefficient neural representations. 99 , 100 The compensation‐related utilization of neural circuits hypothesis further explains these recruitment patterns by proposing that older adults reach their cognitive and neural resource limits at lower task difficulties. Initially, they show increased brain activation to compensate for decline, but as task complexity increases, neural recruitment becomes less efficient. 101
While much of the focus on neuroplasticity has been on cortical regions, recent research suggests that white matter plasticity in older adults may be greater than previously believed. Studies indicate that older adults undergo significant white matter changes during learning, which may help compensate for reduced cortical processing. In contrast, younger individuals primarily exhibit neuroplasticity in cortical areas, reflecting more efficient learning and adaptation mechanisms. 102
At a cellular level, aging affects synaptic function, neurogenesis, and neurochemical regulation. Older brains experience reduced synaptic efficacy and a diminished ability to perform LTP, which is essential for learning and memory. Additionally, neurogenesis in the hippocampus declines with age. While younger brains undergo neurogenesis in four distinct phases—proliferation, migration, differentiation, and maturation—older brains show reduced precursor cell activity, increased apoptosis, and lower neuroblast survival rates. 96 , 103 Neurochemical changes also contribute to age‐related differences in plasticity. Levels of BDNF, a crucial factor for neuronal growth and survival, decrease with aging. Additionally, neurotrophin interactions and inflammatory cytokine responses become altered, further affecting neural plasticity. 96 A detailed overview of the role of neurotrophic factors and neuroinflammation in neurogenesis refer to Section 5, “Neurobiological Processes Facilitating Recovery”.
Despite these challenges, older brains demonstrate remarkable adaptation strategies. They compensate for reduced plasticity by over‐recruiting additional brain regions, engaging in cross‐modal neural reassignment, and reorganizing functional connectivity. However, the balance between neuroplasticity and homeostasis is critical throughout the lifespan. While younger individuals benefit from adaptive changes, older individuals face challenges in maintaining neural stability and functional integrity. 94 , 98
These findings challenge the traditional belief that neuroplasticity peaks in youth and steadily declines with age. Instead, they suggest that the aging brain remains dynamic, continuously adapting through different mechanisms. This underscores the importance of lifelong learning and cognitive engagement, which can help maintain brain function, mitigate age‐related decline, and promote long‐term cognitive resilience.
4.3. Neuroinflammation and glial cell activation
Neuroinflammation and glial cell activation are critical processes that influence recovery and adaptive plasticity following ABI. Early neuroinflammation facilitates debris clearance and repair mechanisms, whereas prolonged activation often contributes to secondary injury and chronic neurodegeneration. In response to ABI, damage‐associated molecular patterns released by injured cells initiate an inflammatory cascade, activating microglia and recruiting peripheral immune cells. Pro‐inflammatory cytokines, such as IL‐1β and TNF‐α, initially support neuronal survival and synaptic plasticity. However, excessive and sustained inflammation disrupts neurotransmitter homeostasis and hampers recovery. 104 , 105 , 106
Targeting glial scars in acquired brain injuries requires a nuanced approach, as these scars serve both protective and inhibitory roles in neurological recovery. In the acute phase, glial scars help contain neural damage, prevent the spread of inflammation, neutralize reactive oxygen species, and protect surrounding healthy tissue. 107 , 108 , 109 , 110 , 111 However, in the chronic phase, they become a barrier to recovery by blocking axonal regrowth, producing inhibitory factors that limit neural regeneration, and contributing to persistent neurological deficits. 109 , 111 , 112
Current research focuses on pharmacological and cellular strategies to modulate glial scar formation while preserving its protective functions. Pharmacological approaches include microtubule‐stabilizing agents like taxol, collagen synthesis inhibitors, iron chelators to reduce fibrotic scarring, and targeted modulation of molecular pathways such as MEK/extracellular regulated protein kinases (ERK) and integrin signaling. Cellular strategies involve NSC transplantation, endogenous cell reprogramming, selective modulation of NG2‐oligodendrocyte progenitor cells, and controlled reduction of scar density while maintaining structural integrity. 107 , 109 , 111 , 112 , 113 , 114 , 115
The success of glial scar modulation depends on factors such as injury severity, timing of intervention, and brain region specificity. Since complete scar elimination may increase tissue vulnerability, researchers emphasize the need for a balanced approach—preserving the scar's initial protective functions while minimizing its long‐term inhibitory effects. Future advancements in targeted therapies will focus on optimizing this balance to enhance neurological recovery. 108 , 109 , 112
The glial scar plays a complex role in ABI recovery, acting as both a protective barrier and an obstacle to regeneration. In the early stages, it serves as a damage‐containment mechanism, preventing the spread of cellular injury and inflammatory mediators to surrounding healthy tissue. Additionally, it helps restore the physical and chemical integrity of the CNS, supports revascularization to ensure metabolic and nutritional supply, and seals the boundary between nervous and non‐nervous tissue. 107 , 111 , 114 , 116
Despite these protective functions, the glial scar also poses significant challenges to neural regeneration. It forms a dense physical barrier composed of astrocytes, which restrict axonal regrowth, and secretes inhibitory molecules such as chondroitin sulfate proteoglycans (CSPGs) that chemically block axonal extension. Furthermore, NG2+ oligodendrocyte precursor cells (OPCs) and inflammatory cells contribute to an inhibitory microenvironment that hinders neural repair. At the molecular level, CSPGs—primarily released by neurons and reactive astrocytes—suppress axonal regeneration by affecting both oligodendrocytes and neurons. NG2+ OPCs further produce inhibitors that impede neuronal repair, while modifications in the ECM create an environment resistant to axonal regrowth. Physically, the scar forms a rigid, compact structure that obstructs regenerating axons and limits neural plasticity. Cellular mechanisms also reinforce the scar's inhibitory nature, with overexpression of ECM molecules creating a regeneration‐resistant environment. Astrocytes and other glial cells further support this microenvironment, making neuronal repair particularly challenging. Research suggests that while the glial scar is beneficial in the early phases of recovery, its inhibitory effects peak around 4 weeks post‐injury, often leading to a plateau in functional improvement. 110 , 112 , 114 , 117
However, emerging evidence highlights that the glial scar is not entirely detrimental. It plays a crucial role in tissue preservation by isolating inflammatory responses, preventing secondary injury propagation, and recruiting immune cells to promote tissue repair. Additionally, it establishes a physicochemical barrier composed of astrocytes, fibroblasts, and microglia, protecting viable neural tissue from further damage. Structurally, the glial scar consists of astrocytes organized through signal transducer and activator of transcription 3 (STAT3)‐dependent mechanisms, along with inflammatory cells and ECM components such as CSPGs and collagen. 107 , 111 , 112 , 114 , 116 , 118
Add on to this, a type of glial cell, microglia, can be seen exhibiting a dual role: during the acute phase, they aid repair and regeneration, but chronic activation leads to the release of neurotoxic factors that impair synaptic plasticity and neuronal function. Likewise, astrocytes contribute to axonal growth and synaptic support in the early stages of injury but, upon chronic activation, form glial scars that inhibit axonal regeneration and neural repair. 104 , 105 , 119 , 120 This persistent inflammatory environment interferes with synaptic plasticity processes, including LTP and LTD, thereby compromising learning, memory, and functional recovery. Chronic neuroinflammation is also associated with long‐term complications such as chronic traumatic encephalopathy, further complicating the healing process. Therapeutic strategies that modulate inflammation in a timely manner may balance its beneficial effects while mitigating detrimental outcomes, ultimately enhancing recovery and functional outcomes. 105 , 106 , 119
Given its dual nature, complete removal of the glial scar is not ideal. Instead, therapeutic strategies aim to modulate its properties—preserving its neuroprotective benefits while minimizing its inhibitory effects on neural regeneration.
5. NEUROBIOLOGICAL PROCESSES FACILITATING RECOVERY
5.1. Role of growth factors (BDNF & insulin‐like growth factor 1 [IGF‐1])
BDNF is a key neurotrophin that supports the survival of existing neurons and encourages the growth and differentiation of new neurons and synapses. Following an injury, BDNF levels can increase, promoting neurogenesis and synaptic plasticity, which are essential for recovery. This factor enhances the brain's ability to reorganize itself functionally and structurally after damage, facilitating recovery of lost functions. BDNF acts primarily through its receptor tropomyosin receptor kinase B (TrkB), activating various signaling pathways that lead to improved neuronal health and connectivity. Recovery from ABI, including strokes and TBI, is governed by intricate neurobiological processes mediated by growth factors such as BDNF and IGF‐1. These molecules are pivotal in facilitating neurogenesis, synaptic plasticity, neuroprotection, and the reorganization of neural networks while modulating the balance between adaptive and maladaptive plasticity. 121 , 122 , 123 , 124 , 125
BDNF plays a multifaceted role in neurogenesis. It promotes the survival of NSCs by shielding them from apoptosis, as evidenced by increased cell death when BDNF signaling is inhibited. It also drives the proliferation of NPCs by activating pathways such as protein kinase B (AKT), ensuring a sustained pool of cells available for differentiation. Once proliferated, these progenitor cells differentiate into mature neurons under the influence of BDNF, which facilitates their integration into existing neural circuits. This process is particularly active in the hippocampus, a region critical for learning and memory. 34 , 121
Beyond neurogenesis, BDNF significantly influences dendritic growth and synaptic plasticity. It promotes dendritic remodeling by modulating actin, a structural protein that shapes dendritic spines, enhancing their size and complexity. This remodeling is supported by the trafficking of proteins like the postsynaptic density 95 to dendritic spines, ensuring the structural integrity required for effective synaptic communication. Additionally, BDNF modulates NMDA receptor activity, which is pivotal for initiating synapse formation and strengthening connections. These actions are foundational to LTP, the synaptic mechanism underlying learning and memory. BDNF also enhances the overall morphology of dendrites, increasing their length and branching complexity. Experimental studies have demonstrated that exogenous BDNF application significantly boosts dendritic growth, emphasizing its role in neural connectivity and plasticity. By facilitating both the formation of new neurons and the development of robust synaptic networks, BDNF acts as a central mediator of cognitive health and neural repair. 34 , 35 , 121 The profound impact of BDNF on neurogenesis and dendritic development underscores its potential as a therapeutic target for neurodegenerative diseases and brain injuries. Its ability to foster neural regeneration, support synaptic plasticity, and enhance cognitive function positions BDNF as a critical focus in neuroscience research and clinical applications. Continued exploration of BDNF pathways offers promising opportunities to advance treatments aimed at brain repair and resilience (Table 1).
Table 1.
Recent pharmacological intervention for promoting neurogenesis.
| No. | Therapeutic agent | Mechanism | Study type | References |
|---|---|---|---|---|
| 1 | 3,4,5‐tri‐feruloylquinic acid and 3,4,5‐tri‐caffeoylquinic acid | Upregulation of the ErbB, AKT, and MAPK signaling pathway | Preclinical (NSCs from adult mice brains) | [126] |
| 2 | 4‐octyl itaconate | Upregulation of Nrf2/ERK signaling pathway | Preclinical (C57BL/6 mice) | [127] |
| 3 | Acetyl‐l‐Carnitine | It boosts mitochondrial metabolism, reduces oxidative stress, and promotes neuronal survival. By activating the NF‐κB pathway, it increases metabotropic glutamate receptor 2 expression, supporting neurogenesis, and inhibits excitotoxicity and apoptosis in neuronal cells | Preclinical (6‐hydroxydopamine induced mouse model of Parkinson's disease ‐ like phenotypes) | [128] |
| 4 | Alpha‐asarone | Activation of the BDNF/ERK/CREB signaling pathway | Preclinical (pMCAO rats) | [129] |
| 5 | CNTs | CNTs are being explored as a novel drug delivery system for neurodegenerative disorders, enabling targeted delivery of therapeutic agents to the brain and potentially improving the efficacy of neurogenic drugs | Preclinical (pheochromocytoma 12 cells) | [130] |
| 6 | CCL01 | It boosts memory by promoting neurogenesis through NGF release. Animal studies show that CCL01 enhances markers of neuronal proliferation and differentiation in the hippocampus, suggesting its potential to improve cognitive function | Preclinical (mouse model) | [131] |
| 7 | Chrysin | Upregulation of TrkB and fibroblast growth factor receptor 1 signaling pathway | Preclinical (human NSCs) | [132] |
| 8 | CCL5 | Upregulation of semaphorin, ephrin, p70S6/mTOR, neuregulin/ErbB and fibroblast growth factor/FAK signaling pathways | Preclinical (CCL5 knockout mice) | [133] |
| 9 | Curcumin | Upregulation of Wnt/β‐catenin signaling pathway | Preclinical (C57BL/6 mice) | [134] |
| 10 | Catalpol | Upregulation of SDF‐1α/CXCR4 signaling pathway | Preclinical (rat [pMCAO] and oxygen‐glucose deprivation model) | [135] |
| 11 | Dexmedetomidine | Upregulation of BDNF/TrkB/CREB signaling pathway | Preclinical (mouse model) | [136, 137] |
| 12 | Fluoxetine | Upregulation of CREB, BDNF, NGF, and MAPK1in the hippocampus | Preclinical (mouse model) | [138, 139] |
| 13 | Fisetin | Downregulation of microglia/macrophage M1 polarization and JAK2/STAT3 signaling pathway | Preclinical (PC12 cells) | [140] |
| 14 | Glatiramer acetate | Upregulation of neurotrophic factors such as BDNF | Preclinical/clinical | [141] |
| 15 | Genistein | Upregulation of C/cAMP/CREB/PKA and mitochondrial ETC‐complex signaling pathways | Preclinical (mouse model) | [142] |
| 16 | Gallic acid | Downregulation of GSK3β related signaling pathways | Preclinical (mouse model) | [143] |
| 17 | Ginsenoside Rk3 | Upregulation of CREB/BDNF signaling pathway | Preclinical (C57BL/6 mice and PC12 cells) | [144] |
| 18 | Ketamine | It enhances synaptic connectivity and promotes neurogenesis through NMDA receptor modulation, while increasing the release of BDNF, crucial for neuronal growth and differentiation | Preclinical (C57BL/6 mice) | [145, 146] |
| 19 | Leptin + withaferin | Upregulation of STAT3/SOCS3 signaling pathway | Preclinical (mouse model) | [147] |
| 20 | Memantine | As an NMDA receptor antagonist, it reduces excitotoxicity, improving synaptic plasticity and neuron survival, while enhancing cognitive recovery and potentially promoting neurogenesis through its neuroprotective effects | Preclinical (mouse model) | [148] |
| 21 | Minocycline | It has anti‐inflammatory properties that may protect against neuronal death, promote neuroprotection, and enhance cognitive recovery post‐injury, potentially aiding neurogenesis | Preclinical (Sprague‐Dawley rats) | [149] |
| 22 | Mesenchymal stem cells loaded with miR‐206‐3p antagomir | Upregulation of BDNF and activation of the BDNF/TrkB signaling pathway promote hippocampal neurogenesis and synaptic plasticity while reducing amyloid‐beta deposition | Preclinical (mouse model) | [150] |
| 23 | NAC | It acts as an antioxidant, reducing oxidative stress that can hinder neurogenesis, and modulates glutamate levels to support neuronal survival and differentiation | Preclinical (undifferentiated mouse ES‐D3 cells) | [151] |
| 24 | NA | It promotes neurogenesis and angiogenesis, key processes for tissue repair. NA protects neural cells from oxidative stress and boosts nerve regeneration by upregulating NGF and other markers linked to nerve growth and vascularization | Preclinical (RSC96 and PC12 cells) | [152] |
| 25 | Neuropeptide Y1 receptor agonist | NPY enhances neurogenesis by activating Y1 receptors in neurogenic regions, triggering ERK1/2 and other signaling pathways to promote neural progenitor proliferation, differentiation, and survival. It reduces excitotoxicity by modulating calcium levels and protects neurons in toxic environments like those induced by amyloid‐beta. NPY also supports neuronal integration into circuits, aiding cognitive functions such as learning and memory | Preclinical (animal model) | [153, 154, 155, 156, 157] |
| 27 | NeuroAiDTM‐II (MLC901) | Upregulation of PI3K/AKT/GSK‐3β signaling pathway | Preclinical (mouse model) | [158] |
| 28 | Quinic acid | Upregulates Notch intracellular signaling | Preclinical (neural progenitor cells) | [159] |
| 29 | Recombinant human MFGE8 | Upregulation of integrin β3/PI3K/AKT/mTOR signaling pathway | Preclinical (adult male Sprague–Dawley rats) | [160] |
| 30 | Rosmarinic acid | Upregulation of BDNF/TrkB/CREB and PI3K/Akt/mTOR signaling pathway | Preclinical (C57BL/6 J mice) | [161] |
| 31 | Safranal | Upregulation of SIRT1 expression | Preclinical (MCAO/R mouse model) | [162] |
| 32 | Salidroside |
|
|
[163, 164] |
| 33 | Saroglitazar | Upregulation of Wnt/β Catenin signaling pathway | Preclinical (mouse model of dementia) | [165] |
| 35 | Taurine (2‐aminoethanesulfonic acid) |
|
Preclinical (rat cortical neuronal cell culture); Preclinical (mouse stem cell & mouse model); Preclinical (BTBR mouse model) | [166, 167, 168] |
Abbreviations: AKT, protein kinase B; BDNF, brain‐derived neurotrophic factor; BTBR, Black and Tan Brachyury; cAMP, cyclic adenosine monophosphate; CCL01, cuscuta seeds and lactobacillus paracasei NK112; CCL5, C‐C motif chemokine ligand 5; CNTs, carbon nanotubes; CREB, cAMP response element‐binding protein; CXCR4, C‐X‐C chemokine receptor type 4; ErbB, the epidermal growth factor receptor; ERK, extracellular regulated protein kinases; ETC, electron transport chain; FAK, focal adhesion kinase; GABAAR, gamma‐aminobutyric acid type A receptor; GSK3β, glycogen synthase kinase 3β; JAK2, Janus kinase 2; MAPK, mitogen‐activated protein kinase; MCAO, middle cerebral artery occlusion; MFGE8, milk fat globule epidermal growth factor 8; mTOR, mammalian target of rapamycin; NA, nervonic acid; NAC, N‐acetyl cysteine; NF‐κB, nuclear factor kappaB; NGF, nerve growth factor; NMDA, N‐methyl‐D‐aspartate; NPY, neuropeptide Y; Nrf2, nuclear factor E2‐related factor 2; NSCs, neural stem cells; p70S6, 70 kDa ribosomal protein S6; PGC‐1α, PPAR‐gamma coactivator 1alpha; PI3K, phosphatidylinositol 3‐kinase; PKA, protein kinase A; pMCAO, permanent middle cerebral artery occlusion; PSD95, the postsynaptic density 95; PTEN, phosphatase and tensin homolog; SDF‐1α, the stromal‐derived factor 1alpha; SIRT1, the silent information regulator sirtuin 1; SOCS, the suppressors of cytokine signaling; STAT3, signal transducer and activator of transcription 3; TrkB, tropomyosin receptor kinase B; Wnt, the wingless‐related integration site.
Neuroplasticity, the brain's ability to reorganize its neural connections, varies between younger and older individuals, with BDNF playing a crucial role. BDNF interacts with CAMs such as the neural cell adhesion molecule (NCAM), N‐cadherin, and integrins to promote neuronal survival, synaptic development, and plasticity. In younger individuals, BDNF actively supports synaptic remodeling and learning, while in older adults, reduced BDNF levels contribute to diminished synaptic plasticity and cognitive decline. BDNF regulates CAMs by modulating NCAM expression during synaptic development, thereby enhancing neuronal connectivity. It also plays a role in cadherin signaling, contributing to LTP, which is more pronounced in youth. Additionally, BDNF facilitates neuronal attachment and outgrowth via integrin receptors. Age‐related declines in BDNF impair these processes, emphasizing the connection between neuroplasticity and aging. 25 , 169 , 170 , 171 , 172 BDNF is crucial for neuronal plasticity by regulating CAMs, such as NCAM and its polysialylated form (PSA‐NCAM), which are involved in LTP in the hippocampus. This process is vital for synaptic plasticity, especially in younger individuals, where it supports learning and memory. However, in older adults, this capacity declines, leading to reduced neuroplasticity and cognitive impairments. BDNF activates key signaling pathways through TrkB receptors, including phospholipase‐C‐gamma (PLCγ), phosphatidylinositol 3‐kinase (PI3K), and MAPK, which promote neurite outgrowth, cell differentiation, and synaptic plasticity. While these processes are efficient in younger individuals, they diminish with age. Additionally, BDNF regulates CAM expression through transcriptional and calcium‐dependent mechanisms, which become less effective in aging brains. 35 , 173 , 174
BDNF plays a critical role in neuroplasticity following peripheral nerve injury, with complex temporal and cellular dynamics that support recovery and regeneration. Its release follows a biphasic pattern: an immediate upregulation within hours of injury, marking the acute phase, followed by sustained expression over several weeks. In the acute phase, BDNF is rapidly upregulated, with significant increases in BDNF and TrkB mRNA observed within 30 min to 4 h post‐injury. This early surge is crucial for initiating neuronal survival and plasticity. As the recovery progresses, BDNF levels remain elevated for weeks, with the most significant increases occurring during the early recovery phases. The sciatic nerve, which typically has low baseline BDNF levels, shows a pronounced upregulation, highlighting BDNF's importance in tissue repair and neuroplasticity during recovery. The primary cells responsible for BDNF secretion during this process include motoneurons, dorsal root ganglion (DRG) neurons, and Schwann cells. Motoneurons and DRG neurons are key contributors, releasing BDNF to support neuronal survival and growth. Schwann cells also play a critical role, producing BDNF to aid in nerve regeneration and promote synaptic plasticity. This coordinated release of BDNF by multiple cell types is essential for both the acute and chronic phases of nerve injury recovery 175 , 176 , 177 , 178 , 179 (Figure 3).
Figure 3.
Brain‐derived neurotrophic factor (BDNF)‐TrkB signaling pathway and its role in neurogenesis. BDNF binds to TrkB, inducing receptor dimerization and autophosphorylation, which activates key intracellular pathways: RAS‐mitogen activated protein kinase (MAPK) (regulating transcription via cyclic AMP response element‐binding protein [CREB]), phosphatidylinositol 3‐kinase (PI3K)/protein kinase B (PKB/AKT) (promoting survival and differentiation), and phospholipase‐C‐gamma (PLCγ) (enhancing calcium signaling and transcription). The BDNF‐TrkB complex undergoes endosomal internalization for sustained signaling, influencing synaptic transmission, receptor responsiveness, and synapse formation. TrkB activation also modulates ion channels, affecting neuronal excitability. Additionally, TrkB can be activated in the absence of BDNF via G protein‐coupled receptors (GPCRs)‐mediated trans‐activation, while BDNF signaling through p75 receptors may have neuroprotective or apoptotic effects. 180 , 181 , 182 , 183 IGF‐1 activates the same signaling pathways as BDNF, specifically the MAPK and PI3K‐AKT1 pathways. In particular, the PI3K/AKT pathway, stimulated by insulin‐like growth factor 1 (IGF‐1), plays a crucial role in the survival of hippocampal neurons. 184 , 185
IGF‐1 plays a multifaceted role in post‐injury recovery by promoting neuronal survival, stimulating neurogenesis, and enhancing synaptic plasticity. It also attenuates inflammation, mitigates secondary damage, and supports the integration of new neurons into existing circuits. 123 Notably, IGF‐1 exhibits a synergistic relationship with BDNF, as it upregulates BDNF expression through the PI3K‐AKT signaling pathway, thereby promoting neuronal growth and preventing apoptosis. Moreover, IGF‐1 facilitates the conversion of pro‐BDNF into its mature, biologically active form, amplifying BDNF's neuroprotective and regenerative effects. A study found that IGF‐1 and BDNF play a crucial role in the development and maintenance of neural circuits, and alterations in these factors may contribute to autism spectrum disorder (ASD). The findings reported increased IGF‐1 levels in ASD serum, while proBDNF levels were decreased. Additionally, there was a significant negative correlation between the proBDNF/total BDNF ratio and IGF‐1 levels in the autism group. This suggests that higher IGF‐1 levels are associated with lower proBDNF levels, potentially due to enhanced conversion of proBDNF to mature BDNF through IGF‐1‐mediated activation of proteolytic enzymes such as tissue plasminogen activator and MMPs. Alternatively, the reduction in proBDNF levels may result from transcriptional or posttranscriptional regulatory mechanisms influenced by IGF‐1, rather than direct conversion. 184 , 186 , 187 , 188 Further, IGF‐1 promotes neurogenesis in the adult DG and directs hippocampal neural precursor cells to differentiate into mature granule neurons. It increases synapse formation in the hippocampal molecular layer and plays a crucial role in brain development by supporting neurogenesis, synaptogenesis, neurite growth, myelination, and cell survival. Additionally, IGF‐1 enhances brain weight and dendritic spine density. 125 , 189 , 190 , 191 Additional growth factors, such as fibroblast growth factor 2 (FGF2), collaborate with IGF‐1 to stimulate NSC proliferation and repair mechanisms. 125 Evidence also indicates that physical exercise significantly enhances the release of IGF‐1 and BDNF and downregulates the nuclear factor kappaB (NF‐κB), creating a neuroplastic environment conducive to cognitive enhancement and memory restoration 186 , 188 , 192 (Figure 4).
Figure 4.
Role of insulin‐like growth factor 1 (IGF‐1) in neurogenesis and brain development. IGF‐1 promotes neurogenesis in the adult dentate gyrus and directs hippocampal neural precursor cells to differentiate into mature granule neurons. It enhances synapse formation in the hippocampal molecular layer and supports key processes in brain development, including neurogenesis, synaptogenesis, neurite growth, myelination, and cell survival. Additionally, IGF‐1 increases brain weight and dendritic spine density.
In short, the interplay between BDNF, IGF‐1, CAMs and other growth factors underpins the recovery process following ABI. Their combined actions promote neural repair, functional restoration, and protection of neural circuits, offering valuable insights for the development of targeted therapeutic strategies to optimize brain recovery.
5.2. Neural network reorganization
Neural network reorganization is a fundamental neurobiological process that enables recovery from ABIs such as strokes and TBIs. This adaptive mechanism involves the formation of new neural connections to compensate for lost functions, often through the recruitment of neurons from adjacent or distant brain regions. For instance, post‐stroke studies have demonstrated an initial reduction in connectivity between the primary motor cortex and remote areas, followed by recovery‐associated improvements in functional pathways. Similarly, TBIs induce widespread changes, including enhanced cross‐hemispheric collaboration to establish compensatory neural pathways. This task‐specific reorganization involves dynamic activity changes in distinct neural substrates, with some regions showing increased activation and others decreasing, reflecting functional adaptation. Key mechanisms driving this reorganization include axonal sprouting, where intact neurons extend new connections—often across hemispheres—stimulated by rehabilitation and synchronized neuronal activity, and neurogenesis, particularly in the hippocampus. Neurogenesis generates new neurons that integrate into pre‐existing networks, contributing to cognitive and functional recovery. 9 , 103 , 193
By supporting functional reorganization, promoting cross‐hemispheric collaboration, and coordinating axonal sprouting with neurogenesis, neural network reorganization underscores the brain's resilience and capacity for recovery. A deeper understanding of these processes provides critical insights for designing therapeutic strategies to optimize rehabilitation outcomes in ABIs.
5.3. Compensatory versus maladaptive plasticity
Compensatory plasticity refers to the brain's capacity to adapt following injury by reorganizing neural networks to restore lost functions. When specific brain regions are damaged, unaffected areas can take over their functions, as observed in stroke patients, where the contralesionally hemisphere compensates for motor deficits, enhancing task performance. Key mechanisms driving this process include axonal sprouting and synapse formation, which increase circuit connectivity and facilitate recovery. For example, after TBI, increased dendritic growth and synapse formation correlate with improved motor behaviors, particularly when rehabilitation fosters alternative strategies and task‐specific training. In contrast, maladaptive plasticity occurs when compensatory changes lead to suboptimal outcomes. Over‐reliance on alternative pathways, such as excessive use of the unaffected limb post‐stroke, can hinder the recovery of damaged regions and delay functional restoration. Maladaptive changes, such as abnormal synaptic growth or the formation of inefficient neural circuits, may result in persistent deficits or cognitive impairments, limiting the potential for full recovery. 8 , 194 , 195
Effective rehabilitation strategies must balance the promotion of compensatory plasticity with the prevention of maladaptive changes. Approaches like constraint‐induced movement therapy (CIMT) encourage the use of the affected limb, leveraging experience‐dependent neuroplasticity to enhance recovery. Task‐specific, repetitive training aligned with natural movement patterns supports adaptive reorganization while minimizing maladaptive behaviors. 8 , 194 , 195 , 196
In summary, compensatory plasticity drives recovery through adaptive neural changes, while maladaptive plasticity can impede progress by reinforcing inefficient neural pathways. Rehabilitation strategies should aim to enhance beneficial plasticity and minimize detrimental changes to optimize recovery outcomes.
6. CLINICAL IMPLICATIONS OF ADAPTIVE PLASTICITY
6.1. Spontaneous recovery versus therapeutic interventions
Spontaneous recovery refers to the natural process by which individuals regain lost functions following a neurological injury, such as a stroke or TBI. This recovery typically occurs within the initial weeks post‐injury and is characterized by neuroplastic changes, during which the brain undergoes both structural and functional reorganization. Undamaged regions of the brain may compensate for the functions previously managed by the injured areas. The extent of spontaneous recovery varies based on several factors, including the severity of the injury, the individual's age (with younger brains generally exhibiting greater plasticity), and overall health. For example, children possess a greater synaptic reserve and tend to be more resilient to neuronal loss compared to adults. Although spontaneous recovery can lead to substantial improvements, it often reaches a plateau after a certain period. This plateau means that some deficits may persist, necessitating additional therapeutic interventions to further optimize recovery outcomes. 6 , 197
Therapeutic interventions are structured rehabilitation strategies designed to facilitate recovery beyond the natural processes of spontaneous healing. These interventions capitalize on the principles of neuroplasticity and encompass approaches such as Physical Therapy, Cognitive Rehabilitation, and Occupational Therapy. Physical Therapy focuses on improving motor function through repetitive practice and task‐specific training. Techniques like CIMT promote the use of affected limbs, stimulating neural reorganization in the brain's motor regions and enhancing functional movement. CIMT is a rehabilitation technique that capitalizes on use‐dependent plasticity. By restraining the unaffected limb, patients are compelled to use their impaired limb intensively, promoting the activation and reorganization of neural circuits associated with motor control and coordination. This forced use facilitates neural reorganization, strengthening connections in the brain's motor regions. Research has demonstrated that CIMT can result in significant improvements in motor function, encouraging greater engagement of the affected brain areas and supporting the restoration of motor capabilities, ultimately enhancing overall recovery. 198 , 199 , 200 In addition to CIMT, task‐specific training and functional electrical stimulation (FES) are also effective physical therapy techniques for promoting recovery. Task‐specific training involves repetitive practice of specific tasks that target impaired functions. By engaging patients in focused activities, TST stimulates relevant neural pathways, driving neuroplastic changes. This type of training promotes motor learning and functional recovery by facilitating LTP in the synapses involved in these tasks, ultimately enhancing motor function and supporting overall recovery. FES employs electrical currents to induce muscle contractions in paralyzed or weakened limbs. This technique aids in strengthening muscles and promotes adaptive changes in the neural circuits that control these muscles. Research has shown that FES can enhance motor recovery by supporting the reorganization of motor pathways in the brain, leading to improved motor function. 6 , 201 , 202
Cognitive rehabilitation therapy (CRT) encompasses a range of interventions aimed at restoring and enhancing cognitive functions in individuals with brain injuries or cognitive impairments. CRT includes restorative rehabilitation, which strengthens neural connections through exercises such as memory and problem‐solving tasks, and compensatory rehabilitation, which focuses on developing strategies to manage cognitive deficits, often using assistive devices and environmental modifications. Techniques such as cognitive restructuring, dual‐task training, and computer‐assisted learning are employed to improve cognitive performance. CRT progresses from targeting basic cognitive skills to fostering functional and social integration, promoting neuroplasticity through consistent practice. When full cognitive restoration is not achievable, CRT helps individuals manage daily life and adapt to their environment. Additional methods like neurofeedback and attention training further enhance cognitive flexibility, making CRT a crucial approach to improving both cognitive function and overall quality of life. 6 , 203
Occupational Therapy integrates both physical and cognitive rehabilitation to address challenges in daily activities, fostering greater independence. This approach targets physical limitations as well as cognitive difficulties, helping individuals overcome barriers to engaging in everyday life. 6 , 8 , 204
6.2. Impact of pharmacological agents and neuromodulation
Pharmacological agents and neuromodulation techniques, including BDNF enhancers (e.g., selective serotonin reuptake inhibitors), pleiotropic neuroprotective agents like statins (e.g., atorvastatin), and the NMDA receptor antagonist memantine, are promising strategies to enhance adaptive plasticity after ABI. These interventions modulate neurotransmitter systems, promote synaptic plasticity, and reduce neuroinflammation. BDNF is crucial for neuronal survival and synaptic plasticity, and agents that elevate its effects support cognitive and motor recovery. Statins, besides lowering cholesterol, release growth factors and reduce neuroinflammation, while memantine improves synaptic plasticity and cognitive function. These agents together aid in neural network reorganization, improving recovery outcomes after ABI. 205 , 206
Neuromodulation techniques, including transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), FES, neurofeedback, and translingual neurostimulation (TLNS), offer promising approaches to enhancing adaptive plasticity in individuals recovering from ABI by modulating neuronal activity and promoting neuroplastic changes. These techniques work by altering cortical excitability, inducing synaptic changes such as LTP and LTD, and recruiting undamaged brain areas to compensate for lost functions. TMS and tDCS have been shown to modulate cortical excitability, FES aids motor recovery by stimulating weakened muscles, neurofeedback improves cognitive functions through self‐regulation of brain activity, and TLNS targets cranial nerves to enhance motor function. Evidence indicates that when these neuromodulation techniques are combined with rehabilitation therapies, they lead to significant improvements in both motor and cognitive functions. However, continued research is necessary to optimize these methods and refine their clinical applications for ABI recovery. 8 , 207 , 208 , 209 , 210
7. CHALLENGES AND FUTURE DIRECTIONS
Adaptive plasticity, the brain's capacity to reorganize and form new neural connections following injury, is essential for recovery after ABIs like strokes and TBIs. However, several challenges complicate effective rehabilitation and optimization of adaptive plasticity. One major difficulty is understanding the intricate mechanisms of neuroplasticity. While key processes like synaptic adaptability, axonal sprouting, and dendritic remodeling are critical for recovery, distinguishing between adaptive and maladaptive changes remains a challenge, as maladaptive plasticity can result in dysfunctional outcomes that hinder recovery. Another issue is the variability among patients; individual differences in response to rehabilitation are influenced by factors such as age, genetics, and the severity of the injury, making personalized rehabilitation strategies vital but difficult to implement effectively. Moreover, the lack of standardized protocols often leads to fragmented care, reducing the potential benefits of a multidisciplinary approach. Access to advanced therapies like virtual reality‐based rehabilitation and brain‐computer interfaces is limited by technological constraints and training gaps, leaving many patients unable to benefit from these innovations. Ethical considerations, particularly around patient consent, the use of new technologies, and dependence on devices, must also be addressed to ensure that neurorehabilitation is both effective and ethically sound. 2 , 8 , 103 , 211
To overcome these challenges, several future directions could enhance adaptive plasticity and recovery outcomes following ABI. These include personalized neurorehabilitation, advancements in neuroimaging techniques, deeper cellular and molecular insights into neuroplasticity, and improved access to innovative therapies. Each of these areas holds the potential to significantly improve recovery outcomes and is summarized briefly below:
Personalized neurorehabilitation optimizes recovery by tailoring interventions to individual needs. This includes cognitive profiling to identify strengths and weaknesses, with targeted interventions like memory training for those with cognitive impairments. Motor rehabilitation is customized based on age, medical conditions, and the type of impairment, using task‐specific training, adaptive equipment, and targeted exercises. Technological advances, such as real‐time functional magnetic resonance imaging (fMRI), neurofeedback, wearable sensors, and brain‐computer interfaces, enhance personalized care by monitoring neurological responses. Emerging methods like machine learning and computational models adjust rehabilitation parameters to improve recovery. Holistic personalization also addresses psychological factors and support networks. Ongoing research integrates genetic data, neuroimaging, and cognitive profiles to create dynamic, effective rehabilitation plans that maximize recovery and neuroplasticity. 8 , 212
Advanced neuroimaging techniques are revolutionizing brain function understanding and personalized neurorehabilitation. Key methods, such as fMRI, diffusion tensor imaging (DTI), magnetic resonance spectroscopy (MRS), perfusion‐weighted imaging, and functional near‐infrared spectroscopy, provide crucial insights that conventional imaging often misses, especially in conditions like mild TBI. DTI maps white matter connectivity, while fMRI monitors brain activity in real‐time during rehabilitation. MRS reveals brain metabolism and recovery markers. Emerging research focuses on biomarkers to predict recovery, detect neuroinflammation, and guide personalized treatments. The integration of artificial intelligence (AI) and machine learning with advanced neuroimaging enables detailed, individualized assessments of brain function, functional connectivity, and dynamic treatment plans. These technologies are shaping the future of neurorehabilitation, offering more effective and targeted rehabilitation strategies. 213 , 214 , 215
Neuroplasticity is the process by which neural networks adapt and reorganize in response to experiences or injuries. This involves key cellular processes like modifying synaptic connections, reorganizing neural networks, and making structural and functional adaptations within neurons. The core mechanisms include changes in synaptic strength, the formation of new synapses, and reconfiguring neural pathways to refine circuits. Molecular regulators of neuroplasticity include signaling pathways that affect gene expression, protein kinase activation, and neurotransmitter receptor modulation. Synaptic plasticity, such as changes in neurotransmitter release and receptor sensitivity, is central to strengthening or weakening synaptic connections. Structural changes like axonal regeneration and synaptogenesis also play crucial roles. Factors influencing neuroplasticity include inflammatory cytokines, neurotrophic proteins (e.g., B‐cell lymphoma 2 [Bcl‐2]), mitochondrial energy production, and sex hormones (e.g., estrogen and testosterone). These molecules promote or inhibit plasticity and support neuron survival and growth. Key signaling pathways involved in neuroplasticity include LTP, glutamate receptor activation, calcium ion signaling, and protein kinase modulation. These processes are essential for learning, memory, and synaptic remodeling. Emerging research focuses on real‐time monitoring of neurogenesis, the role of miRNAs in synaptic remodeling, and developing targeted pharmacological interventions to optimize or enhance neuroplasticity. Understanding these intricate mechanisms provides valuable insights into brain function and offers potential therapeutic strategies for neurological disorders. 103 , 197 , 216 , 217
Increasing access to innovative neurorehabilitation therapies requires a multifaceted approach combining advanced technologies with strategic policy initiatives. Emerging technologies like virtual reality (VR), robotic‐assisted rehabilitation, telemedicine, AI‐driven personalized treatments, and wearable neurotechnology offer significant potential to enhance accessibility. Successful implementation depends on healthcare provider training. Comprehensive programs on emerging technologies, certification courses, and integration of tech skills into medical education will equip clinicians to effectively use new tools. Multicenter clinical trials and standardized protocols are essential for evaluating and scaling innovative therapies. Reimbursement frameworks for advanced technologies must be established to ensure broader patient access. Barriers such as high costs, limited infrastructure, insufficient training, and complex regulations must be addressed. Healthcare reimbursement policies, national guidelines for technology integration, and funding mechanisms for research and development will help overcome these challenges. The future vision for neurorehabilitation is a comprehensive ecosystem that fosters innovation, professional development, and widespread access to cutting‐edge therapies. Technologies like AI and VR should be central to rehabilitation strategies, providing personalized, adaptive, and engaging therapies to improve patient outcomes. 218 , 219 , 220 , 221
In summary, personalized neurorehabilitation programs, customized to individual patient profiles, hold the potential to improve recovery significantly. Advanced imaging techniques, such as fMRI, and the use of biomarkers could enable clinicians to predict patient responses to specific therapies, facilitating the development of more effective, individualized treatment plans. Further research into the cellular and molecular processes underlying neuroplasticity will improve our understanding of how to promote adaptive changes while minimizing maladaptive ones, leading to more targeted therapies. Interprofessional collaboration is crucial for ensuring comprehensive care, with standardized protocols that enhance treatment efficacy. Increasing access to innovative therapies by training healthcare providers and advocating for policies that support the integration of new technologies into diverse healthcare settings will also be key. Finally, as new technologies emerge, developing ethical frameworks to guide their use will ensure that patient welfare is prioritized, balancing technological advancements with concerns about consent and device dependency. Despite the challenges in optimizing adaptive plasticity after ABI, targeted research, and innovation hold great promise for improving rehabilitation outcomes and enhancing patients' quality of life. 2 , 8 , 103 , 211
8. CONCLUSION
In conclusion, adaptive plasticity following ABI highlights the brain's ability to reorganize and recover through processes like axonal sprouting, dendritic remodeling, and neurogenesis. While neuroinflammation and reactive astrocytes aid repair, optimizing these responses to minimize secondary damage remains challenging. BDNF plays a key role in neurogenesis and dendritic growth, making it a potential therapeutic target. Rehabilitation strategies that stimulate neuroplasticity can enhance recovery, and understanding the molecular mechanisms underlying these processes offers insights for developing treatments. The severity and type of brain injury influence neuroplasticity and recovery. Severe injuries TBI or stroke may lead to maladaptive plasticity, while mild TBIs allow for greater recovery. Age, genetic, and epigenetic factors, such as BDNF gene polymorphisms, also impact recovery. Neuroinflammation plays a dual role, aiding acute recovery but potentially causing damage in chronic stages. Precision medicine, tailored to genetic and epigenetic profiles, can optimize recovery outcomes. The interplay between BDNF, IGF‐1, and other growth factors is essential for neurogenesis, synaptic plasticity, and neural reorganization. However, maladaptive plasticity must be managed through targeted therapies like physical, cognitive, and occupational therapies, along with pharmacological and neuromodulation techniques, to optimize recovery and personalize ABI treatment.
AUTHOR CONTRIBUTIONS
Ravi Kumar Rajan: Conceptualization (equal); Resources (equal); Writing—original draft (equal); Writing—review and editing (equal).
CONFLICT OF INTEREST STATEMENT
The author declares no conflicts of interest.
ETHICS STATEMENT
Not applicable.
ACKNOWLEDGMENTS
None.
Rajan RK. A comprehensive review on adaptive plasticity and recovery mechanisms post‐acquired brain injury. Neuroprotection. 2025;3:226‐252. 10.1002/nep3.70006
Managing Editor: Lili Wang/Ningning Wang
DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
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Associated Data
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Data Availability Statement
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.