Continuing Education Activity

Neuroplasticity describes the nervous system’s capacity for adaptive structural and functional change in response to intrinsic and extrinsic stimuli, with major clinical relevance following stroke and traumatic brain injury. This course reviews the mechanisms of neuroplasticity, including neuronal regeneration with synaptic plasticity and collateral sprouting, as well as functional reorganization through processes such as vicariation and diaschisis. Participants will also gain an understanding of how plasticity evolves across acute, subacute, and chronic phases, with outcomes that may be restorative, neutral, or maladaptive, including chronic pain and dysfunctional network reinforcement. This activity also explores rehabilitation timing, task-specific therapy, neuromodulation, and pharmacologic strategies. This activity for healthcare professionals is designed to enhance the learner's competence in identifying neuroplastic mechanisms, critically appraising biomarkers and timing considerations, and applying practical approaches to optimize recovery, minimize maladaptive effects, and integrate interprofessional, evidence-based neurorehabilitation strategies into patient care.

Objectives:

• Identify key mechanisms of neuroplasticity that correlate with each phase of recovery after neurologic injury.
• Evaluate risk factors for maladaptive neuroplasticity to guide preventive interventions.
• Apply evidence-based rehabilitation strategies to optimize functional recovery in patients with neurologic injury.
• Collaborate with interprofessional team members to improve neurorehabilitation care coordination and outcomes for patients with stroke.

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Introduction

Neuroplasticity, also known as neural plasticity or brain plasticity, is the process of adaptive structural and functional changes in the brain. A good definition is “the ability of the nervous system to change its activity in response to intrinsic or extrinsic stimuli by reorganizing its structure, functions, or connections.”[1] Clinically, neuroplasticity is the process of brain changes after injury, eg, a stroke or traumatic brain injury (TBI). These changes can be beneficial (restoration of function after injury), neutral (no change), or negative (with pathological consequences).

Neuroplasticity can be divided into 2 major mechanisms. Neuronal regeneration and collateral sprouting encompass processes, eg, synaptic plasticity and neurogenesis, which support structural and functional adaptation at the cellular level. Functional reorganization involves processes, eg, equipotentiality, vicariation, and diaschisis, which reflect the brain’s capacity to redistribute and modify activity across neural networks following injury or experience. The concept of plasticity in the nervous system first appeared in 1890 through the work of William James.[2] The term neural plasticity was later introduced by Jerzy Konorski in 1948 and subsequently popularized by Donald Hebb in 1949.[1][3]

Function

Neuroplasticity after injury is a complex, evolving process that continues to be elucidated, yet the concept remains highly applicable in the context of brain injury. Traditional models describe neuroplasticity as progressing through 3 distinct phases or epochs.[4][5]

1. First 48 hours after brain injury: During this period, the mechanism of injury (eg, stroke or traumatic brain injury) causes initial damage that progresses to cell death and loss of specific cortical pathways associated with the affected neurons. In response, the brain engages secondary neuronal networks in an effort to preserve function.[4]
2. Few weeks after brain injury: Over the following weeks, recruitment of support cells occurs as cortical pathways transition from inhibitory to excitatory states. This phase involves active synaptic plasticity and the formation of new neural connections.[4]
3. Weeks to months after injury: In the weeks to months that follow, continued remodeling occurs through axonal sprouting and further reorganization surrounding the area of injury.[4]

Mechanisms of Neuroplasticity

Neuronal regeneration and collateral sprouting

Synaptic plasticity refers to the capacity for experience-dependent, long-lasting changes in the strength of neuronal connections.[1] This process finds its clearest expression in long-term potentiation. First described in 1973 by Bliss and Lomo while studying the rabbit hippocampus, repetitive stimulation of presynaptic fibers produced amplified responses in postsynaptic granule cells.[6][7] Prolongation of the postsynaptic potential beyond the expected duration led to the designation of long-term potentiation. Current theory suggests that stimulation of a postsynaptic neuron by a presynaptic neuron triggers the addition of neurotransmitter receptors to the postsynaptic membrane, thereby lowering the activation threshold and strengthening the synapse over time, consistent with the principles proposed by Konorski and Hebb. Positive influences on synaptic plasticity include exercise, environmental factors, task repetition, motivation, neuromodulators such as dopamine, and medications or drugs.[8][9][10][11][12]

Aging and neurodegenerative diseases are associated with reduced neuromodulator levels and may impair synaptic plasticity.[13] Expanding models of synaptic plasticity incorporate the growing complexity of synaptic communication.[1] These models include spike-timing-dependent plasticity (STDP), which links the timing of presynaptic and postsynaptic action potentials to synaptic strengthening or weakening; metaplasticity, which describes activity-dependent modulation of synaptic responsiveness across networks; and homeostatic plasticity, which maintains stability within synaptic systems over time. Ongoing research continues to refine the understanding of how these processes influence learning and functional recovery.

Adult neurogenesis refers to the potential for the continued generation of neurons in the mature brain. Early work by Ramon Cajal failed to demonstrate the formation of new neurons in adults, leading to the assertion that neurogenesis ceased after development.[14] This view persisted until Josef Altman identified evidence of neurogenesis in adult rats.[14] Subsequent studies confirmed neurogenesis in birds and other small mammals, although convincing evidence in humans remains lacking.[15]

Proposed sites of adult neurogenesis in humans include the olfactory bulb and the hippocampus. Investigations using biomarkers associated with developing neurons support this hypothesis; however, interpretation remains challenging because these markers also appear in immature neurons that do not represent newly generated or migrating cells.[15] Histological examination has not identified a definitive niche-like structure comparable to those observed in species with established adult neurogenesis, further limiting conclusions. The development of more specific biomarkers will likely be necessary to distinguish newly formed neurons from immature cells and clarify their role in human brain plasticity.[15]

Functional Reorganization

Equipotentiality and vicariation describe key concepts in functional reorganization of the brain following injury. Equipotentiality proposes that when one area of the brain sustains damage, the contralateral hemisphere can assume the lost function. This concept dates back to Galen, who used a “twinned” model of the brain to explain functional redundancy. The theory persisted until Pierre Paul Broca demonstrated that unilateral lesions of the left hemisphere resulted in loss of speech despite the contralateral side remaining intact. Broca further observed that recovery of functions, eg, speech, occurred more readily in children than in adults, leading to the refinement of equipotentiality as a process more effective when injury occurs early in development.[16]

Vicariation differs in that it describes the brain’s ability to reorganize and recruit regions not originally responsible for a given function. Broca proposed this concept after observing preserved function in some patients with left hemispheric damage.[16] In its strictest sense, vicariation refers to the reassignment of entirely new, unrelated functions to different brain regions. Advanced imaging techniques have demonstrated that neither equipotentiality nor vicariation fully explains postinjury adaptation in isolation.

Clinical studies support a combined model of functional reorganization. Graveline, Mikulis, Crawley, and Hwang demonstrated that following hemispherectomy, typically performed for intractable seizures in early life, the remaining cerebral hemisphere can reorganize to restore lost function.[17] Functional magnetic resonance imaging revealed reorganization of supplemental motor and sensory regions to compensate for the affected side.[17] Jaillard et al reported similar findings in 4 adult patients following ischemic stroke of the right primary motor cortex, with serial functional imaging showing early bilateral premotor activation that later localized to the right supplemental motor cortex.[18] These findings illustrate the integration of equipotentiality and vicariation in recovery.

Diaschisis describes loss of function in a brain region remote from, but connected to, the site of injury.[19]  Constantin von Monakow introduced this concept to explain clinical deficits such as speech impairment in the absence of a corresponding focal lesion.[20] A well-described example involves hypoperfusion of the ipsilateral thalamus following an acute middle cerebral artery stroke. Despite an independent blood supply from posterior circulation branches, approximately 20% of acute cases show thalamic hypoperfusion on perfusion computed tomography.[21] Incidence increases to as high as 86% in subacute and chronic phases. Proposed mechanisms include disinhibition resulting from loss of gamma-aminobutyric acid–mediated neuronal input, leading to neurotoxicity and retrograde degeneration, although the impact on clinical outcomes remains unclear.[21]

The concept of diaschisis has expanded to encompass the following multiple patterns of network dysfunction:

• Diaschisis at rest: reflects the classic von Monakow model, eg, thalamic hypoperfusion in middle cerebral artery stroke.
• Functional diaschisis

  • refers to abnormalities that emerge during activation of connected regions, eg, hypoactivation of the ipsilateral cerebellum during task performance following putaminal lesions
  • dynamic diaschisis patterns may include both hypoactive and hyperactive responses, depending on the task
• Connectional diaschisis: involves disruption and rerouting of neural pathways, as demonstrated in animal models that show reduced interhemispheric motor connectivity following subcortical lesions [22]
• Connectome diaschisis: reflects disruption within highly interconnected neural networks, in which damage to critical hub regions produces disproportionately severe effects compared with peripheral nodes

Advances in neuroimaging continue to refine the understanding of functional brain connectivity, and the conceptual framework of diaschisis continues to evolve as knowledge of these complex networks expands.

Issues of Concern

The first concern is conceptual. Plasticity is not synonymous with recovery. A change in activation pattern, cortical map, or excitability may reflect efficient restitution, inefficient compensation, loss of inhibition, or maladaptive reinforcement. This distinction is central in stroke, chronic pain, and phantom limb phenomena, where network reorganization can improve performance or intensify symptoms depending on context.[23][24][25]

The second concern is overinterpretation of biomarkers. Transcranial magnetic stimulation (TMS), functional magnetic resonance imaging (fMRI), electroencephalography (EEG), diffusion imaging, and serum Brain-derived neurotrophic factors (BDNF) do not interrogate the same biology. A patient can show heightened cortical excitability on TMS, reduced functional connectivity on MRI, and unchanged serum BDNF while still making functional gains, because these assays sample different levels of organization and different time scales of change.[26][27][28]

The third concern is dose and timing. Plasticity is highly state-dependent. After acute brain injury, there may be a permissive period for reorganization, but that window can be narrowed by delirium, sleep disruption, pain, sedative exposure, uncontrolled seizures, depression, and prolonged inactivity. Stroke rehabilitation guidelines, therefore, emphasize organized interprofessional rehabilitation, early assessment of deficits, and progressively challenging task-specific therapy once the patient can participate safely.[29][30][29] Similar logic applies after TBI, where early inflammation helps clear debris and initiate repair, but prolonged neuroinflammation becomes toxic to synapses and network integration.[31] The practical implication is that the plasticity process should be supported. If the patient is exhausted, inflamed, immobile, and sleep-deprived, the biologic substrate for adaptive change is poor.

The absence of task specificity is another potential issue. Repetition alone is insufficient when practice is passive, poorly attended, or disconnected from the target function. Plasticity requires relevant firing patterns. In rehabilitation, this means that the task should resemble the impaired function, challenge the correct network, and be repeated at sufficient intensity to drive learning.[29][32] 

Maladaptive neuroplasticity is the main clinical hazard. Chronic pain is the clearest example. Repeated nociceptive input, stress, and avoidance behavior can reinforce central sensitization (activity-dependent amplification of pain processing) and alter sensorimotor and limbic networks. Once established, pain becomes less tightly coupled to the original peripheral lesion and more dependent on self-sustaining network dynamics.[23][24]

Clinical Significance

Neuroplasticity, the process of structural and functional changes in the brain following internal or external insults, is an encompassing term that includes multiple processes. Synaptic plasticity, functional reorganization, and diaschisis are distinct processes the brain employs in response to damage and in the restoration of function. As research continues to explore the brain's functional connections and the factors that influence them, more targeted therapies can be developed to help the brain regain function more quickly and more completely.

Stroke and focal brain injury remain the clearest clinical model for therapeutic neuroplasticity. Stroke rehabilitation guidance supports early, organized, interprofessional care, repeated task-specific training, and progressive strengthening and aerobic exercise once patients are medically stable and able to participate safely.[29]

Paired vagus nerve stimulation is now one of the most compelling examples of intentionally steering plasticity in chronic stroke. In the pivotal VNS-REHAB trial, 108 participants with moderate-to-severe arm weakness at least 9 months after ischemic stroke and baseline Fugl-Meyer Upper Extremity (FM-UE) scores of 20 to 50 were randomized to active or sham stimulation, both paired with upper limb rehabilitation. Active paired VNS produced clinically meaningful gains, with response rates approximately double those of sham, and almost half of treated patients achieved a clinical response.[33] 

Noninvasive brain stimulation has a broad evidence base, but the signal is heterogeneous. A 2023 network meta-analysis concluded that excitatory stimulation protocols appear most promising for upper-limb motor recovery and activities of daily living after stroke, while transcutaneous auricular vagus nerve stimulation also appears promising but requires larger confirmatory trials.[34] A 2024 meta-analysis suggested that dual-site protocols may outperform sham and single-site approaches for upper extremity impairment in selected patients.[35] Theta-burst stimulation also shows benefit for upper extremity motor recovery, with better responses in patients who retain preserved cortical tissue.[36] These techniques can be considered as adjuncts in specialized neurorehabilitation programs. But they should not yet be treated as a universal standard of care across all stroke phenotypes. Brain-computer interface-assisted rehabilitation is moving in the same direction. A 2025 umbrella review concluded that brain-computer interface combined therapy improves upper-limb motor recovery and activities of daily living. However, the strength of inference remains limited by methodological heterogeneity across systematic reviews.[36]

Clinically, several treatment options can be used to guide neuroplasticity to restore function and treat unwanted symptoms. An example is mirror therapy, a technique used in phantom limb pain. In a basic premise, the patient uses a mirror to cover their amputation and focuses on watching their intact limb perform activities while imagining that both limbs are performing the same activity. This has been shown to have increased activation and functional connectivity in the frontoparietal network.[11]

One of the most studied rehabilitation techniques is constraint-induced movement therapy (CIMT). In patients with a stroke, the premise is that constraining the functional limb engages the affected limb in repetitive task practice and behavioral shaping. Using fMRI technology, patients who engage in this therapy have been shown to have increased activity in their contralateral premotor and secondary somatosensory cortex in association with improved function.[37]

While therapies can guide neuroplasticity, multiple medications can also influence brain healing. These include selective serotonin reuptake inhibitors (eg, fluoxetine), serotonin-norepinephrine reuptake inhibitors (eg, duloxetine), cholinergic agonists (eg, donepezil, glutamatergic partial antagonists (eg, amantadine), and several others.[12] Amantadine has been shown to improve recovery in patients in a minimally conscious or vegetative state after a severe TBI.[38] Amantadine has also been shown to increase left prefrontal cortex activation, associated with improved cognitive functioning in patients with chronic TBI.[39] As research continues, we will be able to utilize pharmacological treatments further to help guide the brain back to health.

Maladaptive plasticity reflects the potential for neuroplastic changes to produce harmful outcomes rather than functional recovery. Aberrant neural connections may generate negative or pathological symptoms, as demonstrated in conditions, eg, use-dependent dystonia, including writer’s cramp, and phantom limb pain.[9] Both conditions demonstrate abnormal alterations in the primary sensory cortex associated with persistent pain and dysfunction.

Ongoing research has focused on modulating neuroplasticity through environmental and behavioral interventions. Music therapy demonstrates beneficial effects on neuroplastic processes, with improvements in cognition and executive function.[40][41] Regular exercise supports enhanced episodic memory and processing speed while reducing age-related hippocampal atrophy.[42] Nutritional factors also contribute, with a healthy diet supporting adaptive brain changes, and various dietary supplements under investigation for their potential to promote neuroplasticity. Stress reduction and avoidance of sleep deprivation further support cognitive performance, including improvements in memory, attention, and related cognitive domains.[43][44]

Other Issues

Neurosurgical disease provides another important application of neuroplasticity. Slow-growing brain tumors can permit partial functional redistribution across cortical and subcortical networks, particularly within the language and motor systems. Recent reviews emphasize that this reorganization spans the molecular, structural, and systems levels and is influenced by tumor location, growth rate, white matter involvement, and patient-specific reserves.[45][46] For physicians involved in surgical planning, the implication is that knowledge of normal neuroanatomy alone is insufficient when a lesion approaches the eloquent cortex. Preoperative mapping should be individualized, and discordance between structural imaging and bedside deficits should raise the possibility of compensatory reorganization.[47] Plasticity can expand the safe resection window in selected cases of brain tumors. These surgeries typically require preoperative fMRI and diffusion tensor imaging (DTI), awake mapping with direct cortical stimulation (DCS), tract-sensitive surgical planning, and postoperative rehabilitation because reorganization is often incomplete and network-specific.

Enhancing Healthcare Team Outcomes

Neuroplasticity refers to adaptive structural and functional changes in the nervous system in response to injury or experience, with major relevance in stroke, traumatic brain injury, and chronic pain. Mechanisms include synaptic plasticity, collateral sprouting, and functional reorganization via vicariation and diaschisis, which evolve across the acute, subacute, and chronic phases. Clinical outcomes range from functional recovery to maladaptive changes such as central sensitization. Accurate interpretation of biomarkers, including functional imaging and neurophysiologic studies, remains essential, as these reflect different levels of network activity. Evidence supports early, task-specific, and progressively intensive rehabilitation, with adjunctive use of neuromodulation, pharmacologic agents, and behavioral interventions to optimize recovery and limit complications.

Interprofessional collaboration improves outcomes by aligning timely diagnosis, individualized rehabilitation, and longitudinal monitoring. Physicians and advanced practitioners direct evaluation, guide treatment selection, and coordinate referrals. Primary care clinicians support continuity, risk factor modification, and long-term follow-up. Nurses monitor functional progress, reinforce therapy adherence, and identify complications. Pharmacists optimize medication regimens and mitigate adverse effects. Rehabilitation therapists deliver task-specific interventions, while psychologists address cognitive and behavioral factors. Coordinated communication, shared decision-making, and early referral to specialized services enhance safety, reduce maladaptive plasticity, and promote patient-centered recovery.

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Disclosure: Konstantinos Margetis declares no relevant financial relationships with ineligible companies.

Disclosure: Elsa Vadakekut declares no relevant financial relationships with ineligible companies.