Acquired brain injury

Several million cases of traumatic brain injury occur within the United States, with the majority being mild injuries that do not lead to long-lasting neurologic disability. In 2019, there were nearly 10 million deaths and 349 million disability-adjusted life years (DALYs) worldwide due to neurologic disorders. Among the 18 neurologic disorders, stroke was the biggest contributor, followed by neonatal encephalopathy due to birth asphyxia and trauma (14). Between 1990 and 2019, ischemic stroke rose from the 9th to 4th leading cause of years lost prematurely, and hemorrhagic rose from 13th to 8th (43). In the previously mentioned global burden of disease study, although neurologic diseases belonging to the communicable, maternal, neonatal, and nutritional categories showed a sharp decrease, neurodegenerative conditions such as Alzheimer disease and Parkinson disease showed a large increase (14).

Traumatic brain injury, another common cause of acquired brain injury, is estimated to have an annual worldwide incidence of 295 new cases per 100,000 (32). Roughly 43% of patients hospitalized after traumatic brain injury develop long-term disability. Mass lesions, such as neoplasm and abscess, and anoxic brain injury are additional causes of acquired injury. More recently, the COVID pandemic resulted in millions of infected survivors having persistent prolonged or late-onset sequelae, which has been dubbed “long COVID” or post-acute COVID syndrome. Amongst those with long COVID, approximately one third suffer from neurologic sequelae, including “brain fog” (a type of cognitive impairment), sleep disorders, and depression (42).

Acquired brain injury of either traumatic or nontraumatic origin leads to two major types of deficits. Direct deficits occur from injuries to sites, pathways, and nuclei responsible for certain functions, thereby leading to dysfunction. Examples of such impairments include aphasia, hemiparesis, and visual field deficiencies. On the other hand, indirect deficits, as the term implies, cannot be ascribed to specific lesion sites and classical neurologic lesion localization. Examples include mood disorders (eg, depression), cognitive disorders, and sleep disorders. These deficits are thought to arise from disruption of widely distributed functional networks (09). Indirect deficits may not appear immediately after a brain injury and may take weeks to months to appear. A common example of this phenomenon is spasticity.

Neuroplasticity and neurorehabilitation

The human brain recovers from brain injury in three main ways: adaptation, regeneration, and neuroplasticity. Most successful rehabilitation techniques incorporate at least one of these processes. Adaptation is the reliance on alternative physical movements or devices to compensate for deficits. An example would be using the nondominant hand to feed oneself after hemiplegia affecting dominant hand function. Assistive devices include a walker for gait and balance dysfunction and prisms in glasses to compensate for visual field deficits. Although adaptation is helpful, it may also harm the recovery process because of learned disuse. This phenomenon occurs when individuals do not use their affected limb because they have developed habits to complete actions and tasks bypassing use of the limb, even though they have the capacity to use it. Limiting limb use can also limit that limb’s improvement and recovery. In fact, constraint-induced therapy was developed to address this “learned disuse.”

Regeneration is the growth of neurons, its associated cells and circuity to replace those damaged by an acquired injury. Historically, it has been considered least useful in stroke rehabilitation as it was believed that central nervous system tissue did not have the capacity for regrowth after injury. However, regeneration has been the focus of attention in recent years because of research advances in stem cell and growth factor interventions. Questions remain regarding the type of stem cell to use, how to deliver it (intravenously, via surgical resection, or endovascularly), dosing, and long-term safety effects (04). Nevertheless, ongoing clinical trials attempt to answer these questions, and regeneration holds hope for the future.

Neuroplasticity, generally defined as changes or a rewiring in the neural network, is generally accepted as the main recovery process. Soon after an injury, activity is decreased in areas directly affected by the injury. This phenomenon was named “diaschisis” by Constantin von Monakow in the past. As time progresses through the acute and subacute period, the neural networks, which had been disrupted by the injury, reconnect in adjacent areas and coincide with clinical recovery. These reconnections represent widespread changes in growth of axons, and formation of new synapses occur, leading to further neurologic recovery (38). Research studies have demonstrated that neuroplasticity is driven by several key principles. For plasticity to fully occur, rehabilitation interventions must be task-specific and goal-directed rather than general and nonspecific movements. Furthermore, the goal-directed tasks must be challenging and interesting enough to maintain an individual’s attention, and the task should allow for repetition through multiple attempts. Therapists work to employ these principles and tailor their exercises and treatments to individuals to optimize recovery; they also use adaptive methods when needed.

Rehabilitative programs effectively improve functional outcomes after acquired brain injury, and early access to rehabilitation services is associated with greater functional recovery. A dose effect has been demonstrated, and a program of at least 30 to 60 minutes per day, at least 5 days a week, is noted to provide substantial improvement (36). In general, no particular rehabilitative strategy has been found more effective than another (36).

Uncertainty remains regarding the optimal timing and intensity of rehabilitation. In a study examining differences in outcomes for patients for whom therapy was initiated 20 days apart, a strong inverse relationship between the start date and functional outcome was observed, albeit with wide confidence intervals. In other words, those who initiated therapy soon after stroke onset exhibited significantly higher effectiveness of treatment than did the medium- or late-initiating groups. Treatment initiated within the first 20 days was associated with a significantly higher probability of excellent therapeutic response compared to treatment beginning at 20 or 40 days (34).

In the A Very Early Rehabilitation Trial (AVERT), 2104 patients who were hospitalized with either ischemic or hemorrhagic strokes were randomly assigned to receive customary therapy or a very early intervention. In the intervention arm, the first mobilization was aimed to begin within 24 hours following stroke onset, with the additional goals of the patient being upright and out of bed at least twice daily. This intervention continued for the first 14 days poststroke or until discharge from the acute stroke unit and was delivered by a physical therapy team, including a trained nurse. The early mobilization group had a worse outcome, defined as a modified Rankin Score of less than 3, compared to the standard care group (46% versus 50%; adjusted odds ratio = 0.73, P = .004) (02). However, in a prespecified dose-response analysis of the trial, it appears that shorter but more frequent sessions of early mobilization improved patients’ chances of regaining independence. Similarly, early rehabilitation starting within 48 hours demonstrated benefit in 6-month survival and functional outcomes in patients with intracerebral hemorrhage (30).

Once therapy is initiated, unanswered questions exist regarding the ‘‘dose’’ of rehabilitation. Data from the Very Early Constraint-Induced Movement During Stroke Rehabilitation (VECTORS) trial, a study of the amount of therapy and motor improvement after stroke, suggest that more therapy does not always result in significantly better outcomes (15). Generally accepted practice at this time includes initiating therapy consults within the first 48 hours, using less intense therapy practices as determined by the rehabilitation teams and tolerated by patient, and, for those who can tolerate it, increasing the intensity of rehabilitation in the rehabilitation and outpatient setting.

In addition, the Interdisciplinary Comprehensive Arm Rehabilitation Evaluation (ICARE) clinical trial compared the efficacy of a structured task-oriented motor training program to a dose equivalent of standard therapy versus usual therapy or recovery of the upper extremity (45). In this trial, the task-oriented program and the dose-equivalent therapies were presumed to be at a higher dose of therapy than the standard of care. However, in this randomized, multicenter trial, motor function was not different amongst the groups.

Rehabilitation approach principles

Natural history and pattern of recovery. Observational studies have provided insight into the natural history of recovery from an acquired brain injury. It is generally believed that the first few weeks postinjury, the so-called acute-subacute period, is the time frame for the greatest rate of spontaneous recovery.

Although a great amount of recovery is experienced initially, most survivors who do not achieve early and complete recovery eventually reach a plateau phase without additional significant spontaneous improvement. In the Copenhagen Stroke Study, a cohort study of over 1100 patients hospitalized with acute stroke found maximum arm motor function within 9 weeks poststroke in 95% of patients. Among those with lower extremity paresis, recovery of walking function occurred in 95% of the patients within the first 11 weeks after stroke (28). The time and the degree of recovery were associated with the degree of functional walking impairment and the severity of lower extremity paresis. In a longitudinal study of patients with long COVID and neurologic symptoms, only one third demonstrated complete resolution of symptoms at 6 months, but most showed improvement in cognition (39). A study also showed that most stroke survivors (with exception of patients with initial severe disability) can recover about 70% of their maximal recovery potential (37). This “70% rule” has been replicated in multiple studies. Similar findings have been observed in patients with aphasia or neglect, with recovery plateaus occurring at approximately 6 weeks and 3 months, respectively (24).

General patterns are also seen with respect to rate of recovery among various types of deficits. For motor deficits, proximal recovery usually occurs before distal recovery, and lower extremity deficits have faster recovery in terms of disability measures when compared to upper extremity deficits. Swallowing, facial movement, and gait tend to demonstrate better recovery. Eloquent cortical functions, such as language, dominant hand movement, and spatial attention, are more lateralized in function and recover more slowly (10).

Predictors of recovery and prognostic factors. A common question or issue posed by patients and their families relates to recovery from and prognosis after injury. Similar to other diseases, there are multiple contributing factors that affect overall prognostication. The initial injury serves as an important prognostic factor for subsequent stroke recovery. As an example, the more severe the initial injury as defined by motor function, the more impairment patients will experience in the chronic phase (16). Comorbidities, such as diabetes, degree of periventricular white matter disease, prior stroke, etc., can adversely affect the stroke outcomes (19; 26). Depression is another comorbidity that can occur after a CNS injury; the interaction between poststroke depression and neurorecovery is complex, but studies have demonstrated that depression can impede rehabilitation and jeopardize quality of life.

Although some studies have shown that increased age is a significant prognostic factor for poorer outcomes (31), others have reported different views (03). Socioeconomic status (insurance coverage, educational level, household income, etc.) is tied with access issues and subsequent recovery outcomes. The relative or complete lack of health insurance coverage may delay or limit access to rehabilitative services. Genetic variation may account for some of the inter-individual variability in recovery. Of these gene candidates, brain-derived neurotrophic factor (BDNF) is the most widely investigated. Studies have shown that it plays a major role in synaptic plasticity as well as in learning and memory, thereby possibly affecting stroke recovery (35). In a study of patients with progressive multiple sclerosis, those with the BDNF Val66Met genetic polymorphism were associated with walking function improvement after rehabilitation (21).

For stroke patients, recovery of the upper and lower extremities can be predicted through an algorithm dubbed the PREP2 algorithm. This algorithm uses clinical exam findings of shoulder abduction, finger extension in combination with the presence of motor-evoked potentials, patient age, and stroke severity as measured by the NIH Stroke Scale (NIHSS) to predict recovery within the 1 to 7 days after stroke (41). Algorithms are useful in counseling patients and their families about setting realistic expectations, receiving appropriate rehabilitation, and planning for further rehabilitation. Similar algorithms can help with other stroke disciplines.

Sites for rehabilitation. The goal of neurorehabilitation should be to facilitate relearning of skills that were possible before the brain injury, but in some cases, the focus of rehabilitation must be adaptation and compensation for deficits. This process begins while the patient is hospitalized for stroke and involves motor-skill retraining, preventing complications, and teaching adaptive techniques using a comprehensive approach. In the United States health care system, patients in need of further neurorehabilitation following acute hospitalization have three possible posthospital dispositions: (1) home with outpatient therapy, (2) home with home health therapy, or (3) inpatient rehabilitation facility or skilled nursing facility placement. The disposition is based on the nature and severity of deficits, comorbidities, and insurance or reimbursement options.

Much of the current rehabilitation involves face-to-face contact with a therapist or healthcare professional. However, this may be a limitation for people whose health or stroke severity limits their ability to meet with therapists. Furthermore, patients who live in rural areas may also be unable to access proper rehabilitation services based on distance. With improvements in technology, telemedicine is an option. In fact, a home-based telerehabilitation program demonstrated an equal benefit compared to traditional in-clinic rehabilitation (11).

Rehabilitation team members. Rehabilitation is provided in a team-based approach and involves various disciplines, such as physical therapy, occupational therapy, and speech and language therapy. The role of the team involves setting goals, reevaluating these goals on a regular basis, and making adjustments to the rehabilitation plan as needed. In addition to improving the patient’s function, caregiver training is an important aspect of rehabilitation.

Physical therapists perform evaluations to detect problems with movement and balance. They work with the patient and the rehabilitation team to perform exercises to strengthen muscles for walking, standing, and other activities. Occupational therapists help brain injury survivors learn strategies to manage daily activities, such as eating, bathing, dressing, writing, and cooking. Speech and language pathologists (ie, speech therapists) help brain injury survivors learn strategies to overcome swallowing and language deficits. In the acute setting, they are involved with dysphagia and swallowing evaluations and may make recommendations for alternative methods of oral intake, such as nasogastric tubes or percutaneous endoscopic gastrostomy tubes. In the subacute and outpatient settings, aphasia tends to be the focus of speech and language therapy.

Following the initial evaluation, therapists develop a program and provide exercises that use the principles of neuroplasticity mentioned previously (task specificity, repetition, challenging). The teaching of compensatory and adaptive techniques is another important goal. Therapists train the patient and family in activities such as safe transfers, assisted ambulation, proper feeding, and provision of appropriate adaptive techniques.

Devices and adjunctive therapies. Device-based and adjunctive therapies, such as robotic arms and bodyweight support treadmills, have been proposed; however, studies have failed to demonstrate their superiority over currently used therapies, and evidence to support regular clinical use is lacking (29; 17).

More recently, a device familiar to neurologists but used in a novel way has been shown to improve recovery. Specifically, in the VNS-REHAB study, vagus nerve stimulators when paired with traditional therapy improved motor function in the upper extremity of persons with stroke compared to traditional therapy alone as measured by the Fugl-Meyer Assessment (12). It is important to highlight that the subjects in the study were at least 9 months post-stroke, so well beyond the spontaneous recovery timeline. Noninvasive brain stimulation using transcranial magnetic stimulation or transcranial direct current stimulation induces neuroplasticity by applying an electrical current or magnetic field to induce depolarization in specific areas of the brain. They have been shown, albeit in small studies, to improve motor function in neurologic disorders such as stroke, Parkinson disease, and multiple sclerosis (18). Several nontraditional strategies have demonstrated improved efficacy compared to traditional therapy. Constraint-induced movement therapy is a motor rehabilitation therapy technique in which the unaffected extremity is constrained with a mitt, thereby forcing use of the affected hand. This approach, even in a modified dose using a lower frequency of constraint-induced movement therapy, has been shown to be more effective than standard therapy in the 3- to 9-month poststroke window (46; 33). Melodic intonation therapy has been shown to enhance recovery of poststroke aphasia (44).

Melodic intonation therapy uses musical elements, including melody and rhythm, to improve language production. Spoken language has elements such as intonation, stress, and rhythm, which are referred to as prosody. The theoretical basis of melodic intonation therapy is that language is localized in the dominant hemisphere, but singing and prosody localize to the nondominant hemisphere. In fact, lesions in the nondominant hemisphere can result in aprosody, whereby patients sound monotonous. Consequently, users of melodic intonation therapy take advantage of preserved singing abilities in the unaffected hemisphere and engage language-capable regions in the nondominant (usually right) hemisphere. Although robust evidence for this approach is lacking, it appears that this therapy is most beneficial in stroke survivors with expressive (Broca) aphasia but retained expressive abilities as well as absent bihemispheric damage.

Functional electrostimulation is another technique that can enhance motor recovery in patients with stroke (01; 47). This technique involves applying electrical stimulation to muscles of interest. Functional electrostimulation devices are commercially available, and improving these types of devices is an area of active research interest. The most widely known use for functional electrical stimulation is stimulation of the peroneal nerve to stimulate ankle dorsiflexion, which can be used to treat foot drop. The use of a peroneal nerve functional electrical stimulation device has been found to be as effective in managing foot drop as ankle foot orthosis in patients with chronic stroke (40).

For common sequelae after brain injuries, specific interventions are recommended but require a multidisciplinary approach. For instance, post-stroke pain syndromes can be managed with medications, targeted joint injections with corticosteroids, and psychological approaches, such as biofeedback (13). Another common sequela, spasticity, can be treated with oral medications, botulinum toxin injections, and splinting (07).

Medication management

No medications are currently approved by the Food and Drug Administration to enhance neurologic recovery after acquired brain injury.

The Fluoxetine for Motor Recovery After Acute Ischaemic Stroke (FLAME) trial was a randomized, double-blind, placebo-controlled trial comparing fluoxetine 20 mg/d and placebo beginning 5 to 10 days after stroke in patients with hemiplegia or hemiparesis. In the intervention group, the change in motor function, as measured by the Fugl-Meyer score, was significantly higher than in the placebo group (08). However, in the much larger FOCUS trial, although fluoxetine improved depression scores, it did not improve functional measures 6 months poststroke (20).

Other antidepressant or neuromodulating agents have also been examined with suggested positive benefits. For example, clinical trials using cholinesterase inhibitors and glutaminergic agents suggest improvements in aphasia rehabilitation (05; 06; 25). Similarly, it appears that dopaminergic medications may help address depression and attention (27; 23). The trials are limited by their small numbers, heterogeneity of stroke size, and locations. Given these limitations, insufficient evidence exists to implement these medications in routine clinical practice.

Certain medications can impair poststroke recovery when used in the acute period. Based on their mechanistic effect on neurotransmitters, older antiepileptic agents, such as phenobarbital, diazepam, and phenytoin, can impede synaptic formation in animal models (22). To avoid such detrimental effects on poststroke recovery, newer-generation antiepileptic drugs should be considered as the first-line treatment for poststroke seizures.

Conclusion

Acquired brain injury can occur from both traumatic and nontraumatic causes, leading to a variety of functional deficits. Early access to rehabilitation with a focus on repetitive task-specific training can enhance neuroplasticity and lead to improved functional recovery.