What is currently known about recovery from early brain insult? - Chapter 4

Recovery from early brain insult has been studied for a long time with studies dating back to the 1920s. However, recovery from early brain insult still remains imperfectly understood. Brain insults that almost certainly would result in severe cognitive dysfunction in an adult brain, appear to have rather different consequences for a developing brain. The aim of this chapter is to examine current understandings of outcomes from early brain insult. In doing so, the concepts of vulnerability and plasticity will be discussed and considered as opposite extremes along a recovery continuum. Where the recovery of an individual child falls along this continuum will depend upon a number of factors, including:

• Injury-related factors (nature of the lesion, severity, timing of insult).
• Constitutional factors (developmental stage, cognitive capacity, genes, gender).
• Environmental factors (family function, social status, access to rehabilitation and interventions).

Although these factors may independently impact recovery from early brain insult, it is more likely that they will interact dynamically, yielding a wide spectrum of outcomes observed in children post-early brain insult.

How are brain plasticity and vulnerability related to recovery from early brain insult?

Brain plasticity refers to the capacity of the brain to respond dynamically in response to the environment and experience, through modification to neural circuitry. A further distinction can be made between neural plasticity (the brain's response to the environment; referring to physiological processes at molecular, cellular, neuro chemical, and neuroanatomical levels) and functional plasticity (behavioural change of recovery). Neural recovery may not necessarily lead to functional recovery. Brain plasticity is not specific to the immature brain, and also occurs in a mature brain. Plasticity is a beneficial concept in the context of healthy development, because it facilitates adaptive change in response to environmental stimuli. 

The influence of brain plasticity after brain insult is less well established. Although there may be an opportunity to take advantage of the lack of functional specificity in the immature brain (for example via transfer of functions from damaged to undamaged areas), the brain's capacity for plasticity may also reflect vulnerability with predetermined developmental processes being derailed, neural resources depleted, and an absence of a developmental 'blueprint' to guide recovery. 

Two explanations for the differential susceptibility theory

There is a lot of variability in outcome from early brain insult, which is in agreement with the differential susceptibility theory. Although children may demonstrate great capacity for plasticity, they can also demonstrate poor recovery. Two contradictory explanations have been proposed for these seeming inconsistencies:

1. Early plasticity: the immature brain possesses great flexibility, which facilitates good recovery and outcome.
2. Early vulnerability: the immature brain in uniquely susceptible, with early brain insult leading to incomplete recovery and poor outcome. 

Both views agree that infancy and childhood are developmental stages that are associated with unique responses to brain injury. Both suggest a mainly lineair relationship between age at brain insult and functional outcome. However, they differ drastically with regard to the interpretation of the direction of this relationship. A central concern in this debate is whether specific brain functions are innately specialised to specific brain regions or whether the brain is equipotential (with minimal functional localisation early, hence facilitating healthy brain tissue to adopt functions that were previously the responsibility of the damaged areas). A compromise between these two is offered by interactive specialisation, where brain development is characterised by increasing specialisation or fine-tuning of responses. These responses are specific to brain regions, yet they are changing as they interact and compete to acquire their roles. 

Neurobehavioral recovery from early brain insult: what is the evidence?

Evidence of neurobehavioral recovery from early brain insult derives from various research methods such as human research and animal research. Yet, animal research has been and continues to be of particular influence, having the advantage of being able to control for confounding factors such as lesion size and location, age at lesion, and environment. A common finding in animal research is the Kennard principle, demonstrating that early lesions lead to better outcomes than similar lesions in adulthood. Although human research has demonstrate some good recovery outcomes, the identified relative advantages and disadvantages of early brain plasticity are plagued by methodological flaws, which likely explain some of the inconsistencies in reported findings. 

Which mechanisms underpin recovery? 

Recovery mechanisms can be divided into two general classes:

1. Restitution: as the damaged brain recovers, neural pathways are reactivated and functions are restored. 
2. Substitution: recovery occurs via transfer and reorganisation of functions from damaged brain tissue to healthy sites. 

Restitution

One of the best-established theories of restitution is the one of diaschisis, which refers to the period (acute phase) of rapid recovery of function immediately following brain insult. Research has demonstrated that in humans, damaged cell bodies cannot be replaced and damaged axons show slow and minimal growth. Regeneration processes are highly localised at best and often hindered by scar tissue and blood clots. On the other hand, some neural components have the capacity for sprouting or reinervation by locating a new cell 'target' and reconnecting to functional systems. Another mechanism for restoration of function is denervation supersensitivity: a process whereby post-synaptic cells that are deprived of synaptic input, will develop sensitivity to any neurotransmitter substance leaking from pre-lesion neurons via the emergence of new receptors and a larger surface area. Hence, supersensitivity facilitates activation of post-lesion pathways and restitution of normal functioning. Lastly, restitution of molecular genetic process may occur via protein phosphorylation (neural activity is modulated via regulation of ion channels and neurotransmitter receptions, signal transduction pathways, neurotransmitter synthesis) and regulation of gene expression (producing quantitative and qualitative changes in protein components of neurons, such as modifications of the frequency and nature of ion channels and receptors of the cell membrane). 

Substitution

Substitution of function is largely supported by indirect evidence, such as behavioural data and functional imaging of change in the injured brain. There are a number of possible scenarios for functional reorganisation:

1. Interhemispheric reorganisation: functions are considered to transfer to analogous sites in the non-damaged hemisphere.
2. Intrahemispheric reorganisation: functions are reorganised within the damaged hemisphere.
3. Intrahemispheric maintenance: skills subsumed by damaged tissue are maintained by that tissue, resulting in maximum dysfunction. This is associated with the poorest outcome. It is thought to occur following bilateral or diffuse insults where little healthy brain tissue is available to support reorganisation. 

Which factors influence recovery following early brain insult?

Consider again the recovery continuum in which early plasticity and early vulnerability are not seen as opposing views, but rather represent extremes along a continuum. Where an individual falls on this continuum after early brain insult, depends on multiple factors:

• Injury-related factors: nature, extent, and site of insult:
  • The influence of the extent of a lesion on outcome can be best represented by a U-shaped curve, with small and large lesions leading to better outcomes than intermediate lesions. As expected, small lesions appear most sensitive to plasticity and are consistently associated with good recovery. Interestingly, large, unilateral lesions, may yield such extensive damage, that they force interhemispheric transfer of function, yielding minimal impact on functional abilities. 
  • The worst recovery is documented for early brain insult which is diffuse or bilateral, where greater lesion volume is associated with worse impairment.
  • In contrast to adult findings, there is little evidence for a relationship between brain lesion site and outcome.  
• Age / developmental level at time of brain insult: 
  • There is a complex and non-linear relationship between age at insult and recovery. There is evidence that this relationship is not linear, in particular in early adulthood where rapid, stepwise changes are occurring within the brain. 
• Sex:
  • Girls generally demonstrate a higher development rate of the brain throughout childhood. Grey matter volume peaks at around age 10 in girls, whereas it is above age 12 in boys. Girls also demonstrate greater dendritic volume and more bilateral activation. If female brain are more diffusely organised and have a greater capacity for functional transfer, there ma be greater potential for plasticity and reorganisation of function. 
• Environment and experience:
  • Enriching environments are important for optimal development. Environmental factors have been identified as crucial for recovery from early brain insult.
• Time since testing:
  • Important due to: (i) the rapid recovery that occurs post insult; and (ii) the potential for children with early brain insult to struggle to keep pace with their peers. Children may demonstrate impairments that will recover with time (delayed development) or one may fail to identify impairments in skills that are yet to develop (emerging deficits).