While in some cases focal perinatal brain damage can elicit

While in some cases focal perinatal Calcitriol damage can elicit resilience as above, discrete ischemic events can also have secondary and more widespread consequences for brain function (Volpe, 2009). Some of these secondary effects may be part of the local adaptive response, while others may be toxic. For example, following Periventricular Leukomalacia (a white matter brain injury that effects newborns) primary focal events involve cellular damage and glial “scars”, while secondary more diffuse effects occur in white matter such as increases in astrocytes and microglia, and an initial decrease in oligodendrocytes that can lead to hypo-myelination. Animal models show that these secondary effects can result in diffuse signal processing abnormalities (see Volpe, 2009 for review). In cases where secondary effects are sufficiently widespread, the usual options for alternative structure-function mappings in the brain may be disrupted, making the typical developmental trajectory less attainable. Several authors have suggested graded scales of the extent of neonatal brain injury with the purpose of better predicting later outcome (e.g., Low et al., 1988; Marlow et al., 2005; Van Handel et al., 2007). For example, a common secondary consequence of perinatal asphyxia was neonatal encephalopathy (NE), a clinical syndrome of disturbed neurological function sometimes accompanied by seizures. While now commonly treated by head cooling (Edwards, 2009), NE has been typically graded on one of several severity scores as being mild, moderate or severe (Van Handel et al., 2007). While these are inevitably coarse categories for complex and diffuse brain disturbances, they nevertheless give us the opportunity to assess the consequences of different degrees of early perturbation to the developing brain. Mild NE rarely leads to significant later intellectual or cognitive problems, demonstrating the resilience of the neonatal brain in the face of brief (less than 24h) adverse events, similar to the focal cortical lesions described above. In contrast, severe NE usually results in significant developmental delay, low IQ, and poor educational attainment (reviewed in Van Handel et al., 2007). Most relevant for the present discussion, moderate NE had more variable outcomes. While these children often scored within development norms from infancy to school years, some individuals had deficits in receptive vocabulary, language and visuo-motor integration, in addition to raised rates of hyperactivity and autism (Badawi et al., 2006). A systematic review of the pre and perinatal factors associated with later autism reveals one of the most significant factors across studies is intrapartum hypoxia, and its related measures such as low Apgar score (Kolevzon et al., 2007). Hypoxic effects are usually widespread in the brain, albeit that the hippocampus and thalamus may be particularly susceptible. It is thus conceivable that intrapartum hypoxic injury to the brain is often of the mild and diffuse kind that subsequently triggers the alternative developmental trajectory leading to the behavioral phenotype of autism. These examples illustrate a general principle of developmental pathways (Waddington, 1966) that the typical route (chreod) is generally well buffered against minor or transient perturbations (mild NE), but that more significant and longer lasting disruption within a sensitive period can divert development to an alternate pathway in which a different profile of abilities, disabilities and behaviors can emerge (moderate NE). Finally, a more severe and long lasting disruption of development will exceed the limits of adaptation resulting in slow progression down any developmental pathway, and poor life-long outcomes over all domains (severe NE).
Domain specific effects and uneven cognitive profiles (Question 1) The causal factors underlying atypical neural processing can take a variety of different forms. For example, Rubenstein and Merzenich (2003) proposed that an atypical balance of excitatory and inhibitory activity within brain circuits may be a common feature of autism. While we have some understanding of the consequences of major imbalances between excitatory and inhibitory processes (e.g., epilepsy), the computational consequences of more mild imbalances or dysregulation in early development remain largely unknown. One of the functions of intrinsic inhibitory processing is to increase the signal to noise ratio by “cleaning up” spontaneous neural firing that is not directly linked to stimulus presentation or ongoing processing (Toyoizumi et al., 2013). However, on the flip side certain levels of background “neural noise” may in fact be critical to the development and specialization of cortical regions. Appropriate levels of noise can ensure that neural networks adaptively settle to appropriate configurations for the data processed, as it ensures that the network is not captured by local minima (Davis and Plaisted-Grant, 2015). However, excessive noise can also mask the appropriate signal, resulting in delayed opening of critical periods (Toyoizumi et al., 2013), delayed specialization of neural networks (Rubenstein and Merzenich, 2003) and changes in brain-wide connectivity (Eichler and Meier, 2008). These kinds of changes in the fidelity of neural processing could potentially occur for a number of reasons in addition to, or acting together with, genetic propensity.