Regulatory disorders in children, often stemming from premature birth or perinatal asphyxia, manifest as behavioral, vegetative, sensory, and cognitive disturbances. Perinatal asphyxia, in particular, is a significant cause of brain damage and subsequent neurological sequelae, resulting in high individual and societal costs. These disorders can impact behavior regulation (e.g., hyper- or hypo-reactivity to stimuli), autonomic function (heart rate, temperature, circadian rhythms), sensory processing, and executive cognitive functions, ultimately affecting school performance. Neurodevelopment is a continuous process influenced by intrinsic and extrinsic stimuli, and disruption of this process can lead to chronic low-grade inflammation or parainflammation. Prior research by the authors demonstrated a link between perinatal risks, neurological signs, and altered inflammatory molecule concentrations. This current study aimed to examine whether different expressions of neurological disorders exhibit unique inflammatory molecule profiles or share a common pattern. The researchers hypothesized that the specific inflammatory response would be dependent on the type, chronicity, and location of the neurological dysfunction.

The literature review included studies on the impact of perinatal risks, particularly asphyxia, on neurodevelopment and subsequent inflammatory responses. Studies highlighted the long-term consequences of perinatal brain damage and the potential for chronic low-grade inflammation. The authors referenced previous work demonstrating a correlation between perinatal risks, neurological signs, and alterations in inflammatory molecules, suggesting that even subclinical dysfunction could lead to long-term inflammatory responses. Additional literature discussed the role of inflammation in neurodevelopment, including the effects of cytokines on brain structure and function, as well as the interplay between neuro-immune interactions and homeostatic responses. The researchers reviewed existing knowledge on the inflammatory response, exploring both the acute phase and chronic, low-grade inflammation, and the role of resolution pathways.

This observational, descriptive, cross-sectional, partially retrospective study included preschoolers (4-5 years) born in Mexico City between March 2014 and December 2016 who had undergone neurodevelopmental assessments and neurological diagnoses. Data on dysautonomia diagnosed during the first year of life was retrospectively collected. The Bayley III scale assessed cognitive, motor, language, social-emotional, and adaptive development. Clinical assessments by specialists evaluated muscle tone, reflexes, dysautonomic signs, and developmental patterns. Parents completed the DeGangi instrument to assess the risk of regulatory disorders. The study included 45 children, with 27 having complete inflammatory molecule data. Peripheral blood samples were collected (5-10 ml), serum separated, and stored at -70°C. A multiplex system (Luminex MAGPIX) and Affymetrix Human Inflammation Panel (20-plex) analyzed various inflammatory molecules, including cytokines and chemokines. ELISA kits measured resolvin D1 (RvD1), lipoxin A4 (LXA4), leukotriene B4 (LTB4), and Annexin A1. Data was transformed into Z-scores. Statistical analysis employed ANOVA, Tukey-Kramer post-hoc test, and Wilcoxon test where appropriate, considering p<0.05 as significant and p<0.1 as marginally significant. Inclusion criteria involved children with more than three neurodevelopmental assessments and specific perinatal risks; exclusion criteria included genetic syndromes, cerebral palsy, convulsive syndromes, and chronic inflammatory diseases.

The study revealed distinct inflammatory molecule profiles associated with different neurological disorders. Children at high risk for regulatory disorders exhibited a "hyper-resolution" state, characterized by low concentrations of pro-inflammatory (INF-gamma, IL1beta, IL-8) and anti-inflammatory (IL-4, IL-13) cytokines and elevated levels of the pro-resolving mediator lipoxin. Conversely, children at low risk showed the opposite pattern. Children with neurological alterations (asymmetry and dysautonomia) also showed lower cytokine levels (IL-12p70, IFN-gamma, TNF, IL-4, IL-13, and IL-10) compared to those without these alterations. In contrast, children with below-average cognitive development demonstrated higher concentrations of several pro-inflammatory molecules (IL1-b, IL-6, IL-8, IL-12p70, IL-17, MIP1, INF-g, and P-Selectin) and IL-4, with lower levels of lipoxin. This suggests a sustained pro-inflammatory response in children with cognitive impairment, and a dampened inflammatory response with a predominant pro-resolving state in those with regulatory disorders and motor asymmetries. The authors proposed a theoretical model depicting how chronic dysfunction could lead to either a sustained pro-inflammatory response (as seen in cognitive impairment) or a hyper-resolution state (observed in regulatory disorders and motor asymmetries).

The findings support the hypothesis that chronic neurodevelopmental dysfunction is associated with characteristic but variable inflammatory molecule profiles. The contrasting patterns observed between children with cognitive impairment and those with neurovegetative disorders highlight the complex interplay between neuroinflammation and the specific nature of the dysfunction. The hyper-resolution state identified in children at high risk for regulatory disorders suggests that a sustained inflammatory stimulus might lead to a compensatory mechanism that ultimately limits the full inflammatory response. These results emphasize the need for a detailed mapping of immune/inflammatory response mediators in different states of chronic dysfunction to better understand and manage these conditions. This study contributes to a deeper understanding of the role of neuroinflammation in various neurodevelopmental disorders, potentially informing targeted interventions.

This study demonstrates the association of neurodevelopmental disorders with distinct inflammatory molecule profiles, highlighting a "hyper-resolution" state in high-risk children for regulatory disorders. The findings suggest the importance of considering the type and chronicity of neurological dysfunction when evaluating inflammatory responses. Future research should focus on larger sample sizes, utilize more comprehensive methods for analyzing lipid mediators, and explore the potential of these inflammatory markers as predictors of neurodevelopmental outcomes and targets for interventions.

The study's limitations include the relatively small sample size (complete data for only 27 of the initial 45 children), potentially limiting the generalizability of the findings. Additionally, the use of ELISA kits rather than liquid chromatography coupled to mass spectrometry for lipid mediator analysis could have impacted the precision of the results. The retrospective nature of the data on dysautonomia may also introduce some limitations.