Advanced biomarkers of pediatric mild traumatic brain injury: Progress and perils

Abstract

There is growing public concern about neurodegenerative changes (e.g., Chronic Traumatic Encephalopathy) that may occur chronically following clinically apparent and clinically silent (i.e., sub-concussive blows) pediatric mild traumatic brain injury (pmTBI). However, there are currently no biomarkers that clinicians can use to objectively diagnose patients or predict those who may struggle to recover. Non-invasive neuroimaging, electrophysiological and neuromodulation biomarkers have promise for providing evidence of the so-called "invisible wounds" of pmTBI. Our systematic review, however, belies that notion, identifying a relative paucity of high-quality, clinically impactful, diagnostic or prognostic biomarker studies in the sub-acute injury phase (36 studies on unique samples in 28 years), with the majority focusing on adolescent pmTBI. Ultimately, well-powered longitudinal studies with appropriate control groups, as well as standardized and clearly-defined inclusion criteria (time post-injury, injury severity and past history) are needed to truly understand the complex pathophysiology that is hypothesized (i.e., still needs to be determined) to exist during the acute and sub-acute stages of pmTBI and may underlie post-concussive symptoms.

Relating brain connectivity with persistent symptoms in pediatric concussion

“…Results from our study highlighted how normal variability in median connectivity strength within major resting-state networks arising from mTBI relate to symptoms severity and behavior changes across a PCS cohort with mixed recovery trajectories. Moreover, our CCA results build on prior findings in pediatric mTBI showing that brain network activity plays a key role in mediating recovery from PCS symptoms and behaviors 4,6,8 .…”

“…Such networks have been identified across a range of tasks and are involved in diverse brain functions including interoception, attention, and cognitive reasoning [24][25][26] . The characterization of resting-state brain connectivity offers neurophysiological information to parse variability in the capability of individuals to recover from brain injuries 4,27 . Results from our study highlighted how normal variability in median connectivity strength within major resting-state networks arising from mTBI relate to symptoms severity and behavior changes across a PCS cohort with mixed recovery trajectories.…”

“…Childhood PCS is further compounded by a lack of targeted clinical interventions or management strategies that alleviates prolonged symptom presentation and disturbed brain activity. As a result, PCS may impact the neurodevelopment of a child and the long-term functional outcome 4,5 .…”

Default mode network anatomy and function is linked to pediatric concussion recovery

“…Cognitive functions, including reasoning and working memory, have been associated with higher DMN functional connectivity at rest 52,53 . Accordingly, poorer cognitive functions following TBI have been linked to reduced DMN structural and resting-state connectivity 7,17,54,55 . In our previous exploratory analysis conducted on the same cohort, we were unable to detect a significant change in global DMN resting-state functional connectivity in children following mTBI compared to matched controls 23 .…”

“…There are several PPCS phenotypes with the commonest symptoms being headaches, fatigue, sleep disturbances and cognitive difficulties 6 . These symptoms have a detrimental impact on health-related quality of life and long-term outcomes [7][8][9] .…”