In the neurological intensive care unit (ICU), patients have pathophysiologic alterations in both systemic and intracranial physiology that require targeted interventions. Encased within the skull, diagnostic interrogations of brain physiology are more difficult compared to the rest of the body. The brain is particularly vulnerable to damage after ischemic and traumatic insults due to its high metabolic demands as well as the fact that it is enclosed within a rigid vault with little room to expand. Non-invasive, real-time monitors of brain function that can be deployed at the bedside are sorely needed. Near-infrared spectroscopy (NIRS) offers this possibility and has been studied in multiple forms of brain injury, including diffuse hypoxic-ischemic brain injury after cardiac arrest,¹ subarachnoid hemorrhage (SAH),^2,3 acute ischemic stroke,^4,5 and traumatic brain injury (TBI).^6,7 In this review, we will first discuss principles of cerebrovascular physiology and then discuss the features of and specific applications for NIRS in acute brain injuries.

Transcriptomic investigations of traumatic brain injury (TBI) can give us deep insights into the pathological and compensatory processes post-injury. Thus far, transcriptomic studies in TBI have mostly used microarrays and have focused on rodent models. However, a large animal model of TBI bears a much stronger resemblance to human TBI with regard to the anatomical details, mechanics of injury, genetics, and, possibly, molecular response. Because of the advantages of a large animal TBI model, we investigated the gene expression changes between injured and uninjured sides of pig cerebral cortex after TBI. Given acute inflammation that follows after TBI and the important role that immune response plays in neuroplasticity and recovery, we hypothesized that transcriptional changes involving immune function will be upregulated. Eight female 4-week-old piglets were injured on the right hemisphere with controlled cortical impact (CCI). At 5 days after TBI, pericontusional cortex tissues from the injured side and contralateral cortical tissues were collected. After RNA extraction, library preparation and sequencing as well as gene expression changes between the ipsi- and contralateral sides were compared. There were 6642 genes that were differentially expressed between the ipsi- and contralateral sides, and 1993 genes among them had at least 3-fold differences. Differentially expressed genes were enriched for biological processes related to immune system activation, regulation of immune response, and leukocyte activation. Many of the differentially expressed genes, such as CD4, CD86, IL1A, IL23R, and IL1R1, were major regulators of immune function. This study demonstrated some of the major transcriptional changes between the pericontusional and contralateral tissue at an acute time point after TBI in pigs.

Traumatic brain injury (TBI) results in the generation of tau. As hyperphosphorylated tau (p-tau) is one of the major consequences of TBI, targeting p-tau in TBI may lead to the development of new therapy. Twenty-five pigs underwent a controlled cortical impact. One hour after TBI, pigs were administered either vehicle (n = 13) or PNT001 (n = 12), a monoclonal antibody for the cis conformer of tau phosphorylated at threonine 231. Plasma biomarkers of neural injury were assessed for 14 days. Diffusion tensor imaging was performed at day 1 and 14 after injury, and these were compared to historical control animals (n = 4). The fractional anisotropy data showed significant white matter injury for groups at 1 day after injury in the corona radiata. At 14 days, the vehicle-treated pigs, but not the PNT001-treated animals, exhibited significant white matter injury compared to sham pigs in the ipsilateral corona radiata. The PNT001-treated pigs had significantly lower levels of plasma glial fibrillary acidic protein (GFAP) at day 2 and day 4. These findings demonstrate a subtle reduction in the areas of white matter injury and biomarkers of neurological injury after treatment with PNT001 following TBI. These findings support additional studies for PNT001 as well as the potential use of this agent in clinical trials in the near future.

Given the heterogeneity of traumatic brain injury (TBI), the development of a therapeutic strategy has been difficult despite decades of research. To develop an accurate classification system to guide individualized treatment, new protein biomarkers of TBI have been studied. We explored if different subtypes of TBI have unique biomarker profiles and histological findings using four pig models of TBI: moderate rotational injury (100–110 r/s), mild rotational injury (85–95 r/s), moderate contusional injury (8–9 mm), and mild contusional injury (6–7 mm). Among these groups, we identified unique profile of plasma neurofilament light (NFL) and glial fibrillary acidic protein (GFAP): whereas moderate contusion animals had early peak of NFL (2–3 days) and GFAP (1 day), mild contusion animals had delayed peak of NFL (8 days) and GFAP (3 days). Diffusion tensor imaging analysis found reduced fractional anisotropy in corona radiata for contusional injured animals but rotational injured animals showed no significant changes compared to control animals. Histological analysis showed prominent vascular inflammation and axonal injury in the pericontusional cortex in contusional injured animals. In rotational injured animals, prominent axonal injury was found in perivascular white matter. Future studies for mechanistic underpinning of biomarker changes are needed to establish therapeutic targets, predict severity of injury, and determine clinical trial enrollment and therapeutic response.