The impact of non-neurological organ dysfunction on outcomes in severe isolated traumatic brain injury.

INTRODUCTION: Organ dysfunction following traumatic brain injury (TBI) is common and has been associated with unpredictable outcomes. The aim of our study is to describe the incidence of non-neurological organ dysfunction (NNOD) and its impact on outcomes in patients with severe TBI admitted to our intensive care unit (ICU). METHODS: We performed a 3-year (2015-2017) review of our Level 1 trauma center's prospectively maintained TBI database and included all adult (age ≥18y) patients with isolated severe TBI (head abbreviated injury severity (AIS) ≥3 and other AIS <3) and an ICU stay >48 hours. Organ dysfunction (OD) was measured by multiple organ dysfunction scores. Organ system failure was defined as a non-neurological component score of ≥3 on any day during the ICU stay. Outcomes measured were the incidence of NNOD and its effect on outcomes. Multivariate regression analysis was performed. RESULTS: A total of 285 patients were included. The mean age was 48 ± 22 years, 72% were males, median [IQR] Glasgow Coma Scale (GCS) was 8[5-10], and median Injury Severity Score (ISS) was 17[10-26]. Epidural hematoma was the most common intracranial hemorrhage (49%) followed by subdural hematoma (46%). The overall incidence of NNOD was 33%, with the most common dysfunctional organ system being the respiratory (23%) followed by the cardiovascular (12%) and hepatic system (8%). The overall in-hospital mortality rate was 19% (NNOD:36% vs. No-NNOD:9%, p< 0.01). On regression analysis, NNOD was associated with higher in-hospital mortality (aOR: 2.0 [1.6-2.7]), discharge to skilled nursing facility (SNF) (aOR: 1.8 [1.4-2.2]), and Glasgow Outcome Scale-Extended (GOS-E) ≤4 (OR: 1.7 [1.3-2.3]) and p-values <0.01. CONCLUSION: One in every three isolated severe TBI patients develop NNOD. NNOD is independently associated with worse outcomes. Understanding the mechanisms associated with NNOD in the setting of TBI may promote prevention practices and improve outcomes in TBI. LEVEL OF EVIDENCE: Prognostic, level III.

Distinct roles for the deacetylase domain of HDAC3 in the hippocampus and medial prefrontal cortex in the formation and extinction of memory.

Histone deacetylases (HDACs) are chromatin modifying enzymes that have been implicated as powerful negative regulators of memory processes. HDAC3has been shown to play a pivotal role in long-term memory for object location as well as the extinction of cocaine-associated memory, but it is unclear whether this function depends on the deacetylase domain of HDAC3. Here, we tested whether the deacetylase domain of HDAC3has a role in object location memory formation as well as the formation and extinction of cocaine-associated memories. Using a deacetylase-dead point mutant of HDAC3, we found that selectively blocking HDAC3 deacetylase activity in the dorsal hippocampus enhanced long-term memory for object location, but had no effect on the formation of cocaine-associated memory. When this same point mutant virus of HDAC3 was infused into the prelimbic cortex, it failed to affect cocaine-associated memory formation. With regards to extinction, impairing the HDAC3 deacetylase domain in the infralimbic cortex had no effect on extinction, but a facilitated extinction effect was observed when the point mutant virus was delivered to the dorsal hippocampus. These results suggest that the deacetylase domain of HDAC3 plays a selective role in specific brain regions underlying long-term memory formation of object location as well as cocaine-associated memory formation and extinction.

HDAC3-selective inhibitor enhances extinction of cocaine-seeking behavior in a persistent manner.

Nonspecific histone deacetylase (HDAC) inhibition has been shown to facilitate the extinction of drug-seeking behavior in a manner resistant to reinstatement. A key open question is which specific HDAC is involved in the extinction of drug-seeking behavior. Using the selective HDAC3 inhibitor RGFP966, we investigated the role of HDAC3 in extinction and found that systemic treatment with RGFP966 facilitates extinction in mice in a manner resistant to reinstatement. We also investigated whether the facilitated extinction is related to the enhancement of extinction consolidation during extinction learning or to negative effects on performance or reconsolidation. These are key distinctions with regard to any compound being used to modulate extinction, because a more rapid decrease in a defined behavior is interpreted as facilitated extinction. Using an innovative combination of behavioral paradigms, we found that a single treatment of RGFP966 enhances extinction of a previously established cocaine-conditioned place preference, while simultaneously enhancing long-term object-location memory within subjects. During extinction consolidation, HDAC3 inhibition promotes a distinct pattern of histone acetylation linked to gene expression within the infralimbic cortex, hippocampus, and nucleus accumbens. Thus, the facilitated extinction of drug-seeking cannot be explained by adverse effects on performance. These results demonstrate that HDAC3 inhibition enhances the memory processes involved in extinction of drug-seeking behavior.