Pulsed Microwave Energy Transduction of Acoustic Phonon Related Brain Injury.

Pulsed microwaves above specific energy thresholds have been reported to cause brain injury in animal models. The actual physical mechanism causing brain damage is unexplained while the clinical reality of these injuries remains controversial. Here we propose mechanisms by which pulsed microwaves may injure brain tissue by transduction of microwave energy into damaging acoustic phonons in brain water. We have shown that low intensity explosive blast waves likely initiate phonon excitations in brain tissues. Brain injury in this instance occurs at nanoscale subcellular levels as predicted by physical consideration of phonon interactions in brain water content. The phonon mechanism may also explain similarities between primary non-impact blast-induced mild Traumatic Brain Injury (mTBI) and recent clinical and imaging findings of unexplained brain injuries observed in US embassy personnel possibly due to directed radiofrequency radiation. We describe experiments to elucidate mechanisms, RF frequencies and power levels by which pulsed microwaves potentially injure brain tissue. Pathological documentation of nanoscale brain blast injury has been supported experimentally using transmission electron microscopy (TEM) demonstrating nanoscale cellular damage in the absence of gross or light microscopic findings. Similar studies are required to better define pulsed microwave brain injury. Based upon existing findings, clinical diagnosis of both low intensity blast and microwave-induced brain injury likely will require diffusion tensor imaging (DTI), a specialized water based magnetic resonance imaging (MRI) technique.

Recommendations towards standards for quantitative MRI (qMRI) and outstanding needs.

LEVEL OF EVIDENCE: 5 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2019.

Combat blast related traumatic brain injury (TBI): Decade of recognition; promise of progress.

Between April 2007 and December 2015, the Veterans Health Administration (VHA) screened one million combat veterans for traumatic brain injury (TBI), among 2.6 million deployed during operations Enduring Freedom, Iraqi Freedom and New Dawn (OEF/OIF/OND). Since 2007, among those reporting, screened and referred for definitive evaluation, approximately 8.4% of these Veterans received a diagnosis of TBI, the majority characterized as mTBI/Concussion (mTBI) and, in great proportion, related to blast exposures. Mild Traumatic brain injury called "a signature injury" is also known as 'the invisible injury' of these conflicts. Identifying and assessing neuropathological, cellular and resulting cognitive, emotional, behavioral and neurological consequences of mTBI comprise vast clinical and research challenges. We provide a brief overview of current history, injury mechanisms related to blast exposure, coordinated research support, and the need to understand specific cellular and neurological changes occurring with blast injury, particularly mTBI.

Environmental enrichment protects against functional deficits caused by traumatic brain injury.

Environmental enrichment (EE) increases cortical weight, neuronal density, dendritic branching, and angiogenesis, all of which may be critical for functional recovery following insult. Our study was designed to determine possible benefits of pre-exposure to EE in preventing functional deficits following traumatic brain injury (TBI) to the prefrontal cortex. To examine the benefit of EE, adult male rats were placed in an enriched environment for 15 days. Enrichment was provided through social interaction, exercise, olfactory stimulation, and new objects/toys to explore. Following enrichment, experimental and age-matched controls were subjected to a moderate medial prefrontal cortex injury via controlled cortical impact (CCI). After 1 week recovery, animals were behaviorally tested to assess memory, anxiety, and sensory neglect. Lesion-induced deficits in spatial memory [Morris water maze (MWM)] were significantly attenuated in EE pre-exposed rats 18-21 days following injury. In addition, TBI-induced sensory neglect was significantly reduced in EE rats relative to non-enriched animals. No differences in anxiety-like behavior on the elevated plus maze (EPM) were detected. The behavioral data suggest that EE is neuroprotective when applied prior to TBI, resulting in improved recovery following injury.

Enhanced neurorehabilitation techniques in the DVBIC Assisted Living Pilot Project.

Traumatic Brain Injury has been labeled the "silent epidemic" in our current wars. Both CBO and the RAND reports predict that the costs of these injuries will be both extensive and enduring. The projected costs are based not only upon the loss contribution of these warriors to our economy, but also the long-term medical and assistive care that will be needed to support these veterans for decades to come. Thus, the primary goal of the Assisted Living Pilot Project (ALPP) at the Defense and Veterans Brain Injury Center - Johnstown (DVBIC-J) is to promote the ability of the injured warrior to move from assisted living to living independently and to be self-supporting by providing a continuum of care. To accomplish this goal the DVBIC-J ALPP is providing full set of traditional services (physical, occupational, speech, psychological/cognitive, social/familial, vocational, and spiritual), along with "cutting-edge" rehabilitative treatment technologies. These cutting-edge therapies include transdisciplinary clinical consultations, interactive patient and family counseling, and telemedicine-teleconferencing for clinical evaluations and family/significant other care participation. These services will be available to those who require assisted living through their progression to community re-entry. The ALPP also serves as a vehicle for clinical trials to investigate the effects of an enriched environment (e.g., recreational therapies, massage, multisensory stimulation, etc.) on neurorehabilitation therapy, rural telemedicine for servicemembers with traumatic brain injury, and long-term outcome measures of those who have received neurorehabilitation services at the DVBIC-J site. DVBIC-J is also developing collaborative projects with universities and private industry to create an incubator for new rehabilitation technologies. The technologies that DVBIC-J will be focusing on will include assistive technologies (to assist cognitive, physical, and communicative impairments), virtual and augmented reality simulations (for both diagnosis and treatment of TBI and PTSD), and telecommunication technologies to improve rehabilitation services to those warriors that have returned to their homes in rural areas.

The interaction between psychological health and traumatic brain injury: a neuroscience perspective.

The occurrence of traumatic brain injury (TBI) and psychological health issues in the current theater of military operations has become a major factor in planning for the long-term healthcare of our wounded warriors. Post-traumatic stress disorder (PTSD) can co-exist with brain injury in military members who have been exposed to blasts. Specific areas of the brain may be more susceptible to damage from blasts. In particular, damage to the prefrontal cortex can lead to disinhibition of cerebral structures that control fear and anxiety. Reactive systemic inflammatory processes related to TBI may also impair psychological health. Impaired psychological health may lead to increased psychological distress that impedes brain repair due to the release of stress-related hormones. Since the external environment has been shown to exert a significant influence on the internal environment of the organism, enriching the external environment may well reduce anxiety and facilitate the neuroplasticity of brain cells, thus promoting recovery of function after TBI.

Progesterone and its metabolite allopregnanolone differentially regulate hemostatic proteins after traumatic brain injury.

Our laboratory has shown in numerous experiments that the neurosteroids progesterone (PROG) and allopregnanolone (ALLO) improve molecular and functional outcomes after traumatic brain injury (TBI). As coagulopathy is an important contributor to the secondary destruction of nervous tissue, we hypothesized that PROG and ALLO administration may also have a beneficial effect on coagulation protein expression after TBI. Adult male Sprague-Dawley rats were given bilateral contusions of the medial frontal cortex followed by treatments with PROG (16 mg/kg), ALLO (8 mg/kg), or vehicle (22.5% hydroxypropyl-beta-cyclodextrin). Controls received no injury or injections. Progesterone generally maintained procoagulant (thrombin, fibrinogen, and coagulation factor XIII), whereas ALLO increased anticoagulant protein expression (tissue-type plasminogen activator, tPA). In addition, PROG significantly increased the ratio of tPA bound to neuroserpin, a serine protease inhibitor that can reduce the activity of tPA. Our findings suggest that in a model of TBI, where blood loss may exacerbate injury, it may be preferable to treat patients with PROG, whereas it might be more appropriate to use ALLO as a treatment for thrombotic stroke, where a reduction in coagulation would be more beneficial.

Effects of medroxyprogesterone acetate on cerebral oedema and spatial learning performance after traumatic brain injury in rats.

BACKGROUND: Given after brain injury (TBI), progesterone reduces cerebral oedema and facilitates functional recovery. Progesterone analogues have been synthesized for use in many medical conditions and exhibit different chemical and biological properties. Medroxyprogesterone acetate (MPA) is widely used in clinical practice, but oestrogen/MPA combinations may increase the risk of stroke and cardiovascular disease rather than preventing them. In some conditions, MPA can exhibit pharmacological actions that are different from those of natural progesterone. PRIMARY OBJECTIVE AND HYPOTHESIS: Using laboratory rats, this study assessed the efficacy of MPA to determine whether this progestin and natural progesterone exert similar effects as a treatment after bilateral injury to the frontal cortex. MAIN OUTCOMES AND RESULTS: MPA produced a dose-related reduction of cerebral oedema at 48 hours post-TBI but neither 4 nor 16 mg/kg doses of MPA enhanced behavioural recovery. CONCLUSION: These findings help to clarify the divergent results from prior positive progesterone studies and the negative MPA clinical trials for hormone replacement therapy. The results can be taken to suggest that the control of cerebral oedema, while clearly desirable, is not the only contributor to progesterone-induced behavioural recovery.

Neurosteroids reduce inflammation after TBI through CD55 induction.

The inflammatory cascade that follows traumatic brain injury may lead to secondary cell death and can impede recovery of function. Complement factors and their convertases are increased in glia after brain injury and lead to the production of inflammatory products that kill vulnerable neurons. Progesterone and its metabolite allopregnanolone (5alpha-pregnan-3beta-ol-20-one) have been shown to reduce the expression of inflammatory cytokines in the acute stages of brain injury, although how they do this is not completely understood. In this study we show that both progesterone and allopregnanolone treatments enhance the production of CD55 following contusion injuries of the cerebral cortex in rats. CD55, a single-chain type 1 cell surface protein, is a potent inhibitor of the complement convertases which are activators of the inflammatory cascade. The increased expression of CD55 could be an important mechanism by which steroids help to reduce the cerebral damage caused by inflammation.

ProTECT: a randomized clinical trial of progesterone for acute traumatic brain injury.

STUDY OBJECTIVE: Laboratory evidence indicates that progesterone has potent neuroprotective effects. We conducted a pilot clinical trial to assess the safety and potential benefit of administering progesterone to patients with acute traumatic brain injury. METHODS: This phase II, randomized, double-blind, placebo-controlled trial was conducted at an urban Level I trauma center. One hundred adult trauma patients who arrived within 11 hours of injury with a postresuscitation Glasgow Coma Scale score of 4 to 12 were enrolled with proxy consent. Subjects were randomized on a 4:1 basis to receive either intravenous progesterone or placebo. Blinded observers assessed patients daily for the occurrence of adverse events and signs of recovery. Neurologic outcome was assessed 30 days postinjury. The primary safety measures were differences in adverse event rates and 30-day mortality. The primary measure of benefit was the dichotomized Glasgow Outcome Scale-Extended 30 days postinjury. RESULTS: Seventy-seven patients received progesterone; 23 received placebo. The groups had similar demographic and clinical characteristics. Laboratory and physiologic characteristics were similar at enrollment and throughout treatment. No serious adverse events were attributed to progesterone. Adverse and serious adverse event rates were similar in both groups, except that patients randomized to progesterone had a lower 30-day mortality rate than controls (rate ratio 0.43; 95% confidence interval 0.18 to 0.99). Thirty days postinjury, the majority of severe traumatic brain injury survivors in both groups had relatively poor Glasgow Outcome Scale-Extended and Disability Rating Scale scores. However, moderate traumatic brain injury survivors who received progesterone were more likely to have a moderate to good outcome than those randomized to placebo. CONCLUSION: In this small study, progesterone caused no discernible harm and showed possible signs of benefit.

The enantiomer of progesterone acts as a molecular neuroprotectant after traumatic brain injury.

Previous work shows that neurosteroid enantiomers activate specific molecular receptors that relay neuroprotection. However, the actions of the enantiomer of progesterone (ent-PROG) at the PROG receptor (PR) are unknown. PR binding and transcriptional assays were performed to determine the actions of ent-PROG at the classical PR. Additionally, the neuroprotective effects of ent-PROG in traumatic brain injury (TBI) were investigated and compared to the actions of PROG and its metabolite allopregnanolone (ALLO), both of which have been shown to have neuroprotective properties when given after TBI. Binding studies performed in COS cells over-expressing the PR showed that ent-PROG inhibited PROG binding to the PR. In contrast, ent-PROG did not activate PR-mediated transcription. Rats received bilateral medial frontal cortex injury followed by treatments at 1, 6, 24 and 48h with PROG, ALLO or ent-PROG. Brains were processed for edema, protein and enzyme activity. ent-PROG treatment in vivo decreased cerebral edema, cell death mediators, inflammatory cytokines, and reactive gliosis, and increased antioxidant activity. These findings suggest that the progestin-mediated pro-survival response seen with TBI is regulated either independently of the classical PR or via nongenomic PR-regulated actions.

Allopregnanolone, a progesterone metabolite, is more effective than progesterone in reducing cortical infarct volume after transient middle cerebral artery occlusion.

STUDY OBJECTIVE: We compare the effects of postinjury administration of allopregnanolone, a metabolite of progesterone, to progesterone in an animal model of transient middle cerebral artery occlusion. METHODS: Focal cerebral ischemia was induced in age-matched, adult, male, Sprague-Dawley rats by using an intraluminal filament and suture method to occlude the right middle cerebral artery. After 120 minutes of middle cerebral artery occlusion, the occluding filament was withdrawn to allow reperfusion. Laser-Doppler flowmetry was used to monitor cerebral blood flow for the entire 2-hour period of occlusion and for 5 minutes after reperfusion. Animals subjected to middle cerebral artery occlusion received injections of allopregnanolone (8 mg/kg, n=6), progesterone (8 mg/kg, n=6) and vehicle (2-hydroxypropyl-beta-cyclodextrin, n=7) at 2 hours (intraperitoneally 5 minutes before reperfusion) and 6 hours (subcutaneously) postocclusion. Brains were removed at 72 hours post-middle cerebral artery occlusion, sectioned into coronal slices, and stained with 2,3,5-triphenyltetrazolium chloride (TTC). In a blinded analysis, infarct volume was calculated by using computer-aided morphometry to measure brain areas not stained with TTC. RESULTS: After progesterone or allopregnanolone treatment, stained sections revealed a significant reduction in cortical, caudate-putamen, and hemispheric infarct volumes (percentage of contralateral structure) compared with vehicle-injected controls. Cortical infarction (percentage of contralateral cortex) was 37.47%+/-10.57% (vehicle), 25.49%+/-7.38% (progesterone; P<.05 from vehicle), and 11.40%+/-7.09% (allopregnanolone; P<.05 from vehicle; P<.05 from progesterone). Caudate-putamen infarction (percentage of contralateral caudate-putamen) was 78.02%+/-22.81% (vehicle), 48.41%+/-22.44% (progesterone; P<.05 from vehicle), and 50.44%+/-10.90% (allopregnanolone; P<.05 from vehicle). Total hemispheric infarction (percentage of contralateral hemisphere) was 24.37%+/-6.69% (vehicle), 15.95%+/-3.59% (progesterone; P<.05 from vehicle), and 11.54%+/-3.71% (allopregnanolone; P<.05 from vehicle). No significant differences in cerebral blood flow between groups and time points during ischemia and early reperfusion were observed, suggesting that the relative ischemic insult was equivalent among all groups. CONCLUSION: Although progesterone and allopregnanolone are effective in reducing infarct pathology, allopregnanolone is more potent than progesterone in attenuating cortical damage. Our results suggest that both neurosteroids should be examined for safety and efficacy in a clinical trial for ischemic stroke.

Progesterone administration modulates AQP4 expression and edema after traumatic brain injury in male rats.

This study investigates whether progesterone administration regulates AQP4 and GFAP expression in rats with bilateral contusion injuries of the medial frontal cortex. Male rats were given 0 or 16 mg/kg injections of progesterone at 1, 6, 24, and 48 h post-injury. Brains were extracted at 24 h or 72 h post-injury and assayed for cerebral edema and AQP4 and GFAP expression using Western blot analysis. Progesterone treatments reduced brain water content significantly in the brain-injured groups. There was no significant change in AQP4 expression 24 h after progesterone treatment compared to lesion + vehicle animals. However, progesterone significantly reduced AQP4 expression at 72 h post-injury in the tissue bounded by the lateral ventricles and the peri-contusion areas compared to lesion+ vehicle rats, but increased AQP4 expression in the tissue surrounding the third ventricle. Also progesterone effects on GFAP expression varied according to brain region. Our results can be taken to show that the expression of AQP4 protein after TBI is time-dependent, region-specific, and possibly implicated in the formation and resolution of TBI-induced cerebral edema.

Tapered progesterone withdrawal enhances behavioral and molecular recovery after traumatic brain injury.

Systemic injections of the neurosteroid progesterone improve cognitive recovery after traumatic brain injury (TBI) and stroke, and decrease molecular indicators of neuronal damage. Suddenly withdrawing progesterone after repeated dosing (PW) exacerbates ischemia and causes increased anxiety, seizure susceptibility, and excitotoxicity. Adult male Sprague-Dawley rats received either bilateral medial frontal cortex contusions or sham surgery. Injections were administered at 1 and 6 h post-injury, then every 24 h for 7 days. Vehicle-treated rats received 2-hydroxypropyl-beta-cyclodextrin (HBC). Acute PW (AW) rats received a full 16 mg/ml of progesterone for 7 days, and tapered PW (TW) rats received 5 days at full dosage, then 2 days with progressively halved dosages. Anxiety behaviors were observed pre- and post-surgery, and compared to levels at the peak of withdrawal. AW rats with lesions exhibited significantly more anxiety than any other treatment group, while both lesion- and sham-operated TW rats were indistinguishable from vehicle-treated intact animals. After behavioral tests were complete, the brains were extracted and prepared for Western blotting. TNFalpha, cFos, Caspase-3, and NFkappaB, among others, were investigated. While all progesterone treatments resulted in improved molecular recovery, TW animals had significantly fewer active markers for apoptosis and inflammation than AW animals. In conclusion, although progesterone treatment decreases inflammation and apoptosis, acute withdrawal increases activity in some apoptotic and inflammatory pathways and increases anxiety behavior during the acute healing phase. A tapered withdrawal of the hormone further enhances short-term recovery after TBI.

Progesterone treatment inhibits the inflammatory agents that accompany traumatic brain injury.

Progesterone given after traumatic brain injury (TBI) has been shown to reduce the initial cytotoxic surge of inflammatory factors. We used Western blot techniques to analyze how progesterone might affect three inflammation-related factors common to TBI: complement factor C3 (C3), glial fibrillary acidic protein (GFAP), and nuclear factor kappa beta (NFkappaB). One hour after bilateral injury to the medial frontal cortex, adult male rats were given injections of progesterone (16 mg/kg) for 2 days. Brains were harvested 48 h post-TBI, proteins were extracted from samples, each of which contained tissue from both the contused and peri-contused areas, then measured by Western blot densitometry. Complete C3, GFAP, and NFkappaB p65 were increased in all injured animals. However, in animals given progesterone post-TBI, NFkappaB p65 and the inflammatory metabolites of C3 (9 kDa and 75 kDa) were decreased in comparison to vehicle-treated animals. Measures of NFkappaB p50 showed no change after injury or progesterone treatment, and progesterone did not alter the expression of GFAP. The therapeutic benefit of post-TBI progesterone administration may be due to its salutary effect on inflammatory proteins known to increase immune cell invasion and cerebral edema.

The neurosteroids progesterone and allopregnanolone reduce cell death, gliosis, and functional deficits after traumatic brain injury in rats.

This report compares the effects of progesterone and its metabolite, allopregnanolone, on the early injury cascade (apoptosis) and long-term functional deficits after TBI. Progesterone (16 mg/kg) or allopregnanolone (4, 8, or 16 mg/kg) were injected at 1 h, 6 h, and then for 5 consecutive days after bilateral contusions of the frontal cortex in adult male rats. Within one day after injury, progesterone and allopregnanolone reduced both the expression of pro-apoptotic proteins caspase-3 and Bax, and apoptotic DNA fragmentation. Progesterone and allopregnanolone also reduced the size of glial fibrillary acid protein (GFAP)-positive astrocytes at the lesion site 24 h after injury. Compared to sham-operated controls at 19 days after injury, injured rats given either progesterone or any of three doses of allopregnanolone had equivalent numbers of ChAT-positive cells in the nucleus basalis magnocellularis. At 19 days post-injury, rats given progesterone or allopregnanolone (8 mg/kg) showed improved performance in a spatial learning task compared to injured rats given only the vehicle. These results provide evidence of the anti-apoptotic and anti-astrogliotic effects of progesterone and allopregnanolone and help to explain why better cognitive performance is observed after injury when animals are given either neurosteroid.

Neural progenitor cell transplants promote long-term functional recovery after traumatic brain injury.

Studies demonstrating the versatility of neural progenitor cells (NPCs) have recently rekindled interest in neurotransplantation methods aimed at treating traumatic brain injury (TBI). However, few studies have evaluated the safety and functional efficacy of transplanted NPCs beyond a few months. The purpose of this study was to assess the long-term survival, migration, differentiation and functional significance of NPCs transplanted into a mouse model of TBI out to 1 year post-transplant. NPCs were derived from E14.5 mouse brains containing a transgene-expressing green fluorescent protein (GFP) and cultured as neurospheres in FGF2-containing medium. Neurospheres were injected into the ipsilateral striatum of adult C57BL/6 mice 1 week following unilateral cortical impact injury. Behavioral testing revealed significant improvements in motor abilities in NPC-treated mice as early as 1 week, and the recovery was sustained out to 1 year post-transplant. In addition, mice receiving NPC transplants showed significant improvement in spatial learning abilities at 3 months and 1 year, whereas an intermediate treatment effect on this behavioral parameter was detected at 1 month. At 14 months post-transplant, GFP(+) NPCs were observed throughout the injured hippocampus and adjacent cortical regions of transplanted brains. Immunohistochemical analysis revealed that the majority of transplanted cells co-labeled for NG2, an oligodendrocyte progenitor cell marker, but not for neuronal, astrocytic or microglial markers. In conclusion, transplanted NPCs survive in the host brain up to 14 months, migrate to the site of injury, enhance motor and cognitive recovery, and may play a role in trophic support following TBI.

Progesterone and allopregnanolone reduce inflammatory cytokines after traumatic brain injury.

Following a traumatic brain injury (TBI), the excessive release of interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) is a major cause of cerebral edema, which, in turn, can cause permanent neuronal loss and cognitive deficits in laboratory rats. This study examined the changes in expression of the proinflammatory cytokines IL-1beta and TNF-alpha after progesterone (8 mg/kg) or allopregnanolone (4 mg/kg) treatment in brain-injured rats at 3, 8, and 12 h and 6 days post-injury. Adult male rats received either bilateral prefrontal cortical contusion or sham surgery. The hormones were given intraperitoneally at 1 and 6 h, and continued once per day for up to 5 days. The gene expression of IL-1beta and TNF-alpha was measured by mRNA using real-time quantitative reverse transcripted polymerase chain reaction (RT-PCR). The protein concentrations of IL-1beta and TNF-alpha were measured using enzyme-linked immunosorbent assay (ELISA) to confirm the translation from mRNA to protein. The results indicated that progesterone and allopregnanolone reduce both IL-1beta and TNF-alpha at 3 h post-injury, when the expression of these cytokines peaks. At 8 and 12 h post-injury, IL-1beta and TNF-alpha gene expression in injured rats was still elevated compared to shams. By the sixth day post-injury, cytokine expression was back to the level of intact rats. We conclude that progesterone and allopregnanolone may attenuate the production of proinflammatory cytokines early after TBI, and this may be one mechanism by which progesterone and allopregnanolone reduce cerebral edema and promote functional recovery from TBI.

Allopregnanolone, a progesterone metabolite, enhances behavioral recovery and decreases neuronal loss after traumatic brain injury.

PURPOSE: In the current study we investigated whether allopregnanolone, a metabolite of progesterone, could replicate progesterone's beneficial effects in promoting spatial learning ability after bilateral medial prefrontal cortex contusions in rats. Allopregnanolone has been shown to enhance GABA neurotransmission, whereas its isomer epiallopregnanolone does not have this property. Thus, epiallopregnanolone was chosen as a control substance to examine further the role of GABA transmission in post-trauma neuroprotection. METHODS: After the contusion, rats were given 4 mg/kg treatment of either allopregnanolone or epiallopregnanolone for five consecutive days beginning 1 hr post-injury. Control groups only received vehicle treatment at the same time points. A spatial learning task (Morris Water Maze, MWM) was performed at 7 days post-injury for 10 days. Subsequent histological analyses of brain tissue were conducted to determine quantitatively the neuronal losses in both the mediodorsal nucleus of the thalamus (MDN) and the nucleus basalis magnocellularis (NBM). RESULTS: Allopregnanolone-treated rats showed better performance in the MWM compared to the vehicle-treated injury group. The histological analyses also revealed that the allopregnanolone-treated injury group had less neuronal loss in both the MDN and the NBM compared to the vehicle-treated injury group. In contrast, epiallopregnanolone did not facilitate MWM performance or reduce neuronal loss in the MDN and the NBM after TBI. CONCLUSION: Based on our findings, we suggest that allopregnanolone may mediate the effects of progesterone in promoting cognitive and morphological recovery from TBI through, among others, its direct or indirect effects on GABA-modulated neurons in the MDN and the NBM.