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To establish the clinical relevance of porcine model of traumatic brain injury (TBI) using the plasma biomarkers of injury with diffusion tensor imaging (DTI) over 30 days, we performed a randomized, blinded, pre-clinical trial using Yorkshire pigs weighing 7-10 kg. Twelve pigs were subjected to Sham injury (n = 5) by skin incision or TBI (n = 7) by controlled cortical impact. Blood samples were collected before the injury, then at approximately 5-day intervals until 30 days. Both groups also had DTI at 24 h and at 30 days after injury. Plasma samples were isolated and single molecule array (Simoa) was performed for glial fibrillary acidic protein (GFAP) and neurofilament light (NFL) levels. Afterwards, brain tissue samples were stained for β-APP. DTI showed fractional anisotropy (FA) decrease in the right corona radiata (ipsilateral to injury), contralateral corona radiata, and anterior corpus callosum at 1 day. At 30 days, ipsilateral corona radiata showed decreased FA. Pigs with TBI also had increase in GFAP and NFL at 1-5 days after injury. Significant difference between Sham and TBI animals continued up to 20 days. Linear regression showed significant negative correlation between ipsilateral corona radiata FA and both NFL and GFAP levels at 1 day. To further validate the degree of axonal injury found in DTI, β-APP immunohistochemistry was performed on a perilesional tissue as well as corona radiata bilaterally. Variable degree of staining was found in ipsilateral corona radiata. Porcine model of TBI replicates the acute increase in plasma biomarkers seen in clinical TBI. Further, long term white matter injury is confirmed in the areas such as the splenium and corona radiata. However, future study stratifying severe and mild TBI, as well as comparison with other subtypes of TBI such as diffuse axonal injury, may be warranted.

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.

Timely detection and monitoring of acute brain injury in children is essential to mitigate causes of injury and prevent secondary insults. Increasing survival in critically ill children has emphasized the importance of neuroprotective management strategies for long-term quality of life. In emergent and critical care settings, traditional neuroimaging modalities, such as computed tomography and magnetic resonance imaging (MRI), remain frontline diagnostic techniques to detect acute brain injury. Although detection of structural and anatomical abnormalities remains crucial, advanced MRI sequences assessing functional alterations in cerebral physiology provide unique diagnostic utility. Head ultrasound has emerged as a portable neuroimaging modality for point-of-care diagnosis via assessments of anatomical and perfusion abnormalities. Application of electroencephalography and near-infrared spectroscopy provides the opportunity for real-time detection and goal-directed management of neurological abnormalities at the bedside. In this review, we describe recent technological advancements in these neurodiagnostic modalities and elaborate on their current and potential utility in the detection and management of acute brain injury.

Despite multiple prior pharmacological trials in traumatic brain injury (TBI), the search for an effective, safe, and practical treatment of these patients remains ongoing. Given the ease of delivery and rapid absorption into the systemic circulation, inhalational gases that have neuroprotective properties will be an invaluable resource in the clinical management of TBI patients. In this review, we perform a systematic review of both pre-clinical and clinical reports describing inhalational gas therapy in the setting of TBI. Hyperbaric oxygen, which has been investigated for many years, and some of the newest developments are reviewed. Also, promising new therapies such as hydrogen gas, hydrogen sulfide gas, and nitric oxide are discussed. Moreover, novel therapies such as xenon and argon gases and delivery methods using microbubbles are explored.

Traumatic brain injury (TBI) causes significant white matter injury, which has been characterized by various rodent and human clinical studies. The exact time course of imaging changes in a pediatric brain after TBI and its relation to biomarkers of injury and cellular function, however, is unknown. To study the changes in major white matter structures using a valid model of TBI that is comparable to a human pediatric brain in terms of size and anatomical features, we utilized a four-week-old pediatric porcine model of injury with controlled cortical impact (CCI). Using diffusion tensor imaging differential tractography, we show progressive anisotropy changes at major white matter tracts such as the corona radiata and inferior fronto-occipital fasciculus between day 1 and day 30 after injury. Moreover, correlational tractography shows a large part of bilateral corona radiata having positive correlation with the markers of cellular respiration. In contrast, bilateral corona radiata has a negative correlation with the plasma biomarkers of injury such as neurofilament light or glial fibrillary acidic protein. These are expected correlational findings given that higher integrity of white matter would be expected to correlate with lower injury biomarkers. We then studied the magnetic resonance spectroscopy findings and report decrease in a N-acetylaspartate/creatinine (NAA/Cr) ratio at the pericontusional cortex, subcortical white matter, corona radiata, thalamus, genu, and splenium of corpus callosum at 30 days indicating injury. There was also an increase in choline/creatinine ratio in these regions indicating rapid membrane turnover. Given the need for a pediatric TBI model that is comparable to human pediatric TBI, these data support the use of a pediatric pig model with CCI in future investigations of therapeutic agents. This model will allow future TBI researchers to rapidly translate our pre-clinical study findings into clinical trials for pediatric TBI.

In this study, we used diffuse optics to address the need for non-invasive, continuous monitoring of cerebral physiology following traumatic brain injury (TBI). We combined frequency-domain and broadband diffuse optical spectroscopy with diffuse correlation spectroscopy to monitor cerebral oxygen metabolism, cerebral blood volume, and cerebral water content in an established adult swine-model of impact TBI. Cerebral physiology was monitored before and after TBI (up to 14 days post injury). Overall, our results suggest that non-invasive optical monitoring can assess cerebral physiologic impairments post-TBI, including an initial reduction in oxygen metabolism, development of cerebral hemorrhage/hematoma, and brain swelling.

With increasing use of direct oral anticoagulants (DOACs) and availability of new reversal agents, the risk of traumatic intracranial hemorrhage (tICH) requires better understanding. We compared hemorrhage expansion rates, mortality, and morbidity following tICH in patients treated with vitamin k antagonists (VKA: warfarin) and DOACs (apixaban, rivaroxaban, dabigatran). Retrospective chart review of patients from 2010 to 2017 was performed to identify patients with imaging diagnosis of acute traumatic intraparenchymal, subdural, subarachnoid, and epidural hemorrhage with preadmission use of DOACs or VKAs. We identified 39 patients on DOACs and 97 patients on VKAs. Demographic information, comorbidities, hemorrhage size, and expansion over time, as well as discharge disposition and Glasgow Outcome Scale (GOS) were collected. Primary outcome was development of new or enlargement of tICH within the first 48 h of initial CT imaging. Of 136 patients with mean (SD) age 78.7 (13.2) years, most common tICH subtype was subdural hematoma (N = 102/136; 75%), and most common mechanism was a fall (N = 130/136; 95.6%). Majority of patients in the DOAC group did not receive reversal agents (66.7%). Hemorrhage expansion or new hemorrhage occurred in 11.1% in DOAC group vs. 14.6% in VKA group (p = 0.77) at a median of 8 and 11 h from initial ED admission, respectively (p = 0.82). Patients in the DOAC group compared to VKA group had higher median discharge GOS (4 vs. 3 respectively, p = 0.03), higher percentage of patients with good outcome (GOS 4–5, 66.7% vs. 40.2% respectively, p = 0.005), and higher rate of discharge to home or rehabilitation (p = 0.04). We report anticoagulation-associated tICH outcomes predominantly due to fall-related subdural hematomas. Patients on DOACs had lower tICH expansion rates although not statistically significantly different from VKA-treated patients. DOAC-treated patients had favorable outcomes versus VKA group following tICH despite low use of reversal strategies. DOAC use may be a safer alternative to VKA in patients at risk of traumatic brain hemorrhage.

Objectives We explore the correlation of contrast-enhanced ultrasound (CEUS) parameters to intracranial pressure (ICP) in a porcine experimental model of pediatric cardiac arrest. Methods Eleven pediatric pigs underwent electrically induced cardiac arrest followed by cardiopulmonary resuscitation. ICP was measured using intracranial bolt monitor and CEUS was monitored through a cranial window. Various CEUS parameters were monitored at baseline, immediately post return of spontaneous circulation (ROSC), 1 hour-post ROSC, and 3 hours post-ROSC. Results There was significant ICP correlation with wash-out slope assessed by CEUS time intensity curve analysis at immediate post-ROSC. At 3 hours post-ROSC there was also significant negative correlation between ICP and peak enhancement which may be due to the evolution of anoxic injury. Conclusion The use of CEUS in assessing disruption of cerebral hemodynamics and ICP post cardiac arrest will need future validation and comparison to other imaging modalities. The correlation between CEUS parameters and ICP may be due to the alterations in cerebral autoregulation that result from anoxic brain injury.

OBJECTIVEBased on a null hypothesis that the use of short-term lumbar drainage (LD) after endoscopic endonasal surgery (EES) for intradural pathology does not prevent postoperative CSF leaks, a trial was conducted to assess the effect of postoperative LD on postoperative CSF leak following standard reconstruction.METHODSA prospective, randomized controlled trial of lumbar drain placement after endoscopic endonasal skull base surgery was performed from February 2011 to March 2015. All patients had 3-month follow-up data. Surgeons were blinded to which patients would or would not receive the drain until after closure was completed. An a priori power analysis calculation assuming 80% of power, 5% postoperative CSF leak rate in the no-LD group, and 16% in the LD group determined a planned sample size of 186 patients. A routine data and safety check was performed with every 50 patients being recruited to ensure the efficacy of randomization and safety. These interim tests were run by a statistician who was not blinded to the arms they were evaluating. This study accrued 230 consecutive adult patients with skull base pathology who were eligible for endoscopic endonasal resection. Inclusion criteria (high-flow leak) were dural defect greater than 1 cm2 (mandatory), extensive arachnoid dissection, and/or dissection into a ventricle or cistern. Sixty patients were excluded because they did not meet the inclusion criteria. One hundred seventy patients were randomized to either receive or not receive a lumbar drain.RESULTSOne hundred seventy patients were randomized, with a mean age of 51.6 years (range 19–86 years) and 38% were male. The mean BMI for the entire cohort was 28.1 kg/m2. The experimental cohort with postoperative LD had an 8.2% rate of CSF leak compared to a 21.2% rate in the control group (odds ratio 3.0, 95% confidence interval 1.2–7.6, p = 0.017). In 106 patients in whom defect size was measured intraoperatively, a larger defect was associated with postoperative CSF leak (6.2 vs 2.9 cm2, p = 0.03). No significant difference was identified in BMI between those with (mean 28.4 ± 4.3 kg/m2) and without (mean 28.1 ± 5.6 kg/m2) postoperative CSF leak (p = 0.79). Furthermore, when patients were grouped based on BMI < 25, 25–29.9, and > 30 kg/m2, no difference was noted in the rates of CSF fistula (p = 0.97).CONCLUSIONSAmong patients undergoing intradural EES judged to be at high risk for CSF leak as defined by the study’s inclusion criteria, perioperative LD used in the context of vascularized nasoseptal flap closure significantly reduced the rate of postoperative CSF leaks.Clinical trial registration no.: NCT03163134 (clinicaltrials.gov).

Traumatic brain injury (TBI) is challenging to assess even with recent advancements in computed tomography and magnetic resonance imaging. Ultrasound (US) imaging has previously been less utilized in TBI compared to conventional imaging because of limited resolution in the intracranial space. However, there have been substantial improvements in contrast-enhanced US and development of novel techniques such as intravascular US. Also, continued research provides further insight into cerebrovascular parameters from transcranial Doppler imaging. These advancements in US imaging provides the community of TBI imaging researchers and clinicians new opportunities in clinically monitoring and understanding the pathologic mechanisms of TBI.

Sensitive, specific, and safe bedside evaluation of brain perfusion is key to the early diagnosis, treatment, and improved survival of neonates with hypoxic ischemic injury. Contrast-enhanced ultrasound (US) imaging is a novel imaging technique in which intravenously injected gas-filled microbubbles generate enhanced US echoes from an acoustic impedance mismatch. This article describes contrast-enhanced US imaging in 2 neonates with hypoxic ischemic injury and future directions on developing quantitative contrast-enhanced US techniques for improved characterization of perfusion abnormalities. The importance of studying the temporal evolution of brain perfusion in neonatal hypoxic ischemic injury is also highlighted.

A majority of patients with traumatic brain injury (TBI) present as mild injury with no findings on conventional clinical imaging methods. Due to this difficulty of imaging assessment on mild TBI patients, there has been much emphasis on the development of diffusion imaging modalities such as diffusion tensor imaging (DTI). However, basic science research in TBI shows that many of the functional and metabolic abnormalities in TBI may be present even in the absence of structural damage. Moreover, structural damage may be present at a microscopic and molecular level that is not detectable by structural imaging modality. The use of functional and metabolic imaging modalities can provide information on pathological changes in mild TBI patients that may not be detected by structural imaging. Although there are various differences in protocols of positron emission tomography (PET), single photon emission computed tomography (SPECT), functional magnetic resonance imaging (fMRI), electroencephalography (EEG), and magnetoencephalography (MEG) methods, these may be important modalities to be used in conjunction with structural imaging in the future in order to detect and understand the pathophysiology of mild TBI. In this review, studies of mild TBI patients using these modalities that detect functional and metabolic state of the brain are discussed. Each modality's advantages and disadvantages are compared, and potential future applications of using combined modalities are explored.

Conservative therapy is often the first-line treatment for many symptoms of various disease processes, including pain. Nevertheless, if pharmacological or medical management fails for those patients with severe and chronic pain, a surgical strategy may be a reasonable option. First performed for psychiatric disorders, cingulotomy now has been recognized as a viable option for the management of pain. The authors review the literature on anterior cingulotomy for intractable pain to provide guidelines for management and expected outcomes.

The Kryptopterus bicirrhis (glass catfish) is known to respond to electromagnetic fields (EMF). Here we tested its avoidance behavior in response to static and alternating magnetic fields stimulation. Using expression cloning we identified an electromagnetic perceptive gene (EPG) from the K. bicirrhis encoding a protein that responds to EMF. This EPG gene was cloned and expressed in mammalian cells, neuronal cultures and in rat’s brain. Immunohistochemistry showed that the expression of EPG is confined to the mammalian cell membrane. Calcium imaging in mammalian cells and cultured neurons expressing EPG demonstrated that remote activation by EMF significantly increases intracellular calcium concentrations, indicative of cellular excitability. Moreover, wireless magnetic activation of EPG in rat motor cortex induced motor evoked responses of the contralateral forelimb in vivo. Here we report on the development of a new technology for remote, non-invasive modulation of cell function.

Tremor is a common movement disorder that can be disabling, and its initial treatment is in the form of medical therapies. Often patients are refractory and seek surgical intervention. Treatment options for these patients include surgical radiofrequency thalamotomy and deep brain stimulation. There are a subset of patients who, for various reasons, are not candidates for open surgical procedures, or who opt to avoid them. For these patients, radiosurgical thalamotomy is a safe and useful alternative. Herein, we provide a review of the use of radiosurgical thalamotomy for the treatment of medically refractory tremor by discussing its history, defining the technique and its indications, evaluating its efficacy, and exploring its complications and shortcomings.

Research on the mechanism of concussion in recent years has been focused on the mechanism of injury as well as strategies to minimize or reverse injury. Sports-related head injury research has led to the development of head protective gear that has evolved over the years. Headgears have been designed to protect athletes from skull fractures, subdural hemorrhages and concussions. Over the years, through experience of athletes and continued scientific research, improvements in helmet design have been made. Although these advances have decreased the number of catastrophic injuries throughout sports, the effects on concussions are promising, but largely unproven. In this review, we will discuss development of helmets and studies analyzing their level of protection for both concussion and head injury. This will help us understand what future developments are still needed to minimize the risk of concussion among athletes in various forms of sports.

Background: Therapeutic strategies for traumatic brain injury (TBI) in the last three decades have failed to show significant benefit in large scale studies. Given the multitude of pathological mechanisms involved in TBI, strategies focusing on multimodality regimen have gained interest as promising future interventions. Hypothesis: We hypothesized that combining noninvasive transcranial magnetic stimulation (TMS) with rehabilitative training in an environmental enrichment (EE) can facilitate post-TBI recovery in rats via cortical excitability and reorganization. Methods: We subjected rats to controlled cortical impact, and then assigned them to one of four groups: 1. No treatments (TBI), 2. EE after injury (TBI + EE), 3. TMS for one week (TBI + TMS), and 4. TMS for one week combined with EE (TBI + TMS/EE). For TMS, a 10 Hz repetitive TMS protocol was used. Results: At 7 days, TBI + TMS and TBI + TMS/EE groups had significantly increased primary somatosensory cortex local field potential (LFP) compared to TBI and TBI + EE groups (P

Traumatic brain injury (TBI) is challenging to assess even with recent advancements in computed tomography and magnetic resonance imaging. Ultrasound (US) imaging has previously been less utilized in TBI compared to conventional imaging because of limited resolution in the intracranial space. However, there have been substantial improvements in contrast-enhanced US and development of novel techniques such as intravascular US. Also, continued research provides further insight into cerebrovascular parameters from transcranial Doppler imaging. These advancements in US imaging provides the community of TBI imaging researchers and clinicians new opportunities in clinically monitoring and understanding the pathologic mechanisms of TBI.

Interhemispheric interaction has a major role in various neurobehavioral functions. Its disruption is a major contributor to the pathological changes in the setting of brain injury such as traumatic brain injury, peripheral nerve injury, and stroke, as well as neurodegenerative diseases. Because interhemispheric interaction has a crucial role in functional consequence in these neuropathological states, a review of noninvasive and state-of-the-art molecular based neuromodulation methods that focus on or have the potential to elucidate interhemispheric interaction have been performed. This yielded approximately 170 relevant articles on human subjects or animal models. There has been a recent surge of reports on noninvasive methods such as transcranial magnetic stimulation and transcranial direct current stimulation. Since these are noninvasive techniques with little to no side effects, their widespread use in clinical studies can be easily justified. The overview of novel neuromodulation methods and how they can be applied to study the role of interhemispheric communication in neural injury and neurodegenerative disease is provided. Additionally, the potential of each method in therapeutic use as well as investigating the pathophysiology of interhemispheric interaction in neurodegenerative diseases and brain injury is discussed. New technologies such as transcranial magnetic stimulation or transcranial direct current stimulation could have a great impact in understanding interhemispheric pathophysiology associated with acquired injury and neurodegenerative diseases, as well as designing improved rehabilitation therapies. Also, advances in molecular based neuromodulation techniques such as optogenetics and other chemical, thermal, and magnetic based methods provide new capabilities to stimulate or inhibit a specific brain location and a specific neuronal population.

After experimental traumatic brain injury (TBI), calcineurin is upregulated; blocking calcineurin is associated with improved outcomes. In humans, variation in the calcineurin A-gamma gene (PPP3CC) has been associated with neuropsychiatric disorders, though any role in TBI recovery remains unknown. This study examines associations between PPP3CC genotype and mortality, as well as gross functional status assessed at admission using the Glasgow Coma Scale (GCS) and at 3, 6, and 12 months after severe TBI using the Glasgow Outcome Score (GOS). The following tagging single nucleotide polymorphisms (tSNPs) in PPP3CC were genotyped: rs2443504, rs2461491, rs2469749, and rs10108011. The rs2443504 AA genotype was univariately associated with GCS (p = 0.022), GOS at 3, 6, and 12 months (p = 0.002, p = 0.034, and p = 0.004, respectively), and mortality (p = 0.007). In multivariate analysis controlling for age, sex, and GCS, the AA genotype of rs2443504 was associated with GOS at 3 (p = 0.02), and 12 months (p = 0.01), with a trend toward significance at 6 months (p = 0.05); the AA genotype also was associated with mortality in the multivariate model (p = 0.04). Further work is warranted to better understand the role of calcineurin, as well as the genes encoding it and their relevance to outcomes after brain injury.

Traumatic brain injury (TBI) remains a significant public health problem and is a leading cause of death and disability in many countries. Durable treatments for neurological function deficits following TBI have been elusive, as there are currently no FDA-approved therapeutic modalities for mitigating the consequences of TBI. Neurostimulation strategies using various forms of electrical stimulation have recently been applied to treat functional deficits in animal models and clinical stroke trials. The results from these studies suggest that neurostimulation may augment improvements in both motor and cognitive deficits after brain injury. Several studies have taken this approach in animal models of TBI, showing both behavioral enhancement and biological evidence of recovery. There have been only a few studies using deep brain stimulation (DBS) in human TBI patients, and future studies are warranted to validate the feasibility of this technique in the clinical treatment of TBI. In this review, the authors summarize insights from studies employing neurostimulation techniques in the setting of brain injury. Moreover, they relate these findings to the future prospect of using DBS to ameliorate motor and cognitive deficits following TBI.

Over last 20 years, extracellular matrices have been shown to be useful in promoting tissue regeneration. Recently, they have been used and have had success in achieving neurogenesis. Recent developments in extracellular matrix design have allowed their successful in vivo incorporation to engender an environment favorable for neural regeneration in animal models. Promising treatments under investigation include manipulation of the intrinsic extracellular matrix and incorporation of engineered naometer-sized scaffolds through which inhibition of molecules serving as barriers to neuroregeneration and delivery of neurotrophic factors and/or cells for successful tissue regeneration can be achieved. Further understanding of the changes incurred within the extracellular matrix following central nervous system injury will undoubtedly help design a clinically efficacious extracellular matrix scaffold that can mitigate or reverse neural degeneration in the clinical setting.

Explosive blast-induced traumatic brain injury (TBI) is the signature insult in modern combat casualty care and has been linked to post-traumatic stress disorder, memory loss, and chronic traumatic encephalopathy. In this article we report on blast-induced mild TBI (mTBI) characterized by fiber-tract degeneration and axonal injury revealed by cupric silver staining in adult male rats after head-only exposure to 35 psi in a helium-driven shock tube with head restraint. We now explore pathways of secondary injury and repair using biochemical/molecular strategies. Injury produced ∼25% mortality from apnea. Shams received identical anesthesia exposure. Rats were sacrificed at 2 or 24 h, and brain was sampled in the hippocampus and prefrontal cortex. Hippocampal samples were used to assess gene array (RatRef-12 Expression BeadChip; Illumina, Inc., San Diego, CA) and oxidative stress (OS; ascorbate, glutathione, low-molecular-weight thiols [LMWT], protein thiols, and 4-hydroxynonenal [HNE]). Cortical samples were used to assess neuroinflammation (cytokines, chemokines, and growth factors; Luminex Corporation, Austin, TX) and purines (adenosine triphosphate [ATP], adenosine diphosphate, adenosine, inosine, 2'-AMP [adenosine monophosphate], and 5'-AMP). Gene array revealed marked increases in astrocyte and neuroinflammatory markers at 24 h (glial fibrillary acidic protein, vimentin, and complement component 1) with expression patterns bioinformatically consistent with those noted in Alzheimer's disease and long-term potentiation. Ascorbate, LMWT, and protein thiols were reduced at 2 and 24 h; by 24 h, HNE was increased. At 2 h, multiple cytokines and chemokines (interleukin [IL]-1α, IL-6, IL-10, and macrophage inflammatory protein 1 alpha [MIP-1α]) were increased; by 24 h, only MIP-1α remained elevated. ATP was not depleted, and adenosine correlated with 2'-cyclic AMP (cAMP), and not 5'-cAMP. Our data reveal (1) gene-array alterations similar to disorders of memory processing and a marked astrocyte response, (2) OS, (3) neuroinflammation with a sustained chemokine response, and (4) adenosine production despite lack of energy failure-possibly resulting from metabolism of 2'-3'-cAMP. A robust biochemical/molecular response occurs after blast-induced mTBI, with the body protected from blast and the head constrained to limit motion.

Experimental investigations into the effects of traumatic brain injury (TBI) have demonstrated significant alterations in dopaminergic systems. Dopaminergic fibers originating within the substantia nigra and ventral tegmental area (VTA) are important for reward learning, addiction, movement, and behavior. However, little is known about the effect of TBI on substantia nigra and VTA function. Environmental enrichment (EE) has been shown to improve functional outcome after TBI, and a number of studies suggest that it may exert some benefits via dopaminergic signaling. To better understand the role of dopamine in chronic TBI pathophysiology and the effect of EE, we examined the mRNA expression profile within the substantia nigra and VTA at 4 weeks post-injury. Specifically, three comparisons were made: 1) TBI versus sham, 2) sham+EE versus sham+standard (STD) housing, and 3) TBI+EE versus TBI+STD. There were differential expressions of 25, 4, and 40 genes in these comparisons, respectively. Chronic alterations in genes post-injury within the substantia nigra and VTA included genes important for cellular membrane homeostasis and transcription. EE-induced gene alterations after TBI included genes important for signal transduction, in particular calcium signaling pathways, membrane homeostasis, and metabolism. Elucidation of these alterations in gene expression within the substantia nigra and VTA provides new insights into chronic changes in dopamine signaling post-TBI, and the potential role of EE in TBI rehabilitation.

We report the outcomes of the endoscopic endonasal approach (EEA) for resection of growth hormone secreting pituitary adenomas using 2010 consensus criteria. We also assess outcomes with additional medical therapy and radiosurgery (RS) for patients not achieving remission with EEA alone. A retrospective review of 53 patients who had follow up endocrinologic data at least 3 months post-surgery was performed among patients who were treated by EEA between 1998 and 2012. Data were analyzed for remission using GH and IGF-I levels based on 2010 consensus criteria. We also analyzed the outcomes using 2000 consensus criteria for ease in comparison to prior studies of outcomes of surgery for acromegaly. In this series of mostly large (88.2 % macroadenomas), invasive (46.9 % Hardy–Wilson C, D, E) adenomas, there were 27 patients (50.9 %) who achieved remission after EEA only. For patients who had no remission with EEA alone, RS and/or medical therapy were used and 37 patients (69.8 %) achieved remission overall. Statistical analysis showed larger tumor size, Hardy Stages C, D, E and Knosp Scores 3, 4 to be predictive against remission for EEA only and EEA with other modalities. The volume of residual tumor after EEA was not found to be predictive of remission with additional therapies. We used stringent consensus criteria from 2010 in a series which included a high proportion of invasive GH secreting adenomas to show that EEA alone or combined with other modalities results in comparable remission rates to earlier studies which used less strict criteria, while retaining low complication rates.

Background Nonvestibular schwannomas of the skull base often represent a challenge owing to their anatomic location. With improved techniques in endoscopic endonasal skull base surgery, resection of various ventral skull base tumors, including schwannomas, has become possible. Objective To assess the outcomes of using endoscopic endonasal approach (EEA) for nonvestibular schwannomas of the skull base. Methods Seventeen patients operated on for skull base schwannomas by EEA at the University of Pittsburgh Medical Center from 2003 to 2009 were reviewed. Results Three patients underwent combined approaches with retromastoid craniectomy (n = 2) and orbitopterional craniotomy (n = 1). Three patients underwent multistage EEA. The rest received a single EEA operation. Data on degree of resection were found for 15 patients. Gross total resection (n = 9) and near-total (>90%) resection (n = 3) were achieved in 12 patients (80%). There were no tumor recurrences or postoperative cerebrospinal fluid leaks. In 3 of 7 patients with preoperative sensory deficits of trigeminal nerve distribution, there were partial improvements. Patients with preoperative reduced vision (n = 1) and cranial nerve VI or III palsies (n = 3) also showed improvement. Five patients had new postoperative trigeminal nerve deficits: 2 had sensory deficits only, 1 had motor deficit only, and 2 had both motor and sensory deficits. Three of these patients had partial improvement, but 3 developed corneal neurotrophic keratopathy. Conclusion An EEA provides adequate access for nonvestibular schwannomas invading the skull base, allowing a high degree of resection with a low rate of complications.

There is increasing evidence that traumatic brain injury (TBI) induces hypofunction of the striatal dopaminergic system, the mechanisms of which are unknown. In this study, we analyzed the activity of striatal tyrosine hydroxylase (TH) in rats at 1 day, 1 week, and 4 weeks after TBI using the controlled cortical impact model. There were no changes in the level of TH phosphorylated at serine 40 site (pser40TH) at 1 day or 4 weeks. At 1 week, injured animals showed decreased pser40TH to 73.9±7.3% (p≤0.05) of sham injured rats. The in vivo TH activity assay showed no significant difference between injured and sham rats at 1 day. However, there was a decreased activity in injured rats to 62.1±8.2% (p≤0.05) and 68.8±6.2% (p≤0.05) of sham injured rats at 1 and 4 weeks, respectively. Also, the activity of protein kinase A, which activates TH, decreased at 1 week (injured: 87.8±2.8%, sham: 100.0± 4.2%, p≤0.05). To study the release activity of dopamine after injury, potassium (80 mM)-evoked dopamine release was measured by microdialysis in awake, freely moving rats. Dialysates were collected and analyzed by high-performance liquid chromatography. There were no significant differences in dopamine release at 1 day and 4 weeks between sham and injured groups. At 1 week, there was a significant decrease (injured: 0.067±0.015 μM, sham: 0.127 ± 0.027 μM, p ≤ 0.05). These results suggest that TBI-induced dopamine neurotransmission deficits are, at least in part, attributable to deficits in TH activity.

Objective A variety of biomaterials have been developed for cranial reconstruction after craniectomy, including polyethylene titanium mesh and calcium phosphate cement. This study sought to compare complication rates of calcium phosphate cement and titanium mesh cranioplasty in patients undergoing retromastoid craniectomy. Methods The authors retrospectively reviewed clinical data from 672 consecutive patients who underwent retromastoid craniectomy at a single institution for microvascular decompression or tumor resection from July 2009 to July 2014. Of these, 336 patients received calcium phosphate cement cranioplasty and 336 underwent (polyethylene) mesh cranioplasty. Charts were abstracted for occurrence of cerebrospinal fluid (CSF) leak, wound infection and/or other wound complication, and the groups were compared. Results In the mesh cranioplasty group, there were 38 complications related to the surgical site, including 18 infections (5.4%), 20 patients (6%) with CSF leak or pseudomeningocele, and no (0%) other wound complications. In the cement cranioplasty cohort, 2 patients (0.6%) experienced wound infection, no patients (0%) had CSF leak, and 2 patients (0.6%) had other wound complications (including one sterile wound dehiscence and one reoperation for removal of excess cement). There was a statistically significant decrease in the rate of wound infection and CSF leak in the patients who underwent cement cranioplasty ( P Conclusions Calcium phosphate cement cranioplasty offers an alternative to titanium cranioplasty and may reduce the risk of surgical site complication. Randomized, prospective comparisons of cement cranioplasty to traditional techniques are warranted.

Traumatic brain injury (TBI) results in varying degrees of disability in a significant number of persons annually. The mechanisms of cognitive dysfunction after TBI have been explored in both animal models and human clinical studies for decades. Dopaminergic, serotonergic, and noradrenergic dysfunction has been described in many previous reports. In addition, cholinergic dysfunction has also been a familiar topic among TBI researchers for many years. Although pharmacological agents that modulate cholinergic neurotransmission have been used with varying degrees of success in previous studies, improving their function and maximizing cognitive recovery is an ongoing process. In this article, we review the previous findings on the biological mechanism of cholinergic dysfunction after TBI. In addition, we describe studies that use both older agents and newly developed agents as candidates for targeting cholinergic neurotransmission in future studies.

OBJECT Stereotactic radiosurgery (SRS) is a therapeutic option for repeatedly hemorrhagic cavernous malformations (CMs) located in areas deemed to be high risk for resection. During the latency period of 2 or more years after SRS, recurrent hemorrhage remains a persistent risk until the obliterative process has finished. The pathological response to SRS has been studied in relatively few patients. The authors of the present study aimed to gain insight into the effect of SRS on CM and to propose possible mechanisms leading to recurrent hemorrhages following SRS. METHODS During a 13-year interval between 2001 and 2013, bleeding recurred in 9 patients with CMs that had been treated using Gamma Knife surgery at the authors' institution. Microsurgical removal was subsequently performed in 5 of these patients, who had recurrent hemorrhages between 4 months and 7 years after SRS. Specimens from 4 patients were available for analysis and used for this report. RESULTS Histopathological analysis demonstrated that vascular sclerosis develops as early as 4 months after SRS. In the samples from 2 to 7 years after SRS, sclerotic vessels were prominent, but there were also vessels with incomplete sclerosis as well as some foci of neovascularization. CONCLUSIONS Recurrent bleeding after SRS for CM could be related to incomplete sclerosis of the vessels, but neovascularization may also play a role.

OBJECT Brainstem cavernous malformations (CMs) are challenging due to a higher symptomatic hemorrhage rate and potential morbidity associated with their resection. The authors aimed to preoperatively define the relationship of CMs to the perilesional corticospinal tracts (CSTs) by obtaining qualitative and quantitative data using high-definition fiber tractography. These data were examined postoperatively by using longitudinal scans and in relation to patients’ symptomatology. The extent of involvement of the CST was further evaluated longitudinally using the automated “diffusion connectometry” analysis. METHODS Fiber tractography was performed with DSI Studio using a quantitative anisotropy (QA)-based generalized deterministic tracking algorithm. Qualitatively, CST was classified as being “disrupted” and/or “displaced.” Quantitative analysis involved obtaining mean QA values for the CST and its perilesional and nonperilesional segments. The contralateral CST was used for comparison. Diffusion connectometry analysis included comparison of patients’ data with a template from 90 normal subjects. RESULTS Three patients (mean age 22 years) with symptomatic pontomesencephalic hemorrhagic CMs and varying degrees of hemiparesis were identified. The mean follow-up period was 37.3 months. Qualitatively, CST was partially disrupted and displaced in all. Direction of the displacement was different in each case and progressively improved corresponding with the patient’s neurological status. No patient experienced neurological decline related to the resection. The perilesional mean QA percentage decreases supported tract disruption and decreased further over the follow-up period (Case 1, 26%–49%; Case 2, 35%–66%; and Case 3, 63%–78%). Diffusion connectometry demonstrated rostrocaudal involvement of the CST consistent with the quantitative data. CONCLUSIONS Hemorrhagic brainstem CMs can disrupt and displace perilesional white matter tracts with the latter occurring in unpredictable directions. This requires the use of tractography to accurately define their orientation to optimize surgical entry point, minimize morbidity, and enhance neurological outcomes. Observed anisotropy decreases in the perilesional segments are consistent with neural injury following hemorrhagic insults. A model using these values in different CST segments can be used to longitudinally monitor its craniocaudal integrity. Diffusion connectometry is a complementary approach providing longitudinal information on the rostrocaudal involvement of the CST.

We evaluated factors associated with better outcomes after stereotactic radiosurgery (SRS) when it was performed as the first surgical procedure for medically refractory trigeminal neuralgia.A total of 121 patients (median age 72 years) with medically refractory pain and no prior surgery underwent Gamma Knife SRS as their initial surgical procedure for trigeminal neuralgia. Using a single 4-mm isocenter, patients received an average maximum dose of 80 Gy, delivered to the trigeminal nerve target defined by intraoperative MRI. The median follow-up was 36 months.Pain relief (Barrow Neurological Institute [BNI] score I-IIIa) was achieved in 107 (88%) patients at a median time of 1 month. Patients who underwent earlier SRS (within 3 years of pain onset) had a shorter interval until pain relief (1 week, p0.001), had a longer interval of pain relief off medication (BNI-I, p0.001), and had a longer duration of adequate pain control (BNI-I-IIIa, p0.001). Median pain-free intervals for patients who underwent SRS at 1, 2, 3, and more than 3 years after trigeminal neuralgia diagnosis were 68, 37, 36, and 10 months, respectively. Patients who responded to SRS within the first 3 weeks after SRS had a longer duration of complete pain relief compared to those with longer response times (p = 0.001). Fifteen patients (12%) reported new sensory dysfunction after SRS.Early SRS as the initial surgical procedure for management of refractory trigeminal neuralgia was associated with faster, better, and longer pain relief when compared to late SRS.This study provides Class IV evidence that in patients with medically refractory trigeminal neuralgia, early stereotactic radiosurgery as the initial procedure provides faster, better, and longer pain relief.

Objective The purpose of this study was to analyze the outcomes and complications of the endoscopic endonasal approach (EEA) performed on patients with Cushing disease at our Pituitary Center during the past 11 years. Methods Clinical information and imaging in electronic medical records were reviewed for patients who underwent EEA. Statistical analysis was performed with χ 2 testing and Student's t -test. Results Remission was achieved in 39 patients (79.6%) at initial evaluation within 2 weeks of surgery. At last follow-up, remission persisted in 70% of 50 patients with EEA alone (mean follow-up time, 37.5 ± 4.6 months; median, 26.2 months; range, 2.5–155.0 months). At last follow-up, remission rates were 80% among magnetic resonance imaging-negative adenomas, 70.6% among noninvasive or minimally invasive adenomas (Knosp 0, 1, 2), and 50% among invasive adenomas (Knosp 3, 4). There were no statistical differences in the remission rates among these categories ( P = 0.444). Women had higher proportions of initial remission than men ( P = 0.033) and patients who had no initial remission were older ( P = 0.046). Higher preoperative normalized adrenocroticotropic hormone level was associated with a greater degree of invasiveness ( P = 0.021). However, there was no association between preoperative normalized urine-free cortisol levels and degree of invasiveness ( P = 0.582). Complications included panhypopituitarism (n = 3), hypothyroidism (n = 3), growth hormone deficiency (n = 1), hypogonadism (n = 1), postoperative cerebrospinal fluid leak (n = 2), and transient diabetes insipidus (n = 4). Conclusions The EEA for Cushing disease resulted in remission and complication rates comparable with previous analyses of EEA, as well as microsurgical series. Preoperative adrenocorticotropic hormone levels were associated with invasiveness.

Background Diagnosing normal pressure hydrocephalus (NPH) remains challenging. Most clinical tests currently used to evaluate suspected NPH patients for shunt surgery are invasive, require inpatient admission, and are not without complications. An objective, noninvasive, and low-cost alternative would be ideal. Methods A retrospective review was performed of prospectively collected dynamic gait index (DGI) scores, obtained at baseline and on every day of a 3- to 5-day lumbar cerebrospinal fluid (CSF) drainage trial on patients with suspected NPH at our institution. Results Between 2003 and 2014, 170 patients were suspected to have primary NPH (166, 97.6%) or secondary NPH (4, 2.4%). Using responsiveness to lumbar CSF drainage and subsequent shunting as the reference standard, we found that a baseline DGI ≥7 was found to have significant ability in selecting patients for permanent CSF diverting shunt surgery: sensitivity of 84.2% (95% confidence interval [95% CI]: 75.6%–90.2%), specificity of 80.6% (95% CI 70.0%–88.0%), and diagnostic odds ratio of 22.1 (95% CI 9.9–49.3). Conclusions A baseline DGI ≥7 appears to provide an objective, low-cost, noninvasive measure to select patients with suspected NPH for a positive response to CSF diversion with high sensitivity, specificity and diagnostic odds ratio.

PURPOSE In previous studies, collagen based matrices have been implanted into the site of lesion in different models of brain injury. We hypothesized that semisynthetic collagen matrix can have neuroprotective function in the setting of traumatic brain injury. METHODS Rats were subjected to sham injury or controlled cortical impact. They either received extracellular matrix graft (DuraGen) over the injury site or did not receive any graft and underwent beam balance/beam walking test at post injury days 1-5 and Morris water maze at post injury days 14-18. Animals were sacrificed at day 18 for tissue analysis. RESULTS Collagen matrix implantation in injured rats did not affect motor function (beam balance test: p = 0.627, beam walking test: p = 0.921). However, injured group with collagen matrix had significantly better spatial memory acquisition (p < 0.05). There was a significant reduction in lesion volume, as well as neuronal loss in CA1 (p < 0.001) and CA3 (p < 0.05) regions of the hippocampus in injured group with collagen matrix (p < 0.05). CONCLUSIONS Collagen matrix reduces contusional lesion volume, neuronal loss, and cognitive deficit after traumatic brain injury. Further studies are needed to demonstrate the mechanisms of neuroprotection by collagen matrix.