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Aneurysmal subarachnoid hemorrhage (SAH) continues to be a difficult cerebrovascular disease with limited pharmacologic treatment options. Cerebral vasospasm (CV) and delayed cerebral ischemia (DCI) are leading causes of morbidity and mortality after SAH. Despite the advances in the understanding of its pathophysiology and tremendous efforts to date, nimodipine is currently the sole Food and Drug Administration-approved treatment for patients with SAH, with benefits that are marginal at best. The neuromodulation therapies are promising, especially those that target CV and DCI to improve functional outcomes. The aim of this review is therefore to summarize the available evidence for each type of neuromodulation for CV and DCI, with a special focus on its pathophysiological mechanisms, in addition to their clinical utility and drawbacks, which we hope will lead to future translational therapy options after SAH.We conducted a comprehensive review of preclinical and clinical studies demonstrating the use of neuromodulation for SAH. The literature search was performed using PubMed, Embase, and ClinicalTrials.gov. A total of 21 articles published from 1992 to 2021 and eight clinical trials were chosen.The studies reviewed provide a compelling demonstration that neuromodulation is a potentially useful strategy to target multiple mechanisms of DCI and thus to potentially improve functional outcomes from SAH. There are several types of neuromodulation that have been tested to treat CV and DCI, including the trigeminal/vagus/facial nerve stimulation, sphenopalatine ganglion and spinal cord stimulation, transcranial direct electrical stimulation, transcutaneous electrical neurostimulation, and electroacupuncture. Most of them are in the preclinical or early phases of clinical application; however, they show promising results.DCI has a complex pathogenesis, making the unique anatomical distribution and pleiotropic capabilities of various types of neuromodulation a promising field of study. We may be at the cusp of a breakthrough in the use of these techniques for the treatment of this stubbornly difficult disease.

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Despite extensive research efforts, the majority of trialed monotherapies to date have failed to demonstrate significant benefit. It has been suggested that this is due to the complex pathophysiology of TBI, which may possibly be addressed by a combination of therapeutic interventions. In this article, we have reviewed combinations of different pharmacologic treatments, combinations of non-pharmacologic interventions, and combined pharmacologic and non-pharmacologic interventions for TBI. Both preclinical and clinical studies have been included. While promising results have been found in animal models, clinical trials of combination therapies have not yet shown clear benefit. This may possibly be due to their application without consideration of the evolving pathophysiology of TBI. Improvements of this paradigm may come from novel interventions guided by multimodal neuromonitoring and multimodal imaging techniques, as well as the application of multi-targeted non-pharmacologic and endogenous therapies. There also needs to be a greater representation of female subjects in preclinical and clinical studies.

Traumatic peri-contusional penumbra represents crucial targets for therapeutic interventions after traumatic brain injury (TBI). Current resuscitative approaches may not adequately alleviate impaired cerebral microcirculation and, hence, compromise oxygen delivery to peri-contusional areas. Low-frequency oscillations in cerebral blood flow (CBF) may improve cerebral oxygenation in the setting of oxygen deprivation. However, no method has been reported to induce controllable oscillations in CBF and it hasn’t been applied as a therapeutic strategy. Electrical stimulation of the trigeminal nerve (TNS) plays a pivotal role in modulating cerebrovascular tone and cerebral perfusion. We hypothesized that TNS can modulate CBF at the targeted frequency band via the trigemino-cerebrovascular network, and TNS-induced CBF oscillations would improve cerebral oxygenation in peri-contusional areas. In a rat model of TBI complicated by hemorrhagic shock, TNS-induced CBF oscillations conferred significant preservation of peri-contusional tissues leading to reduced lesion volume, attenuated hypoxic injury and neuroinflammation, increased eNOS expression, improved neurological recovery and better 10-day survival rate, despite not significantly increasing CBF as compared with those in immediate and delayed resuscitation animals. Our findings indicate that low-frequency CBF oscillations enhance cerebral oxygenation in peri-contusional areas, and play a more significant protective role than improvements in non-oscillatory cerebral perfusion or volume expansion alone.

Delayed cerebral ischemia (DCI) is the most consequential secondary insult after aneurysmal subarachnoid hemorrhage (SAH). It is a multifactorial process caused by a combination of large artery vasospasm and microcirculatory dysregulation. Despite numerous efforts, no effective therapeutic strategies are available to prevent DCI. The trigeminal nerve richly innervates cerebral blood vessels and releases a host of vasoactive agents upon stimulation. As such, electrical trigeminal nerve stimulation (TNS) has the capability of enhancing cerebral circulation. OBJECTIVE: To determine whether TNS can restore impaired cerebral macrocirculation and microcirculation in an experimental rat model of SAH. METHODS: The animals were randomly assigned to sham-operated, SAH-control, and SAH-TNS groups. SAH was induced by endovascular perforation on Day 0, followed by KCl-induced cortical spreading depolarization on day 1, and sample collection on day 2. TNS was delivered on day 1. Multiple end points were assessed including cerebral vasospasm, microvascular spasm, microthrombosis, calcitonin gene-related peptide and intercellular adhesion molecule-1 concentrations, degree of cerebral ischemia and apoptosis, and neurobehavioral outcomes. RESULTS: SAH resulted in significant vasoconstriction in both major cerebral vessels and cortical pial arterioles. Compared with the SAH-control group, TNS increased lumen diameters of the internal carotid artery, middle cerebral artery, and anterior cerebral artery, and decreased pial arteriolar wall thickness. Additionally, TNS increased cerebrospinal fluid calcitonin gene-related peptide levels, and decreased cortical intercellular adhesion molecule-1 expression, parenchymal microthrombi formation, ischemia-induced hypoxic injury, cellular apoptosis, and neurobehavioral deficits. CONCLUSION: Our results suggest that TNS can enhance cerebral circulation at multiple levels, lessen the impact of cerebral ischemia, and ameliorate the consequences of DCI after SAH.

Hepatocellular carcinoma (HCC) is the primary form of liver cancer and a major cause of cancer death worldwide. Early detection is key to effective treatment. Yet, early diagnosis is challenging, especially in patients with cirrhosis, who are at high risk of developing HCC. Dysfunction or loss of function of the transforming growth factor β (TGF-β) pathway is associated with HCC. Here, using quantitative immunohistochemistry analysis of samples from a multi-institutional repository, we evaluated if differences in TGF-β receptor abundance were present in tissue from patients with only cirrhosis compared with those with HCC in the context of cirrhosis. We determined that TGFBR2, not TGFBR1, was significantly reduced in HCC tissue compared with cirrhotic tissue. We developed an artificial intelligence (AI)-based process that correctly identified cirrhotic and HCC tissue and confirmed the significant reduction in TGFBR2 in HCC tissue compared with cirrhotic tissue. Thus, we propose that a reduction in TGFBR2 abundance represents a useful biomarker for detecting HCC in the context of cirrhosis and that incorporating this biomarker into an AI-based automated imaging pipeline could reduce variability in diagnosing HCC from biopsy tissue.

Hinchazón celular; Edema; Traumatismo cerebral Cellular swelling; Edema; Traumatic brain injury Inflor cel·lular; Edema; Traumatisme cerebral Sulfonylurea receptor 1 (SUR1) is a member of the adenosine triphosphate (ATP)-binding cassette (ABC) protein superfamily, encoded by Abcc8, and is recognized as a key mediator of central nervous system (CNS) cellular swelling via the transient receptor potential melastatin 4 (TRPM4) channel. Discovered approximately 20 years ago, this channel is normally absent in the CNS but is transcriptionally upregulated after CNS injury. A comprehensive review on the pathophysiology and role of SUR1 in the CNS was published in 2012. Since then, the breadth and depth of understanding of the involvement of this channel in secondary injury has undergone exponential growth: SUR1-TRPM4 inhibition has been shown to decrease cerebral edema and hemorrhage progression in multiple preclinical models as well as in early clinical studies across a range of CNS diseases including ischemic stroke, traumatic brain injury, cardiac arrest, subarachnoid hemorrhage, spinal cord injury, intracerebral hemorrhage, multiple sclerosis, encephalitis, neuromalignancies, pain, liver failure, status epilepticus, retinopathies and HIV-associated neurocognitive disorder. Given these substantial developments, combined with the timeliness of ongoing clinical trials of SUR1 inhibition, now, another decade later, we review advances pertaining to SUR1-TRPM4 pathobiology in this spectrum of CNS disease—providing an overview of the journey from patch-clamp experiments to phase III trials. No funding directly supported the writing of this review. R.M.J. is supported by grants from the National Institute of Neurological Disorders and Stroke (NINDS) (K23NS101036; R01NS115815), and the Barrow Neurological Foundation. J.M.S. is supported by grants from the Department of Veterans Affairs (I01RX003060; 1I01BX004652), the Department of Defense (SC170199), the National Heart, Lung and Blood Institute (R01HL082517) and the NINDS (R01NS102589; R01NS105633).

OBJECTIVEIn patients with aneurysmal subarachnoid hemorrhage (aSAH), poor outcomes have been shown to be correlated with subsequent cerebral vasospasm (CV) and delayed cerebral ischemia (DCI). The identification of novel biomarkers may aid in the prediction of which patients are vulnerable to developing vasospasm, cerebral ischemia, and neurological deterioration.METHODSIn this prospective clinical study at North Shore University Hospital, patients with aSAH or normal pressure hydrocephalus (NPH) with external ventricular drains were enrolled. The concentration of macrophage migration inhibitory factor (MIF) in CSF was assessed for correlation with CV or DCI, the primary outcome measures.RESULTSTwenty-five patients were enrolled in the aSAH group and 9 were enrolled in the NPH group. There was a significant increase in aggregate CSF MIF concentration in patients with aSAH versus those with NPH (24.4 ± 19.2 vs 2.3 ± 1.1 ng/ml, p < 0.0002). Incidence of the day of peak MIF concentration significantly correlated with the onset of clinical vasospasm (rho = 0.778, p < 0.0010). MIF concentrations were significantly elevated in patients with versus those without evidence of DCI (18.7 ± 4.93 vs 8.86 ± 1.28 ng/ml, respectively, p < 0.0025). There was a significant difference in MIF concentrations between patients with infection versus those without infection (16.43 ± 4.21 vs 8.5 ± 1.22 ng/ml, respectively, p < 0.0119).CONCLUSIONSPreliminary evidence from this study suggests that CSF concentrations of MIF are correlated with CV and DCI. These results, however, could be confounded in the presence of clinical infection. A study with a larger patient sample size is necessary to corroborate these findings.

The trigeminal nerve, the fifth cranial nerve, is known to innervate much of the cerebral arterial vasculature and significantly contributes to the control of cerebrovascular tone in both healthy and diseased states. Previous studies have demonstrated that stimulation of the trigeminal nerve (TNS) increases cerebral blood flow (CBF) via antidromic, trigemino-parasympathetic, and other central pathways. Despite some previous reports on the role of the trigeminal nerve and its control of CBF, there are only a few studies that investigate the effects of TNS on disorders of cerebral perfusion (i.e., ischemic stroke, subarachnoid hemorrhage, and traumatic brain injury). In this mini review, we present the current knowledge regarding the mechanisms of trigeminal nerve control of CBF, the anatomic underpinnings for targeted treatment, and potential clinical applications of TNS, with a focus on the treatment of impaired cerebral perfusion.

Background The trigeminal nerve directly innervates key vascular structures both centrally and peripherally. Centrally, it is known to innervate the brainstem and cavernous sinus, whereas peripherally the trigemino-cerebrovascular network innervates the majority of the cerebral vasculature. Upon stimulation, it permits direct modulation of cerebral blood flow (CBF), making the trigeminal nerve a promising target for the management of cerebral vasospasm. However, trigeminally mediated cerebral vasodilation has not been applied to the treatment of vasospasm. Objective To determine the effect of percutaneous electrical stimulation of the infraorbital branch of the trigeminal nerve (pTNS) on the cerebral vasculature. Methods In order to determine the stimulus-response function of pTNS on cerebral vasodilation, CBF, arterial blood pressure, cerebrovascular resistance, intracranial pressure, cerebral perfusion pressure, cerebrospinal fluid calcitonin gene-related peptide (CGRP) concentrations, and the diameter of cerebral vessels were measured in healthy and subarachnoid hemorrhage (SAH) rats. Results The present study demonstrates, for the first time, that pTNS increases brain CGRP concentrations in a dose-dependent manner, thereby producing controllable cerebral vasodilation. This vasodilatory response appears to be independent of the pressor response induced by pTNS, as it is maintained even after transection of the spinal cord at the C5-C6 level and shown to be confined to the infraorbital nerve by administration of lidocaine or destroying it. Furthermore, such pTNS-induced vasodilatory response of cerebral vessels is retained after SAH-induced vasospasm. Conclusion Our study demonstrates that pTNS is a promising vasodilator and increases CBF, cerebral perfusion, and CGRP concentration both in normal and vasoconstrictive conditions.

Background: Hepatocellular carcinoma (HCC) is the primary form of liver cancer and patients with cirrhosis are at high risk of developing HCC. Loss of function of the transforming growth factor β (TGF-β) pathway is associated with HCC. Methods: Immunohistochemical analysis of biopsy tissue from patients with cirrhosis with or without HCC was performed to evaluate if the abundance of the receptor proteins TGFBR1 or TGFBR2 differentiated between HCC and cirrhosis. Samples were obtained from 3 independent sites. Analysis was performed using 3 separate sets of samples, and findings were validated by automated image analysis. Logistic regression modeling was performed to evaluate the predictive power of staining intensity of TGFBR1, TGFBR2, or the combination in differentiating HCC from cirrhosis. Findings: Analysis of a multi-institutional repository of tissue samples showed that the abundance of the TGF-β receptor protein TGFBR2 was significantly reduced in HCC tissue compared with cirrhotic tissue (p < 0.05). An artificial intelligence (AI)-based model that correctly identified cirrhotic and HCC tissue confirmed that TGFBR2 was significantly reduced in HCC tissue compared with cirrhotic tissue (p < 0.005). No single value of TGFBR2 staining intensity, with or without that of TGFBR1 staining intensity, effectively differentiated HCC from cirrhosis. Interpretation: TGFBR2 staining intensity alone is insufficient to diagnose HCC in cirrhotic tissue; however, a relative regional reduction in TGFBR2 in liver tissue samples of patients with cirrhosis may be a marker of HCC development. An automated image analysis pipeline could reduce variability in diagnosing HCC from biopsy tissue. Funding Information: This research work was supported by NIH grants R01AA023146 (L. Mishra), NIH R01CA236591 (L. Mishra), NIH U01 CA230690-01 (L. Mishra), VA Merit I01BX003732 (L. Mishra) and Elaine H. Snyder Cancer Research Award (L. Mishra). Declaration of Interests: These authors have no conflict of interest to declare. Ethics Approval Statement: The study was approved by relevant institutional review boards and all patients provided written informed consent before sample collection.

Background: Early detection of hepatocellular carcinoma (HCC) is challenging partly because most patients also have cirrhosis. Furthermore, patients with cirrhosis are at high risk of developing HCC. Loss of function of the transforming growth factor β (TGF-β) pathway is associated with HCC. The goal of this study was to determine if a reduction in TGF-β receptors (TGFBR1, TGFBR2) was able to reliably and reproducibly predict HCC in cirrhotic tissue. Methods: We performed quantitative immunohistochemical (IHC) analysis of biopsy tissue from patients with cirrhosis with or without HCC using 3 separate sets of samples. We developed an automated image analysis pipeline to quantify IHC of TGFBR1 and TGFRB2 in liver biopsies. Using logistic regression modeling, we evaluated the predictive power of staining intensity of TGFBR1, TGFBR2, or the combination in differentiating HCC from cirrhosis. Results: We found a consistently significant reduction in TGFBR2 in HCC (p < 0.02) among independent patient cohorts from 3 separate institutions. With the data, we developed an artificial intelligence-based image analysis pipeline that confirmed the significant reduction in TGFBR2 staining intensity in HCC compared to cirrhotic tissue (p < 0.002). Unfortunately, logistic regression modeling of the quantitative data showed that there is not a simple threshold of TGFBR2 staining intensity that is diagnostic of HCC. Instead, in 84% of samples with HCC, HCC was associated with a relative regional reduction in TGFBR2 compared to tumor-adjacent cirrhotic tissue. Conclusions: The qualitative and quantitative analyses indicate that evaluating biopsy samples for a reduction in TGFBR2 abundance relative to the surrounding cirrhotic tissue could be an early indicator of the development of HCC in high-risk groups undergoing surveillance for HCC. Furthermore, an automated image analysis pipeline for quantitative IHC of TGFBR staining could improve the reliability of image analysis across institutions participating in clinical trials. Citation Format: Krishanu Bhowmick, Richard Amdur, Xiyan Xiang, Herbert Yu, Linda L. Wong, Shuyun Rao, Aiwu R. He, Karan Amin, Daewa Zaheer, Raj K. Narayan, Sanjaya K. Satapathy, Chandan Guha, Patricia S. Latham, Kirti Shetty, Nancy R. Gough, Lopa Mishra. Multi-cohort study shows HCC is associated with a relative regional reduction in TGFBR2 in liver biopsies from patients with cirrhosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3379.

Supplemental Digital Content is available in the text., Objectives: Patients in ICUs often require neuroimaging to rule out a wide variety of intracranial problems. CT may be available in the ICU itself, but MRI has greater sensitivity for many conditions that affect the brain. However, transporting patients who are on ventilators and other life-sustaining devices is a labor-intensive process and involves placing the patient at risk for adverse events. This is a report of portable MRI in a clinical setting. Design: This is a prospective, nonrandomized, observational study at one institution, utilizing a 0.064-T, self-shielding, portable MRI in ventilated patients in an ICU setting. Setting: Academic medical center. Patients: Nineteen patients with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 infection. Patients selected for imaging had any of the following: 1) unexplained encephalopathy or coma, 2) seizures, 3) focal neurologic deficit, or 4) abnormal head CT. Imaging was performed in each patient’s ICU room with a portable, self-shielding, 0.064-T MRI. Interventions: None. Measurements and Main Results: Among 19 patients, 20 MRI scans in seven ICUs were acquired between April 13, 2020, and April 23, 2020. No adverse events to patients or staff from MRI acquisition were reported. In 12 patients, abnormal findings were seen, which included increased fluid attenuated inversion recovery signal (n = 12), hemorrhage (n = 3), and diffusion-weighted imaging positivity (n =3). Imaging led to changes in clinical management in five patients. Conclusions: In this case series of patients, use of portable MRI has been found to be safe, feasible, and led to changes in clinical management based on imaging results. However, future studies comparing results with other imaging modalities are required to understand fully the extent of its clinical utility.

INTRODUCTION Beginning in March, 2020, hospitals across the majority of the United States were required to cancel all elective surgery in preparation for a surge of patients with the coronavirus disease of 2019 (COVID-19). A large number of neurosurgical patients with less than emergency conditions had their surgery postponed indefinitely. METHODS The Delphi method was used to obtain consensus. Twenty-two neurosurgeons actively practicing in two separate geographic regions of the United States where “black level” COVID-19 surges occurred (New York Metropolitan Area and Detroit, Michigan) participated. A total of 86 neurosurgical case scenarios were categorized into six tiers of priority: emergent or within 24 hours, within 48 hours, within 1 week, within 2 weeks, within one month, or post hospital crisis/more than 4 weeks. Consensus was defined as 75% of participants reaching an agreement. Majority opinion (>50% agreement) was also reported. RESULTS 67 of the 86 surgical scenarios (78%) reached a consensus agreement with 85 out of 86 scenarios reaching at least a majority opinion. Only one scenario (central cord syndrome) did not reach any agreement. CONCLUSION The NNPI developed in this study can assist neurosurgical departments in prioritizing the timing of surgery, whether it be due to a pandemic, or any other scenario where the normal work flow has been severely disrupted and resources are limited.

INTRODUCTION Neuroimaging in the intensive care unit (ICU) may be difficult to acquire given the safety concerns and challenges involved in moving critically ill patients. We report on the safety and clinical findings of a portable magnetic resonance imager (MRI) in a cohort of ICU patients who had Covid 19 with suspected neurologic injury. METHODS This is a prospective, non-randomized, observational study at one institution utilizing portable MRI in patients with laboratory confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, known as Covid-19. Patients selected for imaging had any of the following: 1) unexplained encephalopathy or coma, 2) seizures, 3) focal neurologic deficit, and 4) abnormal head CT. Imaging was performed in each patient's ICU room with a portable, self-shielding, 0.064 Tesla (T) MRI. RESULTS Among 19 patients, a total of 20 MRI scans in seven ICUs were acquired between April 13 and April 23, 2020. No adverse events to patients or staff from MRI acquisition were reported. In 12 patients, abnormal findings were seen, which included increased fluid attenuated inversion recovery (FLAIR) signal (n = 12), hemorrhage (n = 3), and diffusion-weighted imaging (DWI) positivity (n = 3). Imaging led to a change in clinical management in five patients, including 3 lumbar punctures, a resumption of anticoagulation therapy, and one previously unplanned move to palliative care. CONCLUSION This study provides the first report on the use of a novel, portable, self-shielding MRI to image patients. In critically ill patients, the use of portable MRI is safe, feasible, and leads to changes in clinical management. This technique can be applied to any ICU patients whose care requires imaging of the brain.

The "diving reflex" (DR) is a very powerful autonomic reflex that facilitates survival in hypoxic/anoxic conditions and could trigger multifaceted physiologic effects for the treatment of various diseases by modulating the cardiovascular, respiratory, and nervous systems. The DR can be induced by cold water or noxious gases applied to the anterior nasal mucosa and paranasal regions, which can stimulate trigeminal thermo- or chemo-receptors to send afferent signals to medullary nuclei which mediate the sympathetic and parasympathetic nervous systems. Although promising, these approaches have yet to be adopted in routine clinical practice due to the inability to precisely control exposure-response relationships, lack of reproducibility, and difficulty implementing in a clinical setting. In this study, we present the ability of electrical Trigeminal (Infraorbital) Nerve Stimulation (eTINS) to induce the DR in a dose-controllable manner. We found that eTINS not only triggered specific physiological changes compatible with the pattern of "classic" DR observed in animals/humans, but also controlled the induced-DR at varying levels. This study demonstrates, for the first time, that the intensity of the DR is controllable by dose and opens possibility to investigate its protective mechanism against various pathologies in well-controlled research settings.

Cerebral edema and contusion expansion are major determinants of morbidity and mortality after TBI. Current treatment options are reactive, suboptimal and associated with significant side effects. First discovered in models of focal cerebral ischemia, there is increasing evidence that the sulfonylurea receptor 1 (SUR1)—Transient receptor potential melastatin 4 (TRPM4) channel plays a key role in these critical secondary injury processes after TBI. Targeted SUR1-TRPM4 channel inhibition with glibenclamide has been shown to reduce edema and progression of hemorrhage, particularly in preclinical models of contusional TBI. Results from small clinical trials evaluating glibenclamide in TBI have been encouraging. A Phase-2 study evaluating the safety and efficacy of intravenous glibenclamide (BIIB093) in brain contusion is actively enrolling subjects. In this comprehensive narrative review, we summarize the molecular basis of SUR1-TRPM4 related pathology and discuss TBI-specific expression patterns, biomarker potential, genetic variation, preclinical experiments, and clinical studies evaluating the utility of treatment with glibenclamide in this disease.

OBJECTIVES To determine if trigeminal nerve stimulation can ameliorate the consequences of acute blood loss and improve survival after severe hemorrhagic shock. DESIGN Animal study. SETTING University research laboratory. SUBJECTS Male Sprague-Dawley rats. INTERVENTIONS Severe hemorrhagic shock was induced in rats by withdrawing blood until the mean arterial blood pressure reached 27 ± 1 mm Hg for the first 5 minutes and then maintained at 27 ± 2 mm Hg for 30 minutes. The rats were randomly assigned to either control, vehicle, or trigeminal nerve stimulation treatment groups. The effects of trigeminal nerve stimulation on survival rate, autonomic nervous system activity, hemodynamics, brain perfusion, catecholamine release, and systemic inflammation after severe hemorrhagic shock in the absence of fluid resuscitation were analyzed. MEASUREMENTS AND MAIN RESULTS Trigeminal nerve stimulation significantly increased the short-term survival of rats following severe hemorrhagic shock in the absence of fluid resuscitation. The survival rate at 60 minutes was 90% in trigeminal nerve stimulation treatment group whereas 0% in control group (p < 0.001). Trigeminal nerve stimulation elicited strong synergistic coactivation of the sympathetic and parasympathetic nervous system as measured by heart rate variability. Without volume expansion with fluid resuscitation, trigeminal nerve stimulation significantly attenuated sympathetic hyperactivity paralleled by increase in parasympathetic tone, delayed hemodynamic decompensation, and improved brain perfusion following severe hemorrhagic shock. Furthermore, trigeminal nerve stimulation generated sympathetically mediated low-frequency oscillatory patterns of systemic blood pressure associated with an increased tolerance to central hypovolemia and increased levels of circulating norepinephrine levels. Trigeminal nerve stimulation also decreased systemic inflammation compared with the vehicle. CONCLUSIONS Trigeminal nerve stimulation was explored as a novel resuscitation strategy in an animal model of hemorrhagic shock. The results of this study showed that the stimulation of trigeminal nerve modulates both sympathetic and parasympathetic nervous system activity to activate an endogenous pressor response, improve cerebral perfusion, and decrease inflammation, thereby improving survival.

An integrated neuro-rehabilitation approach toward the treatment of acquired brain injuries begins with a fundamental understanding of neurosurgical pathologies. Improvements in the neurosurgical knowledge of not only the neuro-rehabilitation team but also the patient family unit allow more cohesive participation and improvements in patient’s outcomes. The purpose of this chapter is to provide a framework for the epidemiology, symptoms, diagnoses, treatment paradigm, and outcomes of the most frequently encountered operative neurosurgical pathologies in the contemporary era. This chapter will seek to illustrate the symptoms, diagnosis, treatment, and outcomes from ABI as a result of traumatic brain injury (concussion, epidural hematoma, subdural hematoma, and penetrating injury) or nontraumatic brain injury (spontaneous intracranial hemorrhage, malignant cerebral infraction, brain tumor, and aneurysmal subarachnoid hemorrhage). It is expected that this information can be utilized by the integrated neuro-rehabilitation team and family unit to improve patient outcomes.

Regional temperature and quantitative regional cerebral blood flow responses to cortical spreading depolarization in the rat were continuously monitored in the same tissue using a microfabricated thermal diffusion sensor that recalibrates and measures in 5-s cycles. The regional cerebral blood flow response had four phases, including early hyperemia (peak: 226% of baseline; duration: 113.1 ± 14.4 s) and late oligemia (minimum: 57%, duration: 28.4 ± 3.7 min). Temperature rose with the start of the regional cerebral blood flow response to a peak increase of 0.28 ± 0.06℃ and returned to baseline near the start of oligemia. This technology may be useful for multimodal monitoring in both the laboratory and clinic.

Traumatic brain injury (TBI), defined as a traumatic blow or jolt to the head, or penetrating trauma to the skull that injures the brain, is a worldwide epidemic that has a substantial impact on global health and function. In this chapter, we overview TBI epidemiology and health care costs as well as discuss the fundamental pathophysiology associated with primary and secondary injury. We discuss TBI across the injury severity spectrum and continuum of care and also in the context of other injury complex elements such as injury due to blast, hypoxic-ischemic brain injury, polytrauma, and shaken-baby syndrome. We discuss how TBI influences neurotransmission and the myriad of secondary symptoms, conditions, and complications that arise due to TBI. Key testing and medical management approaches are discussed, and the roles of rehabilitation team members across the continuum of care are outlined. Translational research perspectives, including biomarkers and imaging modalities, as well as community integration and TBI prevention strategies are discussed. This comprehensive overview of TBI provides up-to-date perspectives and the fundamental literature needed for rehabilitation clinicians to be knowledgeable and address TBI epidemiology, pathophysiology, secondary conditions, management, prognostication, outcome, community reintegration, and prevention. Pediatric perspectives on these areas as also provided.

Following traumatic brain injury (TBI), ischemia and hypoxia play a major role in further worsening of the damage, a process referred to as ‘secondary injury’. Protecting neurons from causative factors of secondary injury has been the guiding principle of modern TBI management. Stimulation of trigeminal nerve induces pressor response and improves cerebral blood flow (CBF) by activating the rostral ventrolateral medulla. Moreover, it causes cerebrovasodilation through the trigemino-cerebrovascular system and trigemino-parasympathetic reflex. These effects are capable of increasing cerebral perfusion, making trigeminal nerve stimulation (TNS) a promising strategy for TBI management. Here, we investigated the use of electrical TNS for improving CBF and brain oxygen tension (PbrO2), with the goal of decreasing secondary injury. Severe TBI was produced using controlled cortical impact (CCI) in a rat model, and TNS treatment was delivered for the first hour after CCI. In comparison to TBI group, TBI animals with TNS treatment demonstrated significantly increased systemic blood pressure, CBF and PbrO2 at the hyperacute phase of TBI. Furthermore, rats in TNS-treatment group showed significantly reduced brain edema, blood-brain barrier disruption, lesion volume, and brain cortical levels of TNF-α and IL-6. These data provide strong early evidence that TNS could be an effective neuroprotective strategy.

Multimodal brain monitoring is an important approach to gain insight into brain function, modulation, and pathology. We have developed a unique micromachined neural probe capable of real-time continuous monitoring of multiple physiological, biochemical and electrophysiological variables. However, to date, it has only been used in anesthetized animals due to a lack of an appropriate interface for awake animals. We have developed a versatile headstage for recording the small neural signal and bridging the sensors to the remote sensing units for multimodal brain monitoring in awake rats. The developed system has been successfully validated in awake rats by simultaneously measuring four cerebral variables: electrocorticography, oxygen tension, temperature and cerebral blood flow. Reliable signal recordings were obtained with minimal artifacts from movement and environmental noise. For the first time, multiple variables of cerebral function and metabolism were simultaneously recorded from awake rats using a single neural probe. The system is envisioned for studying the effects of pharmacologic treatments, mapping the development of central nervous system diseases, and better understanding normal cerebral physiology.

In this paper, we present a flexible temperature sensor with ultra-small polysilicon thermistors for brain temperature monitoring. In vitro sensitivity, resolution, thermal hysteresis and long term stability tests were performed. Temperature coefficient of resistance (TCR) of −0.0031/ °C and resolution of 0.1 °C were obtained for the sensor. Thermal hysteresis for temperature range of 30∼45 °C was less than 0.1 °C. With silicon nitride as the passivation layer, the temperature sensor showed a drift within 0.3 °C for 3 days long term stability test in water. In vivo tests showed a clear correlation between the localized brain temperature and electrocorticography (ECoG) signal during spreading depolarization. The developed flexible temperature sensor with small size polysilicon thermistors can be adopted for high resolution brain temperature mapping as well as multimodal monitoring with limited sensing space.

The management of a trauma patient with multiple injuries requires careful coordination prior to and while in the operating room. In order to consistently assure the best possible outcome for these patients a team-based approach is essential. Defining the relative roles for each team and the priority given to each injury is necessary to ensure a coordinated response and hence the best possible outcome. It is important that airway, breathing, and circulation remain the initial priorities and the correction of hemodynamic instability takes precedence over the workup of intracranial lesions. In turn, the management of intracranial injury takes precedence over the surgical fixation of broken bones. At times it is necessary for the trauma team and neurosurgery teams to work simultaneously in the operating room. An intracranial pressure monitor can be placed during laparotomy or thoracotomy in select cases, particularly when a preoperative CT scan cannot be obtained due to the urgent need for operative surgical resuscitation. Fortunately with the widespread and easy availability of around-the-clock CT scanning at most U.S. trauma centers, this is an uncommon scenario. High intracranial pressure can be treated medically until active systemic bleeding is controlled and the blood pressure is stabilized. A craniotomy for intracranial hematoma evacuation should be performed promptly after the hypotension has been corrected. Clear communication and coordination between the anesthesiologist, the trauma surgeon, the neurosurgeon, and other appropriate specialists are vital in order to obtain the best possible outcomes.

Traumatic brain injury is a serious public health problem in the United States, accounting for nearly 1.7 million injuries and 52,000 deaths annually. The initial brain injury is made worse by secondary events which include, but are not limited to, ischemia, swelling, cell damage and brain functions abnormalities which, while posing therapeutic challenges, offer therapeutic opportunities. Unfortunately, in spite of significant efforts, no effective indisputable treatment which would effectively alleviate consequences of this often devastating event currently exists. Multimodality neuromonitoring could provide early warning of secondary brain injury and guide individualized therapy. However, it is rarely done due to the complexity of using multiple devices and the increased risk of complications. This article presents a novel multifunctional smart catheter to continuously and accurately monitor multiple physiological, metabolic and electrophysiological parameters that are vitally important in guiding the care of patients with traumatic brain injury. In addition to measuring various crucial parameters, the developed smart catheter allows for drainage of excess cerebrospinal fluid as a therapeutic strategy to reduce intracranial pressure. The studies which were performed under a rat permanent middle cerebral artery occlusion model indicate that the smart catheter, a single probe, can dynamically detect changes in cerebral glucose, lactate, oxygen, glutamate, temperature, local cerebral blood flow and intracranial pressure that correlated with spreading depression. These results demonstrate that the smart catheter is capable of simultaneous and continuous measurement of multiple brain variables, within the pathophysiology ranges observed in brain injury. The smart catheter has the potential to improve our understanding of brain pathophysiology and advance the field of neuromonitoring into a completely new era in which medical decisions will be based on comprehensive, real-time measures of brain chemistry and physiology during the critical period immediately following a brain injury.

Traumatic brain injury (TBI) is a significant cause of mortality and morbidity worldwide. Current treatment of acute TBI includes surgical intervention when needed, followed by supportive critical care such as optimizing cerebral perfusion, preventing pyrexia, and treating raised intracranial pressure. While effective in managing the primary injury to the brain and skull, these treatment modalities do not address the complex secondary cascades that occur at a cellular level following initial injury and greatly affect the ultimate neurologic outcome. These secondary processes involve changes in ionic flux, disruption of cellular function, derangement of blood flow and the blood-brain barrier, and elevated levels of free radicals. Over the past few decades, numerous pharmacologic agents and modalities have been investigated in an attempt to interrupt these secondary processes. No neuroprotective agents currently exist that have been proven to improve neurologic outcome following TBI. However, these trials have contributed significantly to the understanding of the clinical sequelae of TBI and to improvements in the quality of care for TBI. With the experience and insights that have been accrued with the trials to date, we will be able to optimize future trial designs and refine established neurologic endpoints to better identify new therapeutic agents and further improve neurologic outcomes from this often devastating condition.

We present a microfabricated neural catheter for real-time continuous monitoring of multiple physiological, biochemical and electrophysiological variables that are critical to the diagnosis and treatment of evolving brain injury. The first generation neural catheter was realized by polyimide-based micromachining and a spiral rolling packaging method. The mechanical design and electrical operation of the microsensors were optimized and tailored for multimodal monitoring in rat brain such that the potential thermal, chemical and electrical crosstalk among the microsensors as well as errors from micro-environmental fluctuations are minimized. In vitro cytotoxicity analyses suggest that the developed neural catheters are minimally toxic to rat cortical neuronal cultures. In addition, in vivo histopathology results showed neither acute nor chronic inflammation for 7 days post implantation. The performance of the neural catheter was assessed in an in vivo needle prick model as a translational replica of a "mini" traumatic brain injury. It successfully monitored the expected transient brain oxygen, temperature, regional cerebral blood flow, and DC potential changes during the passage of spreading depolarization waves. We envisage that the developed multimodal neural catheter can be used to decipher the causes and consequences of secondary brain injury processes with high spatial and temporal resolution while reducing the potential for iatrogenic injury inherent to current use of multiple invasive probes.

The development of in vitro disease models closely mimicking the functions of human disease has captured increasing attention in recent years. Oxygen tensions and gradients play essential roles in modulating biological systems in both physiologic and pathologic events. Thus, controlling oxygen tension is critical for mimicking physiologically relevant in vivo environments for cell, tissue and organ research. We present a new approach for on-demand generation of various oxygen tensions for in vitro hypoxia models. Proof-of-concept prototypes have been developed for conventional cell culture microplate by immobilizing a novel oxygen-consuming biomaterial on the 3D-printed insert. For the first time, rapid (~3.8 minutes to reach 0.5% O2 from 20.9% O2) and precisely controlled oxygen tensions/gradients (2.68 mmHg per 50 μm distance) were generated by exposing the biocompatible biomaterial to the different depth of cell culture media. In addition, changing the position of 3D-printed inserts with immobilized biomaterials relative to the cultured cells resulted in controllable and rapid changes in oxygen tensions (

A new microsensor can simultaneously track drug pharmacokinetics and pharmacodynamics and the resulting electrophysiological activity in live animals.

Background and Purpose— Patients with intracerebral hemorrhage and intraventricular hemorrhage have a reported mortality of 50% to 80%. We evaluated a clot lytic treatment strategy for these patients in terms of mortality, ventricular infection, and bleeding safety events, and for its effect on the rate of intraventricular clot lysis. Methods— Forty-eight patients were enrolled at 14 centers and randomized to treatment with 3 mg recombinant tissue-type plasminogen activator (rtPA) or placebo. Demographic characteristics, severity factors, safety outcomes (mortality, infection, bleeding), and clot resolution rates were compared in the 2 groups. Results— Severity factors, including admission Glasgow Coma Scale, intracerebral hemorrhage volume, intraventricular hemorrhage volume, and blood pressure were evenly distributed, as were adverse events, except for an increased frequency of respiratory system events in the placebo-treated group. Neither intracranial pressure nor cerebral perfusion pressure differed substantially between treatment groups on presentation, with external ventricular device closure, or during the active treatment phase. Frequency of death and ventriculitis was substantially lower than expected and bleeding events remained below the prespecified threshold for mortality (18% rtPA; 23% placebo), ventriculitis (8% rtPA; 9% placebo), symptomatic bleeding (23% rtPA; 5% placebo, which approached statistical significance; P =0.1). The median duration of dosing was 7.5 days for rtPA and 12 days for placebo. There was a significant beneficial effect of rtPA on rate of clot resolution. Conclusions— Low-dose rtPA for the treatment of intracerebral hemorrhage with intraventricular hemorrhage has an acceptable safety profile compared to placebo and historical controls. Data from a well-designed phase III clinical trial, such as CLEAR III, will be needed to fully evaluate this treatment. Clinical Trial Registration— Participant enrollment began before July 1, 2005.

The injured brain is vulnerable to increases in temperature after severe head injury. Therefore, accurate and reliable measurement of brain temperature is important to optimize patient outcome. In this work, we have fabricated, optimized and characterized temperature sensors for use with a micromachined smart catheter for multimodal intracranial monitoring. Developed temperature sensors have resistance of 100.79 ± 1.19Ω and sensitivity of 67.95 mV/°C in the operating range from15–50°C, and time constant of 180 ms. Under the optimized excitation current of 500 μA, adequate signal-to-noise ratio was achieved without causing self-heating, and changes in immersion depth did not introduce clinically significant errors of measurements (

Jacob Chandy, who passed away in 2007 at the age of 97, was born into a deeply religious Christian family in Kerala, South India. After obtaining his medical education at the Madras Medical College, Madras, he serendipitously came to work with Dr Paul Harrison, a renowned medical missionary, in the Gulf state of Bahrain. Harrison urged Chandy to pursue training in the fledgling specialty of neurosurgery in North America. Chandy received his neurosurgical training at the Montreal Neurological Institute with Wilder Penfield and in Chicago with Theodore Rasmussen. At Harrison's urging, Chandy decided to return to India after completing his training to work at the Christian Medical College in Vellore. Thus, it was in 1949 that Chandy established the first neurosurgery department in south Asia in Vellore. He initiated the first neurosurgical training program in India at the Christian Medical College in 1957, with a distinct North American neurosurgical tradition. He went on to train nearly 20 neurosurgeons, many of whom set up new departments of neurosurgery in their home states. Chandy also had several other remarkable achievements to his credit. Despite the pressures of clinical practice, he insisted on fostering both basic and clinical neurosciences within his department, an arrangement that persists to this day in the Department of Neurological Sciences at the Christian Medical College, Vellore. As the Principal (Dean) of the Christian Medical College, Chandy displayed his skills as a medical educator and administrator. In this role, he was instrumental in starting specialty training programs in several other medical and surgical disciplines. His greatest legacies survive in the form of the department that he founded and his trainees and their students who have helped to establish neurosurgery all over the country.

Oxygen and glucose biosensors have been designed, fabricated, characterized and optimized for real-time continuous monitoring on a new smart catheter for use in patients with traumatic brain injury (TBI). Oxygen sensors with three-electrode configuration were designed to achieve zero net oxygen consumption. Glucose sensors were based on the use of platinum nanoparticle-enhanced electrodes that were modified with polycation and glucose oxidase immobilized by chitosan matrix. An iridium oxide electrode was developed to work as a biocompatible reference electrode with enhanced durability and stability in the biological solutions. A study of the effect of temperature on oxygen sensor performance, and both temperature and oxygen effects on glucose sensor performance were accomplished to enhance their operative stability and provide useful information for in vivo applications. A new methodology for automatic correction of the temperature and oxygen dependence of biosensor outputs is demonstrated through programmed LabView™ software. In vitro experiments in both physiological and pathophysiological ranges (oxygen: 0–60 mmHg; glucose: 0.1–10 mM; temperature: 25–40 °C) with clinical samples of cerebrospinal fluid obtained from TBI patients have demonstrated stable measurements with enhanced accuracy, indicating the feasibility of the sensors for a real-time continuous in vivo monitoring.

Objective Intracerebral hemorrhages, whether spontaneous or traumatic (tICH), often expand, and an association has been described between hemorrhage expansion and worse clinical outcomes. Recombinant factor VIIa (rFVIIa) is a hemostatic agent that has been shown to limit hemorrhage expansion and which, therefore, could potentially reduce morbidity and mortality in tICH. This first prospective, randomized, placebo-controlled, dose-escalation study evaluated the safety and preliminary effectiveness of rFVIIa to limit tICH progression. Methods Patients were enrolled if they had tICH lesions of at least 2 ml on a baseline computed tomographic scan obtained within 6 hours of injury. rFVIIa or placebo was administered within 2.5 hours of the baseline computed tomographic scan but no later than 7 hours after injury. Computed tomographic scans were repeated at 24 and 72 hours. Five escalating dose tiers were evaluated (40, 80, 120, 160, and 200 microg/kg rFVIIa). Clinical evaluations and adverse events were recorded until Day 15. Results No significant differences were detected in mortality rate or number and type of adverse events among treatment groups. Asymptomatic deep vein thrombosis, detected on routinely performed ultrasound at Day 3, was observed more frequently in the combined rFVIIa treatment group (placebo, 3%; rFVIIa, 8%; not significant). A nonsignificant trend for rFVIIa dose-response to limit tICH volume increase was observed (placebo, 21.0 ml; rFVIIa, 10.1 ml). Conclusion In this first prospective study of rFVIIa in tICH, there appeared to be less hematoma progression in rFVIIa-treated patients (80-200 microg/kg) compared with that seen in placebo treated patients. The potential significance of this biological effect on clinical outcomes and the significance of the somewhat higher incidence of ultrasound-detected deep vein thromboses in the rFVIIa-treated group need to be examined in a larger prospective randomized clinical trial.

This Case Study describes a 80-year-old patient with lower-body parkinsonism who was diagnosed with vascular parkinsonism on the basis of clinical and neuroimaging findings, but whose gait and, to a lesser extent, cognitive impairments improved following external lumbar drainage. Postmortem neuropathology confirmed a diagnosis of normal pressure hydrocephalus. Background An 80-year-old man with a 60 pack-year smoking habit, hypertension, and hypercholesterolemia presented to a movement disorders clinic with a 30-month history of step-wise progression of gait, balance, and memory impairment. He had experienced multiple falls and two hospitalizations for sudden-onset freezing of gait. Investigations Neurological examination, brain MRI, neuropsychological evaluation, gait analysis, continuous external lumbar drainage of cerebrospinal fluid, and post-mortem neuropathological studies. Diagnosis Vascular parkinsonism was diagnosed on the basis of the patient's history and imaging findings; however, post-mortem neuropathology was consistent with a diagnosis of normal pressure hydrocephalus and did not support that of vascular parkinsonism. Treatment Ventriculoperitoneal shunt placement superseded tighter control of vascular risk factors, as judged by the patient's response to continuous lumbar drainage.

We report a novel single neural probe for real-time simultaneous monitoring of multiple neurochemicals and direct-current electrocorticography (DC-ECoG). A major advance of this probe is the inclusion of two iridium oxide reference electrodes to improve sensor accuracy. The ECoG reference electrode is identical to the ECoG recording electrodes to significantly improve DC stability, while the reference for electrochemical sensors has 10-fold lower polarization rate to minimize the small current-induced drift in the reference electrode potential. In vitro, the single probe selectively measured oxygen (r(2)=0.985 ± 0.01, concentration range=0-60 mmHg, limit of detection=0.4 ± 0.07 mmHg) and glucose (r(2)=0.989 ± 0.009, concentration range=0-4mM, limit of detection=31 ± 8 µM) in a linear fashion. The performance of the single probe was assessed in an in vivo needle prick model to mimic sequelae of traumatic brain injury. It successfully monitored the theoretically expected transient brain oxygen, glucose, and DC potential changes during the passage of spreading depolarization (SD) waves. We envision that the developed probe can be used to decipher the cause-effect relationships between multiple variables of brain pathophysiology with the high temporal and spatial resolutions that it provides.