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1.  Role of Intravenous Levetiracetam in Acute Seizure Management 
doi:10.3389/fneur.2014.00109
PMCID: PMC4073419  PMID: 25018748
levetiracetam; acute seizure management; anticonvulsants; treatment; epilepsy
2.  How Implementation of Systems Biology into Clinical Trials Accelerates Understanding of Diseases 
Systems biology comprises a series of concepts and approaches that have been used successfully both to delineate novel biological mechanisms and to drive translational advances. The goal of systems biology is to re-integrate putatively critical elements extracted from multi-modality datasets in order to understand how interactions among multiple components form functional networks at the organism/patient-level, and how dysfunction of these networks underlies a particular disease. Due to the genetic and environmental diversity of human subjects, identification of critical elements related to a particular disease process from cross-sectional studies requires prohibitively large cohorts. Alternatively, implementation of systems biology principles to interventional clinical trials represents a unique opportunity to gain predictive understanding of complex diseases in comparatively small cohorts of patients. This paper reviews systems biology principles applicable to translational research, focusing on lessons from systems approaches to inflammation applied to multiple sclerosis. We suggest that employing systems biology methods in the design and execution of biomarker-supported, proof-of-principle clinical trials provides a singular opportunity to merge therapeutic development with a basic understanding of disease processes. The ultimate goal is to develop predictive computational models of the disease, which will revolutionize diagnostic process and provide mechanistic understanding necessary for personalized therapeutic approaches. Added, biologically meaningful information can be derived from diagnostic tests, if they are interpreted in functional relationships, rather than as independent measurements. Such systems biology based diagnostics will transform disease taxonomies from phenotypical to molecular and will allow physicians to select optimal therapeutic regimens for individual patients.
doi:10.3389/fneur.2014.00102
PMCID: PMC4073421  PMID: 25018747
systems biology; clinical trials; clinical trials methodology; multiple sclerosis; polygenic diseases
3.  Neuronal Entropy Depends on the Level of Alertness in the Parkinsonian Globus Pallidus in vivo 
A new working hypothesis of Parkinson’s disease (PD) proposes to focus on the central role of entropy increase in the basal ganglia (BG) in movement disorders. The conditions necessary for entropy increase in vivo are, however, still not fully described. We recorded the activity of single globus pallidus pars interna neurons during the transition from deep anesthesia to full alertness in relaxed, head-restrained, control, and parkinsonian (6-hydroxydopamine-lesioned group-lesioned) rats. We found that during awakening from anesthesia, the variation of neuronal entropy was significantly higher in the parkinsonian than in the control group. This implies in our view that in PD the entropy of the output neurons of the BG varies dynamically with the input to the network, which is determined by the level of alertness. Therefore, entropy needs to be interpreted as a dynamic, emergent property that characterizes the global state of the BG neuronal network, rather than a static property of parkinsonian neurons themselves. Within the framework of the “entropy hypothesis,” this implies the presence of a pathological feedback loop in the parkinsonian BG, where increasing the network input results in a further increase of neuronal entropy and a worsening of akinesia.
doi:10.3389/fneur.2014.00096
PMCID: PMC4069479  PMID: 25009529
basal ganglia; Parkinson’s disease; entropy; alertness; emergent properties; non-linear
4.  Functional Magnetic Resonance Imaging in Narcolepsy and the Kleine–Levin Syndrome 
This work aims at reviewing the present state of the art when it comes to understanding the pathophysiology of narcolepsy and the Kleine–Levin syndrome (KLS) from a neuroimaging point of view. This work also aims at discussing future perspectives of functional neuroimaging in these sleep disorders. We focus on functional magnetic resonance imaging (fMRI), which is a technique for in vivo measurements of brain activation in neuronal circuitries under healthy and pathological conditions. fMRI has significantly increased the knowledge on the affected neuronal circuitries in narcolepsy and the Kleine–Levin syndrome. It has been shown that narcolepsy is accompanied with disturbances of the emotional and the closely related reward systems. In the Kleine Levin syndrome, fMRI has identified hyperactivation of the thalamus as a potential biomarker that could be used in the diagnostic procedure. The fMRI findings in both narcolepsy and the Kleine–Levin syndrome are in line with previous structural and functional imaging studies. We conclude that fMRI in combination with multi-modal imaging can reveal important details about the pathophysiology in narcolepsy and the Kleine–Levin syndrome. In the future, fMRI possibly gives opportunities for diagnostic support and prediction of treatment response in individual patients.
doi:10.3389/fneur.2014.00105
PMCID: PMC4069720  PMID: 25009530
functional magnetic resonance imaging; narcolepsy; hypersomnia; Kleine–Levin syndrome; sleep; ascending arousal system; hypothalamus; thalamus
5.  Vagus Nerve Stimulation in Ischemic Stroke: Old Wine in a New Bottle 
Vagus nerve stimulation (VNS) is currently Food and Drug Administration-approved for treatment of both medically refractory partial-onset seizures and severe, recurrent refractory depression, which has failed to respond to medical interventions. Because of its ability to regulate mechanisms well-studied in neuroscience, such as norepinephrine and serotonin release, the vagus nerve may play an important role in regulating cerebral blood flow, edema, inflammation, glutamate excitotoxicity, and neurotrophic processes. There is strong evidence that these same processes are important in stroke pathophysiology. We reviewed the literature for the role of VNS in improving ischemic stroke outcomes by performing a systematic search for publications in Medline (1966–2014) with keywords “VNS AND stroke” in subject headings and key words with no language restrictions. Of the 73 publications retrieved, we identified 7 studies from 3 different research groups that met our final inclusion criteria of research studies addressing the role of VNS in ischemic stroke. Results from these studies suggest that VNS has promising efficacy in reducing stroke volume and attenuating neurological deficits in ischemic stroke models. Given the lack of success in Phase III trials for stroke neuroprotection, it is important to develop new therapies targeting different neuroprotective pathways. Further studies of the possible role of VNS, through normally physiologically active mechanisms, in ischemic stroke therapeutics should be conducted in both animal models and clinical studies. In addition, recent advent of a non-invasive, transcutaneous VNS could provide the potential for easier clinical translation.
doi:10.3389/fneur.2014.00107
PMCID: PMC4067569  PMID: 25009531
stroke; middle cerebral artery occlusion; glutamate excitotoxicity; neuroinflammation; cerebral blood flow
6.  Reviving Intracranial Angioplasty and Stenting “SAMMPRIS and beyond” 
We review the methods and results of Stenting and Aggressive Medical Management for Preventing Recurrent Stroke (SAMMPRIS) and provide a critical review of its strengths and limitations. In SAMMPRIS, the aggressive medical treatment arm (AMT arm) did substantially better than the Wingspan Stenting plus aggressive medical management arm (WS+ arm). Complications in the first 30 days post intervention led to the disparity between treatment arms. A major contribution of SAMMPRIS was the added value that AMT and lifestyle change may provide, when compared to a precursor trial, Warfarin–Aspirin Symptomatic Intracranial Disease (WASID), designed to prevent stroke in persons with high-grade symptomatic intracranial occlusive disease, however, the results of neither of these two trials have ever been reproduced. On the other hand, we argue that technical limitations of the Wingspan stent system (WS System) and lack of an angioplasty only intervention arm may have led to a premature launch of the trial and early termination of the study. Future randomized trials with different devices and modified patient selection criteria are warranted.
doi:10.3389/fneur.2014.00101
PMCID: PMC4066298  PMID: 25002858
intracranial stenosis; best medical therapy; neurointervention; angioplasty; stenting; Wingspan stent
7.  Spinal Central Effects of Peripherally Applied Botulinum Neurotoxin A in Comparison between Its Subtypes A1 and A2 
Because of its unique ability to exert long-lasting synaptic transmission blockade, botulinum neurotoxin A (BoNT/A) is used to treat a wide variety of disorders involving peripheral nerve terminal hyperexcitability. However, it has been a matter of debate whether this toxin has central or peripheral sites of action. We employed a rat model in which BoNT/A1 or BoNT/A2 was unilaterally injected into the gastrocnemius muscle. On time-course measurements of compound muscle action potential (CMAP) amplitudes after injection of BoNT/A1 or BoNT/A2 at doses ranging from 1.7 to 13.6 U, CMAP amplitude for the ipsilateral hind leg was markedly decreased on the first day, and this muscle flaccidity persisted up to the 14th day. Of note, both BoNT/A1 and BoNT/A2 administrations also resulted in decreased CMAP amplitudes for the contralateral leg in a dose-dependent manner ranging from 1.7 to 13.6 U, and this muscle flaccidity increased until the fourth day and then slowly recovered. Immunohistochemical results revealed that BoNT/A-cleaved synaptosomal-associated protein of 25 kDa (SNAP-25) appeared in the bilateral ventral and dorsal horns 4 days after injection of BoNT/A1 (10 U) or BoNT/A2 (10 U), although there seemed to be a wider spread of BoNT/A-cleaved SNAP-25 associated with BoNT/A1 than BoNT/A2 in the contralateral spinal cord. This suggests that the catalytically active BoNT/A1 and BoNT/A2 were axonally transported via peripheral motor and sensory nerves to the spinal cord, where they spread through a transcytosis (cell-to-cell trafficking) mechanism. Our results provide evidence for the central effects of intramuscularly administered BoNT/A1 and BoNT/A2 in the spinal cord, and a new insight into the clinical effects of peripheral BoNT/A applications.
doi:10.3389/fneur.2014.00098
PMCID: PMC4066301  PMID: 25002857
botulinum neurotoxin; spinal cord; central effects; SNAP-25; axonal transport
8.  Effect of Auditory Constraints on Motor Performance Depends on Stage of Recovery Post-Stroke 
In order to develop evidence-based rehabilitation protocols post-stroke, one must first reconcile the vast heterogeneity in the post-stroke population and develop protocols to facilitate motor learning in the various subgroups. The main purpose of this study is to show that auditory constraints interact with the stage of recovery post-stroke to influence motor learning. We characterized the stages of upper limb recovery using task-based kinematic measures in 20 subjects with chronic hemiparesis. We used a bimanual wrist extension task, performed with a custom-made wrist trainer, to facilitate learning of wrist extension in the paretic hand under four auditory conditions: (1) without auditory cueing; (2) to non-musical happy sounds; (3) to self-selected music; and (4) to a metronome beat set at a comfortable tempo. Two bimanual trials (15 s each) were followed by one unimanual trial with the paretic hand over six cycles under each condition. Clinical metrics, wrist and arm kinematics, and electromyographic activity were recorded. Hierarchical cluster analysis with the Mahalanobis metric based on baseline speed and extent of wrist movement stratified subjects into three distinct groups, which reflected their stage of recovery: spastic paresis, spastic co-contraction, and minimal paresis. In spastic paresis, the metronome beat increased wrist extension, but also increased muscle co-activation across the wrist. In contrast, in spastic co-contraction, no auditory stimulation increased wrist extension and reduced co-activation. In minimal paresis, wrist extension did not improve under any condition. The results suggest that auditory task constraints interact with stage of recovery during motor learning after stroke, perhaps due to recruitment of distinct neural substrates over the course of recovery. The findings advance our understanding of the mechanisms of progression of motor recovery and lay the foundation for personalized treatment algorithms post-stroke.
doi:10.3389/fneur.2014.00106
PMCID: PMC4066443  PMID: 25002859
bimanual movements; upper extremity; rehabilitation; motor learning/training; electromyography; task specificity; cerebrovascular disorders
9.  Skilled Reaching and Grasping in the Rat: Lacking Effect of Corticospinal Lesion 
The corticospinal system is a major motor pathway in the control of skilled voluntary movements such as reaching and grasping. It has developed considerably phylogenetically to reach a peak in humans. Because rodents possess advanced forelimb movements that can be used for reaching and grasping food, it is commonly considered that the corticospinal tract (CST) is of major importance for this control also in rodents. A close homology to primate reaching and grasping has been described but with obvious limitations as to independent digit movements, which are lacking in rodents. Nevertheless, it was believed that there are, as in the primate, direct cortico-motoneuronal connections. Later, it was shown that there are no such connections. The fastest excitatory pathway is disynaptic, mediated via cortico-reticulospinal neurons and in the spinal cord the excitation is mainly polysynaptically mediated via segmental interneurons. Earlier behavioral studies have aimed at investigating the role of the CST by using pyramidotomy in the brainstem. However, in addition to interrupting the CST, a pyramidal transection abolishes the input to reticulospinal neurons. It is therefore not possible to conclude if the deficits after pyramidotomy result from interruption of the CST or the input to reticulospinal neurons or both. We have re-investigated the role of the CST by examining the effect of a CST lesion in the C1–C2 spinal segments on the success rate of reaching and grasping. This lesion spares the cortico-reticulospinal pathway. In contrast to investigations using pyramidal transections, the present study did not demonstrate marked deficits in reaching and grasping. We propose that the difference in results can be explained by the intact cortical input to reticulospinal neurons in our study and thus implicate an important role of this pathway in the control of reaching and grasping in the rat.
doi:10.3389/fneur.2014.00103
PMCID: PMC4064553  PMID: 24999340
skilled forelimb movements; reaching; grasping; corticospinal tract lesion; reticulospinal; interneuron; motorneuron
10.  A Modified Controlled Cortical Impact Technique to Model Mild Traumatic Brain Injury Mechanics in Mice 
For the past 25 years, controlled cortical impact (CCI) has been a useful tool in traumatic brain injury (TBI) research, creating injury patterns that includes primary contusion, neuronal loss, and traumatic axonal damage. However, when CCI was first developed, very little was known on the underlying biomechanics of mild TBI. This paper uses information generated from recent computational models of mild TBI in humans to alter CCI and better reflect the biomechanical conditions of mild TBI. Using a finite element model of CCI in the mouse, we adjusted three primary features of CCI: the speed of the impact to achieve strain rates within the range associated with mild TBI, the shape, and material of the impounder to minimize strain concentrations in the brain, and the impact depth to control the peak deformation that occurred in the cortex and hippocampus. For these modified cortical impact conditions, we observed peak strains and strain rates throughout the brain were significantly reduced and consistent with estimated strains and strain rates observed in human mild TBI. We saw breakdown of the blood–brain barrier but no primary hemorrhage. Moreover, neuronal degeneration, axonal injury, and both astrocytic and microglia reactivity were observed up to 8 days after injury. Significant deficits in rotarod performance appeared early after injury, but we observed no impairment in spatial object recognition or contextual fear conditioning response 5 and 8 days after injury, respectively. Together, these data show that simulating the biomechanical conditions of mild TBI with a modified cortical impact technique produces regions of cellular reactivity and neuronal loss that coincide with only a transient behavioral impairment.
doi:10.3389/fneur.2014.00100
PMCID: PMC4061598  PMID: 24994996
controlled cortical impact; mild traumatic brain injury; biomechanics; strain rate; glia reactivity
11.  Small-World Characteristics of EEG Patterns in Post-Anoxic Encephalopathy 
Post-anoxic encephalopathy (PAE) has a heterogenous outcome which is difficult to predict. At present, it is possible to predict poor outcome using somatosensory evoked potentials in only a minority of the patients at an early stage. In addition, it remains difficult to predict good outcome at an early stage. Network architecture, as can be quantified with continuous electroencephalography (cEEG), may serve as a candidate measure for predicting neurological outcome. Here, we explore whether cEEG monitoring can be used to detect the integrity of neural network architecture in patients with PAE after cardiac arrest. From 56 patients with PAE treated with mild therapeutic hypothermia, 19-channel cEEG data were recorded starting as soon as possible after cardiac arrest. Adjacency matrices of shared frequencies between 1 and 25 Hz of the EEG channels were obtained using Fourier transformations. Number of network nodes and connections, clustering coefficient (C), average path length (L), and small-world index (SWI) were derived. Outcome was quantified by the best cerebral performance category (CPC)-score within 6 months. Compared to non-survivors, survivors showed significantly more nodes and connections. L was significantly higher and C and SWI were significantly lower in the survivor group than in the non-survivor group. The number of nodes, connections, and the L were negatively correlated with the CPC-score. C and SWI correlated positively with the CPC-score. The combination of number of nodes, connections, C, and L showed the most significant difference and correlation between survivors and non-survivors and CPC-score. Our data might implicate that non-survivors have insufficient distribution and differentiation of neural activity for regaining normal brain function. These network differences, already present during hypothermia, might be further developed as early prognostic markers. The predictive values are however still inferior to current practice parameters.
doi:10.3389/fneur.2014.00097
PMCID: PMC4058708  PMID: 24982649
small-world network; continuous EEG; post-anoxic encephalopathy; prognosis; resuscitation
12.  Migraine and Patent Foramen Ovale: Barking up the Wrong Tree? 
doi:10.3389/fneur.2014.00099
PMCID: PMC4058756  PMID: 24982650
patent foramen ovale; migraine with aura; right-to-left shunt; closure device; white matter lesion
13.  Brain Morphometry and the Neurobiology of Levodopa-Induced Dyskinesias: Current Knowledge and Future Potential for Translational Pre-Clinical Neuroimaging Studies 
Dopamine replacement therapy in the form of levodopa results in a significant proportion of patients with Parkinson’s disease developing debilitating dyskinesia. This significantly complicates further treatment and negatively impacts patient quality of life. A greater understanding of the neurobiological mechanisms underlying levodopa-induced dyskinesia (LID) is therefore crucial to develop new treatments to prevent or mitigate LID. Such investigations in humans are largely confined to assessment of neurochemical and cerebrovascular blood flow changes using positron emission tomography and functional magnetic resonance imaging. However, recent evidence suggests that LID is associated with specific morphological changes in the frontal cortex and midbrain, detectable by structural MRI and voxel-based morphometry. Current human neuroimaging methods however lack sufficient resolution to reveal the biological mechanism driving these morphological changes at the cellular level. In contrast, there is a wealth of literature from well-established rodent models of LID documenting detailed post-mortem cellular and molecular measurements. The combination therefore of advanced neuroimaging methods and rodent LID models offers an exciting opportunity to bridge these currently disparate areas of research. To highlight this opportunity, in this mini-review, we provide an overview of the current clinical evidence for morphological changes in the brain associated with LID and identify potential cellular mechanisms as suggested from human and animal studies. We then suggest a framework for combining small animal MRI imaging with rodent models of LID, which may provide important mechanistic insights into the neurobiology of LID.
doi:10.3389/fneur.2014.00095
PMCID: PMC4053925  PMID: 24971074
levodopa; magnetic resonance imaging; T1 relaxation; voxel-based morphometry; plasticity; prefrontal cortex
14.  Cognitive Gains from Gist Reasoning Training in Adolescents with Chronic-Stage Traumatic Brain Injury 
Adolescents with traumatic brain injury (TBI) typically demonstrate good recovery of previously acquired skills. However, higher-order and later emergent cognitive functions are often impaired and linked to poor outcomes in academic and social/behavioral domains. Few control trials exist that test cognitive treatment effectiveness at chronic recovery stages. The current pilot study compared the effects of two forms of cognitive training, gist reasoning (top-down) versus rote memory learning (bottom-up), on ability to abstract meanings, recall facts, and utilize core executive functions (i.e., working memory, inhibition) in 20 adolescents (ages 12–20) who were 6 months or longer post-TBI. Participants completed eight 45-min sessions over 1 month. After training, the gist reasoning group (n = 10) exhibited significant improvement in ability to abstract meanings and increased fact recall. This group also showed significant generalizations to untrained executive functions of working memory and inhibition. The memory training group (n = 10) failed to show significant gains in ability to abstract meaning or on other untrained specialized executive functions, although improved fact recall approached significance. These preliminary results suggest that relatively short-term training (6 h) utilizing a top-down reasoning approach is more effective than a bottom-up rote learning approach in achieving gains in higher-order cognitive abilities in adolescents at chronic stages of TBI. These findings need to be replicated in a larger study; nonetheless, the preliminary data suggest that traditional cognitive intervention schedules need to extend to later-stage training opportunities. Chronic-stage, higher-order cognitive trainings may serve to elevate levels of cognitive performance in adolescents with TBI.
doi:10.3389/fneur.2014.00087
PMCID: PMC4052737  PMID: 24966850
adolescence; brain injury; cognitive plasticity; cognitive training; complex information; executive function; frontal lobe; reasoning
15.  Recovery from Emotion Recognition Impairment after Temporal Lobectomy 
Mesial temporal lobe epilepsy (MTLE) can be associated with emotion recognition impairment that can be particularly severe in patients with early onset seizures (1–3). Whereas, there is growing evidence that memory and language can improve in seizure-free patients after anterior temporal lobectomy (ATL) (4), the effects of surgery on emotional processing are still unknown. We used functional magnetic resonance imaging (fMRI) to investigate short-term reorganization of networks engaged in facial emotion recognition in MTLE patients. Behavioral and fMRI data were collected from six patients before and after ATL. During the fMRI scan, patients were asked to make a gender decision on fearful and neutral faces. Behavioral data demonstrated that two patients with early onset right MTLE were impaired in fear recognition while fMRI results showed they lacked specific activations for fearful faces. Post-ATL behavioral data showed improved emotion recognition ability, while fMRI demonstrated the recruitment of a functional network for fearful face processing. Our results suggest that ATL elicited brain plasticity mechanisms allowing behavioral and fMRI improvement in emotion recognition.
doi:10.3389/fneur.2014.00092
PMCID: PMC4047513  PMID: 24936197
mesial temporal lobe epilepsy; functional recovery; facial expression; emotion; functional magnetic resonance
16.  Glucose and the Injured Brain-Monitored in the Neurointensive Care Unit 
Brain has a continuous demand for energy that is met by oxidative metabolism of oxygen and glucose. This demand is compromised in the injured brain and if the inadequate supply persists it will lead to permanent tissue damage. Zero values of cerebral glucose have been associated with infarction and poor neurological outcome. Furthermore, hyperglycemia is common in patients with neurological insults and associated with poor outcome. Intensive insulin therapy (IIT) to control blood glucose has been suggested and used in neurointensive care with conflicting results. This review covers the studies reporting on monitoring of cerebral glucose with microdialysis in patients with traumatic brain injury (TBI), subarachnoid hemorrhage (SAH) and ischemic stroke. Studies investigating IIT are also discussed. Available data suggest that low cerebral glucose in patients with TBI and SAH provides valuable information on development of secondary ischemia and has been correlated with worse outcome. There is also indication that the location of the catheter is important for correlation between plasma and brain glucose. In conclusion considering catheter location, monitoring of brain glucose in the neurointensive care not only provides information on imminent secondary ischemia it also reveals the effect of peripheral treatment on the injured brain.
doi:10.3389/fneur.2014.00091
PMCID: PMC4047514  PMID: 24936196
glucose; microdialysis; subarachnoid hemorrhage; Traumatic brain injury; intensive insulin therapy; hyperglycemia; neurocritical care; neuromonitoring
17.  Behavioral and Neurophysiological Effects of Transdermal Rotigotine in Atypical Parkinsonism 
Effective therapies for the so-called atypical parkinsonian syndrome (APS) such as multiple system atrophy (MSA), progressive supranuclear palsy (PSP), or corticobasal syndrome (CBS) are not available. Dopamine agonists (DA) are not often used in APS because of inefficacy and in a minority of case, their side effects, like dyskinesias, impairment of extrapyramidal symptoms or the appearance of psychosis, and REM sleep behavioral disorders (RBD). Transdermal rotigotine (RTG) is a non-ergot dopamine agonist indicated for use in early and advanced Parkinson’s disease with a good tolerability and safety. Moreover, its action on a wide range of dopamine receptors, D1, D2, D3, unlike other DA, could make it a good option in APS, where a massive dopamine cell loss is documented. In this pilot, observational open-label study we evaluate the efficacy and tolerability of RTG in patients affected by APS. Thirty-two subjects with diagnosis of APS were treated with transdermal RTG. APS diagnosis was: MSA parkinsonian type (MSA-P), MSA cerebellar type (MSA-C), PSP, and CBS. Patients were evaluated by UPDRS-III, neuropsychiatric inventory, mini mental state examination at baseline, and after 6, 12, and 18 months. The titration schedule was maintained very flexible, searching the major clinical effect and the minor possible adverse events (AEs) at each visit. AEs were recorded. APS patients treated with RTG show an overall decrease of UPDRS-III scores without increasing behavioral disturbances. Only three patients were dropped out of the study. Main AEs were hypotension, nausea, vomiting, drowsiness, and tachycardia. The electroencephalographic recording power spectra analysis shows a decrease of theta and an increase of low alpha power. In conclusion, transdermal RTG seems to be effective and well tolerated in APS patients.
doi:10.3389/fneur.2014.00085
PMCID: PMC4046164  PMID: 24926284
rotigotine; atypical parkinsonism; open-label study; safety; efficacy
18.  Temporal Dynamics of Cerebral Blood Flow, Cortical Damage, Apoptosis, Astrocyte–Vasculature Interaction and Astrogliosis in the Pericontusional Region after Traumatic Brain Injury 
Traumatic brain injury (TBI) results in a loss of brain tissue at the moment of impact in the cerebral cortex. Subsequent secondary injury involves the release of molecular signals with dramatic consequences for the integrity of damaged tissue, leading to the evolution of a pericontusional-damaged area minutes to days after in the initial injury. The mechanisms behind the progression of tissue loss remain under investigation. In this study, we analyzed the spatial–temporal profile of blood flow, apoptotic, and astrocytic–vascular events in the cortical regions around the impact site at time points ranging from 5 h to 2 months after TBI. We performed a mild–moderate controlled cortical impact injury in young adult mice and analyzed the glial and vascular response to injury. We observed a dramatic decrease in perilesional cerebral blood flow (CBF) immediately following the cortical impact that lasted until days later. CBF finally returned to baseline levels by 30 days post-injury (dpi). The initial impact also resulted in an immediate loss of tissue and cavity formation that gradually increased in size until 3 dpi. An increase in dying cells localized in the pericontusional region and a robust astrogliosis were also observed at 3 dpi. A strong vasculature interaction with astrocytes was established at 7 dpi. Glial scar formation began at 7 dpi and seemed to be compact by 60 dpi. Altogether, these results suggest that TBI results in a progression from acute neurodegeneration that precedes astrocytic activation, reformation of the neurovascular unit to glial scar formation. Understanding the multiple processes occurring after TBI is critical to the ability to develop neuroprotective therapeutics to ameliorate the short and long-term consequences of brain injury.
doi:10.3389/fneur.2014.00082
PMCID: PMC4044679  PMID: 24926283
astrogliosis; cell death; cerebral blood flow; vasculature; glial scar
19.  Chronic Pain Following Physical and Emotional Trauma: The Station Nightclub Fire 
Objective: The purpose of this study was to evaluate factors associated with chronic pain in survivors of a large fire, including those with and without burn injury.
Methods: This study employed a survey-based cross-sectional design to evaluate data from survivors of The Station nightclub fire. The primary outcome measure was the presence and severity of pain. Multiple linear regressions with a stepwise approach were used to examine relationships among variables. Variables considered included age, gender, marital status, burn injury, total body surface area, skin graft, pre-morbid employment, time off work, return to same employment, depression (Beck depression inventory, BDI), and post-traumatic stress (impact of event scale – revised).
Results: Of 104 fire survivors, 27% reported pain at least 28 months after the event. Multiple factors associated with pain were assessed in the univariate analysis but only age (p = 0.012), graft (p = 0.009), and BDI score (p < 0.001) were significantly associated with pain in the multiple regression model.
Discussion: A significant number of fire survivors with and without burn injuries experienced chronic pain. Depth of burn and depression were significantly associated with pain outcome. Pain management should address both physical and emotional risk factors in this population.
doi:10.3389/fneur.2014.00086
PMCID: PMC4040492  PMID: 24917849
fire; burn; graft; pain; depression
20.  The Correlation between Osteoporosis Occurrences in Both Schizophrenia and Parkinson’s Disease 
doi:10.3389/fneur.2014.00083
PMCID: PMC4040489  PMID: 24917847
Parkinson’s disease; schizophrenia; osteoporosis; AMPK; energy metabolism
21.  Monitoring of Cerebral Blood Flow and Metabolism Bedside in Patients with Subarachnoid Hemorrhage – A Xenon-CT and Microdialysis Study 
Cerebral ischemia is the leading cause of morbidity and mortality following aneurysmal subarachnoid hemorrhage (SAH). Although 70% of the patients show angiographic vasospasm only 30% develop symptomatic vasospasm defined as delayed cerebral ischemia (DCI). Early detection and management of reversible ischemia is of critical importance in patients with SAH. Using a bedside Xenon enhanced computerized tomography (Xenon-CT) scanner makes it possible to measure quantitative regional Cerebral blood flow (CBF) bedside in the neurointensive care setting and intracerebral microdialysis (MD) is a method that offers the possibility to monitor the metabolic state of the brain continuously. Here, we present results from nine SAH patients with both MD monitoring and bedside Xenon-CT measurements. CBF measurements were performed within the first 72 h following bleeding. Six out of nine patients developed DCI at a later stage. Five out of six patients who developed DCI had initial global CBF below 26 ml/100 g/min whereas one had 53 ml/100 g/min. The three patients who did not develop clinical vasospasm all had initial global CBF above 27 ml/100 g/min. High lactate/pyruvate (L/P) ratio was associated with lower CBF values in the area surrounding the catheter. Five out of nine patients had L/P ratio ≥25 and four of these patients had CBF ≤ 22 ml/100 g/min. These preliminary results suggest that patients with initially low global CBF on Xenon-CT may be more likely to develop DCI. Initially low global CBF was accompanied with metabolic disturbances determined by the MD. Most importantly, pathological findings on the Xenon-CT and MD could be observed before any clinical signs of DCI. Combining bedside Xenon-CT and MD was found to be useful and feasible. Further studies are needed to evaluate if DCI can be detected before any other signs of DCI to prevent progress to infarction.
doi:10.3389/fneur.2014.00089
PMCID: PMC4041006  PMID: 24917850
cerebral blood flow; subarachnoid hemorrhage; neurointensive care; Xenon-CT; imaging; vasospasm; microdialysis
22.  Mechanisms of Body Weight Fluctuations in Parkinson’s Disease 
Typical body weight changes are known to occur in Parkinson’s disease (PD). Weight loss has been reported in early stages as well as in advanced disease and malnutrition may worsen the clinical state of the patient. On the other hand, an increasing number of patients show weight gain under dopamine replacement therapy or after surgery. These weight changes are multifactorial and involve changes in energy expenditure, perturbation of homeostatic control, and eating behavior modulated by dopaminergic treatment. Comprehension of the different mechanisms contributing to body weight is a prerequisite for the management of body weight and nutritional state of an individual PD patient. This review summarizes the present knowledge and highlights the necessity of evaluation of body weight and related factors, as eating behavior, energy intake, and expenditure in PD.
doi:10.3389/fneur.2014.00084
PMCID: PMC4040467  PMID: 24917848
Parkinson’s disease; body weight; eating behavior; DBS; dopamine; binge-eating disorder
23.  Brain Stimulation for Combating Alzheimer’s Disease 
doi:10.3389/fneur.2014.00080
PMCID: PMC4040449  PMID: 24917846
Alzheimer’s disease; brain stimulation; cognition; memory; dorsolateral prefrontal cortex; transcranial magnetic stimulation; transcranial direct current stimulation; deep-brain stimulation
24.  Young Adults’ Sleep Duration on Work Days: Differences between East and West 
Human sleep schedules vary widely across countries. We investigated whether these variations were related to differences in social factors, Morningness–Eveningness (ME) preference, or the natural light–dark cycle by contrasting the sleep duration and timing of young adults (age: 18–35 years) on work and free days in Singapore (n = 1898) and the UK (n = 837). On work days, people in Singapore had later bedtimes, but wake times were similar to the UK sample, resulting in shorter sleep duration. In contrast, sleep duration on free days did not differ between the two countries. Shorter sleep on work days, without compensatory extra long sleep hours on free days, suggest greater demands from work and study in Singapore. While the two samples differed slightly in ME preference, the associations between eveningness preference and greater extension in sleep duration as well as delays in sleep timing on free days were similar in the two countries. Thus, differences in ME preference did not account for the differences in sleep schedules between the two countries. The greater variability in the photoperiod in the UK was not associated with more prominent seasonal changes in sleep patterns compared to Singapore. Furthermore, in the UK, daylight saving time did not alter sleep schedules relative to clock time. Collectively, these findings suggest that differences in social demands, primarily from work or study, could account for the observed differences in sleep schedules between countries, and that in industrialized societies, social zeitgebers, which typically involve exposure to artificial light, are major determinants of sleep schedules.
doi:10.3389/fneur.2014.00081
PMCID: PMC4036075  PMID: 24904524
work days; free days; sleep timing; sleep duration; social factors; Morningness–Eveningness preference; natural light
25.  Insulin-Like Growth Factor Receptor Signaling is Necessary for Epidermal Growth Factor Mediated Proliferation of SVZ Neural Precursors in vitro Following Neonatal Hypoxia–Ischemia 
In this study, we assessed the importance of insulin-like growth factor (IGF) and epidermal growth factor (EGF) receptor co-signaling for rat neural precursor (NP) cell proliferation and self-renewal in the context of a developmental brain injury that is associated with cerebral palsy. Consistent with previous studies, we found that there is an increase in the in vitro growth of subventricular zone NPs isolated acutely after cerebral hypoxia–ischemia; however, when cultured in medium that is insufficient to stimulate the IGF type 1 receptor, neurosphere formation and the proliferative capacity of those NPs was severely curtailed. This reduced growth capacity could not be attributed simply to failure to survive. The growth and self-renewal of the NPs could be restored by addition of both IGF-I and IGF-II. Since the size of the neurosphere is predominantly due to cell proliferation we hypothesized that the IGFs were regulating progression through the cell cycle. Analyses of cell cycle progression revealed that IGF-1R activation together with EGFR co-signaling decreased the percentage of cells in G1 and enhanced cell progression into S and G2. This was accompanied by increases in expression of cyclin D1, phosphorylated histone 3, and phosphorylated Rb. Based on these data, we conclude that coordinate signaling between the EGF receptor and the IGF type 1 receptor is necessary for the normal proliferation of NPs as well as for their reactive expansion after injury. These data indicate that manipulations that maintain or amplify IGF signaling in the brain during recovery from developmental brain injuries will enhance the production of new brain cells to improve neurological function in children who are at risk for developing cerebral palsy.
doi:10.3389/fneur.2014.00079
PMCID: PMC4033605  PMID: 24904523
cell proliferation; stem cell niche; growth factors; central nervous system; regeneration

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