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1.  Wake-Up Stroke: Clinical Characteristics, Imaging Findings, and Treatment Option – an Update 
About 25% of all strokes occur during sleep, i.e., without knowledge of exact time of symptom onset. According to licensing criteria, this large group of patients is excluded from treatment with received tissue-plasminogen activator, the only specific stroke treatment proven effective in large randomized trials. This paper reviews clinical and imaging characteristics of wake-up stroke and gives an update on treatment options for these patients. From clinical and imaging studies, there is evidence suggesting that many wake-up strokes occur close to awakening and thus, patients might be within the approved time-window of thrombolysis when presenting to the emergency department. Several imaging approaches are suggested to identify wake-up stroke patients likely to benefit from thrombolysis, including non-contrast CT, CT-perfusion, penumbral MRI, and the recent concept of diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR). A number of small case series and observational studies report results of thrombolysis in wake-up stroke, and no safety concerns have occurred, while conclusions on efficacy cannot be drawn from these studies. To this end, there are ongoing clinical trials enrolling wake-up stroke patients based on imaging findings, i.e., the DWI-FLAIR-mismatch (WAKE-UP) or penumbral imaging (EXTEND). The results of these trials will provide evidence to guide thrombolysis in wake-up stroke and thus, expand treatment options for this large group of stroke patients.
doi:10.3389/fneur.2014.00035
PMCID: PMC3972483  PMID: 24723908
wake-up stroke; acute ischemic stroke; thrombolysis; computed tomography; magnetic resonance imaging; fluid attenuated reversion recovery; DWI-FLAIR-mismatch
2.  Music-Based Cognitive Remediation Therapy for Patients with Traumatic Brain Injury 
Traumatic brain injury (TBI) is one of the common causes of disability in physical, psychological, and social domains of functioning leading to poor quality of life. TBI leads to impairment in sensory, motor, language, and emotional processing, and also in cognitive functions such as attention, information processing, executive functions, and memory. Cognitive impairment plays a central role in functional recovery in TBI. Innovative methods such as music therapy to alleviate cognitive impairments have been investigated recently. The role of music in cognitive rehabilitation is evolving, based on newer findings emerging from the fields of neuromusicology and music cognition. Research findings from these fields have contributed significantly to our understanding of music perception and cognition, and its neural underpinnings. From a neuroscientific perspective, indulging in music is considered as one of the best cognitive exercises. With “plasticity” as its veritable nature, brain engages in producing music indulging an array of cognitive functions and the product, the music, in turn permits restoration and alters brain functions. With scientific findings as its basis, “neurologic music therapy” (NMT) has been developed as a systematic treatment method to improve sensorimotor, language, and cognitive domains of functioning via music. A preliminary study examining the effect of NMT in cognitive rehabilitation has reported promising results in improving executive functions along with improvement in emotional adjustment and decreasing depression and anxiety following TBI. The potential usage of music-based cognitive rehabilitation therapy in various clinical conditions including TBI is yet to be fully explored. There is a need for systematic research studies to bridge the gap between increasing theoretical understanding of usage of music in cognitive rehabilitation and application of the same in a heterogeneous condition such as TBI.
doi:10.3389/fneur.2014.00034
PMCID: PMC3970008  PMID: 24715887
traumatic brain injury; cognitive rehabilitation; neurologic music therapy; neuromusicology; music cognition; music therapy
3.  The Role of Functional Neuroimaging in Pre-Surgical Epilepsy Evaluation 
The prevalence of epilepsy is about 1% and one-third of cases do not respond to medical treatment. In an eligible subset of patients with drug-resistant epilepsy, surgical resection of the epileptogenic zone is the only treatment that can possibly cure the disease. Non-invasive techniques provide information for the localization of the epileptic focus in the majority of cases, whereas in others invasive procedures are required. In the last years, non-invasive neuroimaging techniques, such as simultaneous recording of functional magnetic resonance imaging and electroencephalogram (EEG-fMRI), positron emission tomography (PET), single photon emission computed tomography (SPECT), electric and magnetic source imaging (MSI, ESI), spectroscopy (MRS), have proved their usefulness in defining the epileptic focus. The combination of these functional techniques can yield complementary information and their concordance is crucial for guiding clinical decision, namely the planning of invasive EEG recordings or respective surgery. The aim of this review is to present these non-invasive neuroimaging techniques, their potential combination, and their role in the pre-surgical evaluation of patients with pharmaco-resistant epilepsy.
doi:10.3389/fneur.2014.00031
PMCID: PMC3970017  PMID: 24715886
focal epilepsy; EEG-fMRI; ESI; PET; SPECT; MRS; functional neuroimaging
4.  Developing Precision Stroke Imaging 
Stroke experts stand at the cusp of a unique opportunity to advance the care of patients with cerebrovascular disorders across the globe through improved imaging approaches. NIH initiatives including the Stroke Progress Review Group promotion of imaging in stroke research and the newly established NINDS Stroke Trials network converge with the rapidly evolving concept of precision medicine. Precision stroke imaging portends the coming shift to individualized approaches to cerebrovascular disorders where big data may be leveraged to identify and manage stroke risk with specific treatments utilizing an improved neuroimaging infrastructure, data collection, and analysis. We outline key aspects of the stroke imaging field where precision medicine may rapidly transform the care of stroke patients in the next few years.
doi:10.3389/fneur.2014.00029
PMCID: PMC3970034  PMID: 24715885
stroke; neuroimaging; precision medicine
5.  A Striking Response to Lithium in Kleine–Levin Syndrome 
Kleine–Levin syndrome (KLS) is an episodic hypersomnia with cognitive disturbances such as confusion, apathy, and derealization. Hyperphagia and hypersexuality occur in around 50% of cases. No evidence-based treatments have been established for KLS. Many drugs have been tried, most often with little success. Here, a case with a striking response to lithium is presented.
doi:10.3389/fneur.2014.00033
PMCID: PMC3968761
Kleine–Levin syndrome; lithium; hypersomnia; cognitive disorders; hypothalamus
6.  Parkinsonian Patients and Poor Awareness of Dyskinesias 
doi:10.3389/fneur.2014.00032
PMCID: PMC3960494
Parkinson disease; levodopa-induced dyskinesias; awareness of self; anosognosia; dorsolateral prefrontal cortex
7.  Methods for Surgical Targeting of the STN in Early-Stage Parkinson’s Disease 
Patients with Parkinson’s disease (PD) experience progressive neurological decline, and future interventional therapies are thought to show most promise in early stages of the disease. There is much interest in therapies that target the subthalamic nucleus (STN) with surgical access. While locating STN in advanced disease patients (Hoehn–Yahr Stage III or IV) is well understood and routinely performed at many centers in the context of deep brain stimulation surgery, the ability to identify this nucleus in early-stage patients has not previously been explored in a sizeable cohort. We report surgical methods used to target the STN in 15 patients with early PD (Hoehn–Yahr Stage II), using a combination of image guided surgery, microelectrode recordings, and clinical responses to macrostimulation of the region surrounding the STN. Measures of electrophysiology (firing rates and root mean squared activity) have previously been found to be lower than in later-stage patients, however, the patterns of electrophysiology seen and dopamimetic macrostimulation effects are qualitatively similar to those seen in advanced stages. Our experience with surgical implantation of Parkinson’s patients with minimal motor symptoms suggest that it remains possible to accurately target the STN in early-stage PD using traditional methods.
doi:10.3389/fneur.2014.00025
PMCID: PMC3958735  PMID: 24678307
Parkinson’s disease; subthalamic nucleus; surgical targeting; early stage; neurosurgery
8.  Magnetic Vestibular Stimulation in Subjects with Unilateral Labyrinthine Disorders 
We recently discovered that static magnetic fields from high-strength MRI machines induce nystagmus in all normal humans, and that a magneto-hydrodynamic Lorentz force, derived from ionic currents in the endolymph and pushing on the cupula, best explains this effect. Individuals with no labyrinthine function have no nystagmus. The influence of magnetic vestibular stimulation (MVS) in individuals with unilateral deficits in labyrinthine function is unknown and may provide insight into the mechanism of MVS. These individuals should experience MVS, but with a different pattern of nystagmus consistent with their unilateral deficit in labyrinthine function. We recorded eye movements in the static magnetic field of a 7 T MRI machine in nine individuals with unilateral labyrinthine hypofunction, as determined by head impulse testing and vestibular-evoked myogenic potentials (VEMP). Eye movements were recorded using infrared video-oculography. Static head positions were varied in pitch with the body supine, and slow-phase eye velocity (SPV) was assessed. All subjects exhibited predominantly horizontal nystagmus after entering the magnet head-first, lying supine. The SPV direction reversed when entering feet-first. Pitching chin-to-chest caused subjects to reach a null point for horizontal SPV. Right unilateral vestibular hypofunction (UVH) subjects developed slow-phase-up nystagmus and left UVH subjects, slow-phase-down nystagmus. Vertical and torsional components were consistent with superior semicircular canal excitation or inhibition, respectively, of the intact ear. These findings provide compelling support for the hypothesis that MVS is a result of a Lorentz force and suggest that the function of individual structures within the labyrinth can be assessed with MVS. As a novel method of comfortable and sustained labyrinthine stimulation, MVS can provide new insights into vestibular physiology and pathophysiology.
doi:10.3389/fneur.2014.00028
PMCID: PMC3952138  PMID: 24659983
vestibular; magnetic; semicircular canals; Lorentz; magneto-hydrodynamics
9.  Biochemical Distribution of Tau Protein in Synaptosomal Fraction of Transgenic Mice Expressing Human P301L Tau 
Alzheimer’s disease is a progressive dementia that is characterized by a loss of recent memory. Evidence has accumulated to support the hypothesis that synapses are critical storage sites for memory. However, it is still uncertain whether tau protein is involved in associative memory storage and whether tau is distributed in mature brain synapses. To address this question, we examined the synaptosomal distribution of tau protein in both JNPL3 transgenic mice expressing human P301L tau and non-transgenic littermates. The JNPL3 mouse line is known as one of the mouse models of human tauopathy that develop motor and behavioral deficits with intracellular tau aggregates in the spinal cord and brainstem. The phenotype of disease progression is highly dependent on strain background. In this study, we confirmed that male JNPL3 transgenic mice with C57BL/6J strain background showed neither any sign of motor deficits nor accumulation of hyperphosphorylated tau in the sarkosyl-insoluble fraction until 18 months of age. Subcellular fractionation analysis showed that both mouse tau and human P301L tau were present in the synaptosomal fraction. Those tau proteins were less-phosphorylated than tau in the cytosolic fraction. Human P301L tau was preferentially distributed in the synaptosomal fraction while mouse endogenous tau was more distributed in the cytosolic fraction. Interestingly, a human-specific tau band with phosphorylation at Ser199 and Ser396 was observed in the synaptosomal fraction of JNPL3 mice. This tau was not identical to either tau species in cytosolic fraction or a prominent hyperphosphorylated 64 kDa tau species that was altered to tau pathology. These results suggest that exogenous human P301L tau induces synaptosomal distribution of tau protein with a certain phosphorylation. Regulating the synaptosomal tau level might be a potential target for a therapeutic intervention directed at preventing neurodegeneration.
doi:10.3389/fneur.2014.00026
PMCID: PMC3949102  PMID: 24653715
P301L tau; transgenic mice; subcellular fractions; synaptosomal fraction; tau phosphorylation
10.  Does Disease-Irrelevant Intrathecal Synthesis in Multiple Sclerosis Make Sense in the Light of Tertiary Lymphoid Organs? 
Although partly disease-irrelevant, intrathecal immunoglobulins (Ig) synthesis is a typical feature of multiple sclerosis (MS) and is driven by the tertiary lymphoid organs (TLO). A long-known hallmark of this non-specific intrathecal synthesis is the MRZ pattern, an intrathecal synthesis of Ig against measles, rubella, and zoster viruses. This non-specific intrathecal synthesis could also be directed against a wide range of pathogens. However, it is highly problematic since brain TLO should not be able to drive the clonal expansion of lymphocytes against alien antigens that are thought to be absent in MS brain. We propose to explain the paradox of non-specific intrathecal synthesis by discussing the natural properties of TLO. In fact, besides local antigen-driven clonal expansion, circulating plasmablasts and plasma cells (PC) are non-specifically recruited from blood and gain access to survival niches in the inflammatory CNS. This mechanism, which has been described in other inflammatory disorders, takes place in the TLO. As a consequence, PCs recruited in brain mirror the individual’s history of immunization and intrathecal synthesis of IgG in MS may target a broad range of common infectious agents, a hypothesis in line with epidemiological data. Moreover, the immunization schedule and its timing may interfere with PC recruitment. If this hypothesis is correct, the reaction against EBV appears paradoxical: although early infection of MS patients is systematic, intrathecal synthesis is far lower than expected, suggesting a crucial interaction between MS onset and timing of EBV infection. A growing body of evidence suggests that the non-specific intrathecal synthesis observed in MS is also common in many chronic CNS inflammatory disorders. Assuming that cortical TLO in MS are associated with typical sub-pial lesions, we have coined the concept of “TLO-pathy” to describe these lesions and take examples of them from non-MS disorders. Lastly, we propose that intrathecal synthesis could be considered a strong hallmark of CNS TLO and might be used to monitor future TLO-targeted therapies.
doi:10.3389/fneur.2014.00027
PMCID: PMC3949135  PMID: 24653716
multiple sclerosis; lymphoid tissue; antibody response; cerebrospinal fluid; Epstein–Barr virus
11.  The Involvement of Secondary Neuronal Damage in the Development of Neuropsychiatric Disorders Following Brain Insults 
Neuropsychiatric disorders are one of the leading causes of disability worldwide and affect the health of billions of people. Previous publications have demonstrated that neuropsychiatric disorders can cause histomorphological damage in particular regions of the brain. By using a clinical symptom-comparing approach, 55 neuropsychiatric signs or symptoms related usually to 14 types of acute and chronic brain insults were identified and categorized in the present study. Forty percent of the 55 neuropsychiatric signs and symptoms have been found to be commonly shared by the 14 brain insults. A meta-analysis supports existence of the same neuropsychiatric signs or symptoms in all brain insults. The results suggest that neuronal damage might be occurring in the same or similar regions or structures of the brain. Neuronal cell death, neural loss, and axonal degeneration in some parts of the brain (the limbic system, basal ganglia system, brainstem, cerebellum, and cerebral cortex) might be the histomorphological basis that is responsible for the neuropsychiatric symptom clusters. These morphological alterations may be the result of secondary neuronal damage (a cascade of progressive neural injury and neuronal cell death that is triggered by the initial insult). Secondary neuronal damage causes neuronal cell death and neural injury in not only the initial injured site but also remote brain regions. It may be a major contributor to subsequent neuropsychiatric disorders following brain insults.
doi:10.3389/fneur.2014.00022
PMCID: PMC3949352  PMID: 24653712
neuropsychiatric disorders; secondary neuronal damage; brain insults; traumatic brain injury; neurodegenerative diseases; clinical manifestations; histomorphology; pathophysiology
12.  Hedonic Deficits in Parkinson’s Disease: Is Consummatory Anhedonia Specific? 
Background: Anhedonia, the lowered ability to experience pleasure, is one of the non-motor symptoms of Parkinson’s disease (PD) that is underdiagnosed and consequently undertreated. Few studies have investigated anhedonia in PD by taking into account the influence of socio-demographic variables and versus a control group composed of patients with a pure motor neurologic disease other than PD. The aim of this study was to investigate hedonic deficits in patients with PD compared to a control group of patients with non-Parkinson motor neurologic disease (OND), matched for age, gender, level of education, and inpatient/outpatient status. Distinctions between anticipatory and consummatory anhedonia and between endogenomorphic and non-endogenomorphic depression were taken into account.
Methods: The study population comprised 49 PD patients and 40 subjects with OND. Anhedonia was rated by using the anticipatory [Temporal Experience Pleasure Scale (TEPS)-ANT] and consummatory (TEPS-CONS) subscales of the TEPS and two subscales extracted from the revised Physical Anhedonia Scale (PAS), measuring physical anticipatory (PAS-ANT) and physical consummatory (PAS-CONS) anhedonias. The Snaith–Hamilton Pleasure Scale (SHAPS) and the Beck Depression Inventory-II (BDI-II) were also used together with a subscale extracted from the BDI-II (ENDO-BDI-II) for the diagnosis of endogenomorphic depression. Statistical analyses were performed on the whole group and on the PD group.
Results: As hypothesized, several anhedonia scores varied with age and gender in the whole population or in the PD group. On univariate or multivariate analyses, only PAS-CONS was specific for PD and only SHAPS scores differed between depression subtypes in the whole population or the PD group.
Conclusion: This study suggests that physical consummatory anhedonia could be specific to PD subjects.
doi:10.3389/fneur.2014.00024
PMCID: PMC3948001  PMID: 24653714
anhedonia; depression; dopamine; Parkinson’s disease
13.  Temporal Lobe Epilepsy and Surgery Selectively Alter the Dorsal, Not the Ventral, Default-Mode Network 
The default-mode network (DMN) is a major resting-state network. It can be divided in two distinct networks: one is composed of dorsal and anterior regions [referred to as the dorsal DMN (dDMN)], while the other involves the more posterior regions [referred to as the ventral DMN (vDMN)]. To date, no studies have investigated the potentially distinct impact of temporal lobe epilepsy (TLE) on these networks. In this context, we explored the effect of TLE and anterior temporal lobectomy (ATL) on the dDMN and vDMN. We utilized two resting-state fMRI sessions from left, right TLE patients (pre-/post-surgery) and normal controls (sessions 1/2). Using independent component analysis, we identified the two networks. We then evaluated for differences in spatial extent for each network between the groups, and across the scanning sessions. The results revealed that, pre-surgery, the dDMN showed larger differences between the three groups than the vDMN, and more particularly between right and left TLE than between the TLE patients and controls. In terms of change post-surgery, in both TLE groups, the dDMN also demonstrated larger changes than the vDMN. For the vDMN, the only changes involved the resected temporal lobe for each ATL group. For the dDMN, the left ATL group showed post-surgical increases in several regions outside the ictal temporal lobe. In contrast, the right ATL group displayed a large reduction in the frontal cortex. The results highlight that the two DMNs are not impacted by TLE and ATL in an equivalent fashion. Importantly, the dDMN was the more affected, with right ATL having a more deleterious effects than left ATL. We are the first to highlight that the dDMN more strongly bears the negative impact of TLE than the vDMN, suggesting there is an interaction between the side of pathology and DM sub-network activity. Our findings have implications for understanding the impact TLE and subsequent ATL on the functions implemented by the distinct DMNs.
doi:10.3389/fneur.2014.00023
PMCID: PMC3948047  PMID: 24653713
default-mode network; dorsal and ventral subdivisions; temporal lobe epilepsy; anterior temporal lobectomy; resting-state; fMRI
14.  Flow-Diversion Panacea or Poison? 
Endovascular therapy is now the treatment of choice for intracranial aneurysms (IAs) for its efficacy and safety profile. The use of flow diversion (FD) has recently expanded to cover many types of IAs in various locations. Some institutions even attempt FD as first line treatment for unruptured IAs. The most widely used devices are the pipeline embolization device (PED), the SILK flow diverter (SFD), the flow redirection endoluminal device (FRED), and Surpass. Many questions were raised regarding the long-term complications, the optimal regimen of dual antiplatelet therapy, and the durability of treatment effect. We reviewed the literature to address these questions as well as other concerns on FD when treating IAs.
doi:10.3389/fneur.2014.00021
PMCID: PMC3938101  PMID: 24592254
flow diversion; pipeline; intracranial aneurysm; FRED; Surpass; PED
15.  High-Resolution Spectral Domain-Optical Coherence Tomography in Multiple Sclerosis, Part II – the Total Macular Volume. The First Follow-Up Study over 2 Years 
Background: Recent studies investigating the use of optical coherence tomography (OCT) in multiple sclerosis (MS) patients have resulted in wide-ranging and often contradictory outcomes. This is mainly due to the complex etiology and heterogeneity of MS, physiological variations in the retinal nerve fiber layer (RNFL) and/or total macular volume (TMV), and limitations in methodology. It remains to be discovered whether any retinal changes in MS develop continuously or in a stepwise fashion, and whether these changes occur in all or a subset of patients. High-resolution spectral domain-OCT devices (SD-OCT) would be required to detect subtle retinal changes and longitudinal studies would have to be carried out to investigate retinal changes over time. In addition, if the hypothesis is correct, then retinal and global brain tissue changes should be detected in a substantial majority of MS patients and detection should be possible with a high degree of disease activity and/or long disease course.
Methodology: In order to address the factors above, 37 MS patients (relapsing–remitting, n = 27; secondary progressive, n = 10) were examined prospectively on two occasions with a median interval of 22.4 ± 0.5 months [range 19–27]. SD-OCT was utilized with the Spectralis 3.5 mm circle scan protocol (with locked reference images and eye-tracking mode). None of the patients had optic neuritis 12 months prior to study entry or during the observation period.
Principal Findings: The initial TMV pattern differed between study participants, but remained relatively unchanged over the 2-year observation period despite high disease activity or long disease course. The TMV correlated well with the RNFL.
Conclusion: The significance of differences in TMV (and RNFL) between study participants remains unclear. Until these differences have been explored further, OCT data in MS patients should be interpreted with caution.
doi:10.3389/fneur.2014.00020
PMCID: PMC3932446  PMID: 24605107
MS; OCT; macula lutea; neurodegenerative diseases; MRI
16.  Experimental Models of Brain Ischemia: A Review of Techniques, Magnetic Resonance Imaging, and Investigational Cell-Based Therapies 
Stroke continues to be a significant cause of death and disability worldwide. Although major advances have been made in the past decades in prevention, treatment, and rehabilitation, enormous challenges remain in the way of translating new therapeutic approaches from bench to bedside. Thrombolysis, while routinely used for ischemic stroke, is only a viable option within a narrow time window. Recently, progress in stem cell biology has opened up avenues to therapeutic strategies aimed at supporting and replacing neural cells in infarcted areas. Realistic experimental animal models are crucial to understand the mechanisms of neuronal survival following ischemic brain injury and to develop therapeutic interventions. Current studies on experimental stroke therapies evaluate the efficiency of neuroprotective agents and cell-based approaches using primarily rodent models of permanent or transient focal cerebral ischemia. In parallel, advancements in imaging techniques permit better mapping of the spatial-temporal evolution of the lesioned cortex and its functional responses. This review provides a condensed conceptual review of the state of the art of this field, from models and magnetic resonance imaging techniques through to stem cell therapies.
doi:10.3389/fneur.2014.00019
PMCID: PMC3928567  PMID: 24600434
brain ischemia; brain stroke; animal models; middle cerebral artery occlusion; magnetic resonance imaging; neuro-reparative therapies; stem cells
17.  Effects of Surgical Side and Site on Mood and Behavior Outcome in Children with Pharmacoresistant Epilepsy 
Children with epilepsy have a high rate of mood and behavior problems; yet few studies consider the emotional and behavioral impact of surgery. No study to date has been sufficiently powered to investigate effects of both side (left/right) and site (temporal/frontal) of surgery. One hundred patients (aged 6–16) and their families completed measures of depression, anxiety, and behavioral function as part of neuropsychological evaluations before and after surgery for pharmacoresistant epilepsy. Among children who had left-sided surgeries (frontal = 16; temporal = 38), there were significant interactions between time (pre to post-operative neuropsychological assessment) and resection site (frontal/temporal) on anhedonia, social anxiety, and withdrawn/depressed scales. Patients with frontal lobe epilepsy (FLE) endorsed greater pre-surgical anhedonia and social anxiety than patients with temporal lobe epilepsy (TLE) with scores normalizing following surgery. While scores on the withdrawn/depressed scale were similar between groups before surgery, the FLE group showed greater symptom improvement after surgery. In children who underwent right-sided surgeries (FLE = 20; TLE = 26), main effects of time (patients in both groups improved) and resection site (caregivers of FLE patients endorsed greater symptoms than those with TLE) were observed primarily on behavior scales. Individual data revealed that a greater proportion of children with left FLE demonstrated clinically significant improvements in anhedonia, social anxiety, and aggressive behavior than children with TLE. This is the first study to demonstrate differential effects of both side and site of surgery in children with epilepsy at group and individual levels. Results suggest that children with FLE have greater emotional and behavioral dysfunction before surgery, but show marked improvement after surgery. Overall, most children had good emotional and behavioral outcomes, with most scores remaining stable or improving.
doi:10.3389/fneur.2014.00018
PMCID: PMC3928572  PMID: 24600433
mood; depression; anxiety; behavior; epilepsy surgery; children; pediatrics; neuropsychology
18.  Levetiracetam Differentially Alters CD95 Expression of Neuronal Cells and the Mitochondrial Membrane Potential of Immune and Neuronal Cells in vitro 
Epilepsy is a neurological seizure disorder that affects over 100 million people worldwide. Levetiracetam, either alone, as monotherapy, or as adjunctive treatment, is widely used to control certain types of seizures. Despite its increasing popularity as a relatively safe and effective anti-convulsive treatment option, its mechanism(s) of action are poorly understood. Studies have suggested neuronal, glial, and immune mechanisms of action. Understanding the precise mechanisms of action of levetiracetam would be extremely beneficial in helping to understand the processes involved in seizure generation and epilepsy. Moreover, a full understanding of these mechanisms would help to create more efficacious treatments while minimizing side-effects. The current study examined the effects of levetiracetam on the mitochondrial membrane potential of neuronal and non-neuronal cells, in vitro, in order to determine if levetiracetam influences metabolic processes in these cell types. In addition, this study sought to address possible immune-mediated mechanisms by determining if levetiracetam alters the expression of immune receptor–ligand pairs. The results show that levetiracetam induces expression of CD95 and CD178 on NGF-treated C17.2 neuronal cells. The results also show that levetiracetam increases mitochondrial membrane potential on C17.2 neuronal cells in the presence of nerve growth factor. In contrast, levetiracetam decreases the mitochondrial membrane potential of splenocytes and this effect was dependent on intact invariant chain, thus implicating immune cell interactions. These results suggest that both neuronal and non-neuronal anti-epileptic activities of levetiracetam involve control over energy metabolism, more specifically, mΔΨ. Future studies are needed to further investigate this potential mechanism of action.
doi:10.3389/fneur.2014.00017
PMCID: PMC3927234  PMID: 24600432
epilepsy; Keppra; splenocytes; C17.2; in vitro; Fas; FasL
19.  Relation of Callosal Structure to Cognitive Abilities in Temporal Lobe Epilepsy 
The main objective of this paper is to analyze the influence of mesial temporal lobe epilepsy (mTLE) on the morphology of the corpus callosum (CC) and its relation to cognitive abilities. More specifically, we investigated correlations between intellectual abilities and callosal morphology, while additionally exploring the modulating impact of (a) side of seizure onset (b) age of disease onset. For this reason a large representative sample of patients with hippocampal sclerosis (n = 79; 35 males; 44 females; age: 18–63 years) with disease onset ranging from 0 to 50 years of age, and consisting of 46 left and 33 right mTLE-patients was recruited. Intelligence was measured using the Wechsler-Adult Intelligence Scale Revised. To get localizations of correlations with high anatomic precision, callosal morphology was examined using computational mesh-based modeling methods, applied to anatomical brain MRI scans. Intellectual performance was positively associated with callosal thickness in anterior and midcallosal callosal regions, with anterior parts being slightly more affected by age of disease onset and side of seizure onset than posterior parts. Earlier age at onset of epilepsy was associated with lower thickness in anterior and midcallosal regions. In addition, laterality of seizure onset had a significant influence on anterior CC morphology, with left hemispheric origin having stronger effects. We found that in mTLE, anterior and midcallosal CC morphology are related to cognitive performance. The findings support recent findings of detrimental effects of early onset mTLE on anterior brain regions and of a distinct effect particularly of left mTLE on frontal lobe functioning and structure. The causal nature of the relationship remains an open question, i.e., whether CC morphology impacts IQ development or whether IQ development impacts CC morphology, or both.
doi:10.3389/fneur.2014.00016
PMCID: PMC3920113  PMID: 24575078
MRI; temporal lobe epilepsy; corpus callosum; full-scale IQ; intelligence; Wechsler-adult intelligence scale revised
20.  Fish Oil Diet Associated with Acute Reperfusion Related Hemorrhage, and with Reduced Stroke-Related Sickness Behaviors and Motor Impairment 
Ischemic stroke is associated with motor impairment and increased incidence of affective disorders such as anxiety/clinical depression. In non-stroke populations, successful management of such disorders and symptoms has been reported following diet supplementation with long chain omega-3-polyunsaturated-fatty-acids (PUFAs). However, the potential protective effects of PUFA supplementation on affective behaviors after experimentally induced stroke and sham surgery have not been examined previously. This study investigated the behavioral effects of PUFA supplementation over a 6-week period following either middle cerebral artery occlusion or sham surgery in the hooded-Wistar rat. The PUFA diet supplied during the acclimation period prior to surgery was found to be associated with an increased risk of acute hemorrhage following the reperfusion component of the surgery. In surviving animals, PUFA supplementation did not influence infarct size as determined 6 weeks after surgery, but did decrease omega-6-fatty-acid levels, moderate sickness behaviors, acute motor impairment, and longer-term locomotor hyperactivity and depression/anxiety-like behavior.
doi:10.3389/fneur.2014.00014
PMCID: PMC3915239  PMID: 24567728
polyunsaturated fatty acids; middle-cerebral-artery-occlusion; mood; stroke
21.  Monochromatic Pupillometry in Unilateral Glaucoma Discloses no Adaptive Changes Subserved by the ipRGCs 
Purpose: To detect signs of a possible adaptive mechanism of the intrinsically photosensitive ganglion cells in unilateral glaucoma.
Method: Eleven patients with unilateral glaucoma, classified by automated perimetry (glaucoma: mean deviation <0), were studied by monochromatic pupillometry, employing red (660 nm) or blue (470 nm) light, and by optical coherence tomography of the peripapillary retinal nerve fiber layer. The main outcome measure in pupillometry, the area under the curve (AUC), i.e., the product of pupillary contraction amplitude and time, was determined during and after light exposure in glaucomatous and unafflicted fellow eyes and compared to the AUCs of a healthy, age-matched control group.
Results: The AUC to stimulation with blue light was significantly reduced in glaucomatous eyes, both during and after stimulus, compared with that of fellow, unafflicted eyes (p ≤ 0.014). The AUC to red light stimulation was reduced during (p = 0.035), but not after (p ≥ 0.072), exposure in glaucomatous eyes. In the unafflicted fellow eyes, the pupillary response to blue light did not differ from that of healthy controls.
Conclusion: The pupillary response to blue light was decreased in the glaucomatous eyes of unilateral glaucoma. No difference was detected between the pupillary light response of the unafflicted fellow eyes and that of a healthy, age-matched control group. Thus no sign of an adaptive mechanism was detected, neither in the glaucomatous nor in the unafflicted fellow eyes, and consequently glaucoma appears to differ from non-arteritic anterior ischemic optic neuropathy.
doi:10.3389/fneur.2014.00015
PMCID: PMC3914022  PMID: 24550887
unilateral glaucoma; melanopsin; intrinsically photosensitive retinal ganglion cells; pupillary light reflex
22.  Long-Term Cognitive Impairments and Pathological Alterations in a Mouse Model of Repetitive Mild Traumatic Brain Injury 
Mild traumatic brain injury (mTBI, also referred to as concussion) accounts for the majority of all traumatic brain injuries. The consequences of repetitive mTBI have become of particular concern for individuals engaged in certain sports or in military operations. Many mTBI patients suffer long-lasting neurobehavioral impairments. In order to expedite pre-clinical research and therapy development, there is a need for animal models that reflect the long-term cognitive and pathological features seen in patients. In the present study, we developed and characterized a mouse model of repetitive mTBI, induced onto the closed head over the left frontal hemisphere with an electromagnetic stereotaxic impact device. Using GFAP-luciferase bioluminescence reporter mice that provide a readout of astrocyte activation, we observed an increase in bioluminescence relative to the force delivered by the impactor after single impact and cumulative effects of repetitive mTBI. Using the injury parameters established in the reporter mice, we induced a repetitive mTBI in wild-type C57BL/6J mice and characterized the long-term outcome. Animals received repetitive mTBI showed a significant impairment in spatial learning and memory when tested at 2 and 6 months after injury. A robust astrogliosis and increased p-Tau immunoreactivity were observed upon post-mortem pathological examinations. These findings are consistent with the deficits and pathology associated with mTBI in humans and support the use of this model to evaluate potential therapeutic approaches.
doi:10.3389/fneur.2014.00012
PMCID: PMC3912443  PMID: 24550885
mild traumatic brain injury; long-term; neurobehavior; bioluminescence; astrogliosis
23.  Amyloid-Beta Related Angiitis of the Central Nervous System: Case Report and Topic Review 
Amyloid-beta related angiitis (ABRA) of the central nervous system (CNS) is a rare disorder with overlapping features of primary angiitis of the CNS and cerebral amyloid angiopathy. We evaluated a 74-year-old man with intermittent left sided weakness and MRI findings of leptomeningeal enhancement, vasogenic edema, and subcortical white matter disease proven to have ABRA. We discuss clinicopathological features and review the topic of ABRA.
doi:10.3389/fneur.2014.00013
PMCID: PMC3912456  PMID: 24550886
amyloid-beta related angiitis; primary angiitis of the central nervous system; cerebral amyloid angiopathy; leptomeningeal enhancement; cerebral amyloid angiopathy-related inflammation
24.  Excessive Sensitivity to Uncertain Visual Input in L-DOPA-Induced Dyskinesias in Parkinson’s Disease: Further Implications for Cerebellar Involvement 
When faced with visual uncertainty during motor performance, humans rely more on predictive forward models and proprioception and attribute lesser importance to the ambiguous visual feedback. Though disrupted predictive control is typical of patients with cerebellar disease, sensorimotor deficits associated with the involuntary and often unconscious nature of l-DOPA-induced dyskinesias in Parkinson’s disease (PD) suggests dyskinetic subjects may also demonstrate impaired predictive motor control.
Methods: We investigated the motor performance of 9 dyskinetic and 10 non-dyskinetic PD subjects on and off l-DOPA, and of 10 age-matched control subjects, during a large-amplitude, overlearned, visually guided tracking task. Ambiguous visual feedback was introduced by adding “jitter” to a moving target that followed a Lissajous pattern. Root mean square (RMS) tracking error was calculated, and ANOVA, robust multivariate linear regression, and linear dynamical system analyses were used to determine the contribution of speed and ambiguity to tracking performance.
Results: Increasing target ambiguity and speed contributed significantly more to the RMS error of dyskinetic subjects off medication. l-DOPA improved the RMS tracking performance of both PD groups. At higher speeds, controls and PDs without dyskinesia were able to effectively de-weight ambiguous visual information.
Conclusion: PDs’ visually guided motor performance degrades with visual jitter and speed of movement to a greater degree compared to age-matched controls. However, there are fundamental differences in PDs with and without dyskinesia: subjects without dyskinesia are generally slow, and less responsive to dynamic changes in motor task requirements, but in PDs with dyskinesia, there was a trade-off between overall performance and inappropriate reliance on ambiguous visual feedback. This is likely associated with functional changes in posterior parietal–ponto–cerebellar pathways.
doi:10.3389/fneur.2014.00008
PMCID: PMC3912458  PMID: 24550883
l-DOPA-induced dyskinesias; Parkinson’s disease; dynamical system models; visually guided tracking; visual uncertainty
25.  Mechanisms of Levetiracetam in the Control of Status Epilepticus and Epilepsy 
Status epilepticus (SE) is a major clinical emergency that is associated with high mortality and morbidity. SE causes significant neuronal injury and survivors are at a greater risk of developing acquired epilepsy and other neurological morbidities, including depression and cognitive deficits. Benzodiazepines and some anticonvulsant agents are drugs of choice for initial SE management. Despite their effectiveness, over 40% of SE cases are refractory to the initial treatment with two or more medications. Thus, there is an unmet need of developing newer anti-SE drugs. Levetiracetam (LEV) is a widely prescribed anti-epileptic drug that has been reported to be used in SE cases, especially in benzodiazepine-resistant SE or where phenytoin cannot be used due to allergic side-effects. Levetiracetam’s non-classical anti-epileptic mechanisms of action, favorable pharmacokinetic profile, general lack of central depressant effects, and lower incidence of drug interactions contribute to its use in SE management. This review will focus on LEV’s unique mechanism of action that makes it a viable candidate for SE treatment.
doi:10.3389/fneur.2014.00011
PMCID: PMC3907711  PMID: 24550884
levetiracetam; calcium homeostasis; status epilepticus; anti-epileptic; mechanisms

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