Tamir Ben-Hur

Hadassah Medical Center, Yerushalayim, Jerusalem District, Israel

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Publications (141)674.62 Total impact

  • N Raz, As Bick, T Ben-Hur, N Levin
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    ABSTRACT: Neuronal loss following damage is often greater than expected from the severity of injury to the nerve itself. The visual pathways, which comprise a well-defined system, and optic neuritis (ON), which is usually a discrete event, make a fine model to study this phenomenon. Understand the effect of focal optic nerve demyelination on neighboring white matter. Diffusion tensor imaging and probabilistic tractography were used to identify and characterize the optic tracts and radiations of 17 ON and matched controls. Data were correlated with retinal nerve fiber layer (RNFL) thickness. Patients' optic tracts exhibited reduced axial diffusivity, which correlated with RNFL thickness values. Patients' optic radiations demonstrated intact axial diffusivity but reduced fractional anisotropy and elevated radial diffusivity, which could be explained by intra-bundle lesions. No correlations were found between diffusivity measurements in patients' optic tracts and radiations; or between RNFL thickness and optic radiations' diffusivity. Following ON, chronic axonal loss develops distally in the optic tracts, demonstrating Wallerian degeneration. Degeneration did not proceed to the optic radiations, opposing anterograde trans-neuronal changes. DTI in ON provides fine in-vivo human model for studying histological abnormalities in normal appearing white matter, localized in close proximity to damaged bundle. © The Author(s), 2014.
    Multiple Sclerosis 11/2014; DOI:10.1177/1352458514551452 · 4.86 Impact Factor
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    ABSTRACT: Screening of putative autoimmune targets in multiple sclerosis (MS) revealed a proportion of patients carrying antibodies (Abs) against KIR4.1, a potassium channel that shares functional properties with AQP4. Both are localized at the perivascular astrocytic processes.
    Multiple Sclerosis 11/2014; DOI:10.1177/1352458514551779 · 4.86 Impact Factor
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    ABSTRACT: Multiple sclerosis (MS) is a multifocal disease, and precursor cells need to migrate into the multiple lesions in order to exert their therapeutic effects. Therefore, cell migration is a crucial element in regenerative processes in MS, dictating the route of delivery, when cell transplantation is considered. We have previously shown that inflammation triggers migration of multi-potential neural precursor cells (NPCs) into white matter of experimental autoimmune encephalomyelitis (EAE) rodents, a widely used model of MS. Here we investigated the molecular basis of this attraction. NPCs were grown from E13 embryonic mouse brains and transplanted into the lateral cerebral ventricles of EAE mice. Transplanted NPC migration was directed by three tissue-derived chemokines. Stromal Cell-Derived Factor-1α, Monocyte Chemo-attractant Protein-1 and Hepatocyte Growth Factor were expressed in the EAE brain and specifically in microglia and astrocytes. Their cognate receptors, CXCR4, CCR2 or c-Met were constitutively expressed on NPCs. Selective blockage of CXCR4, CCR2 or c-Met partially inhibited NPC migration in EAE brains. Blocking all three receptors had an additive effect and resulted in profound inhibition of NPC migration, as compared to extensive migration of control NPCs. The inflammation-triggered NPC migration into white matter tracts was dependent on a motile NPC phenotype. Specifically, depriving NPCs from epidermal growth factor (EGF) prevented the induction of glial commitment and a motile phenotype (as indicated by an in vitro motility assay), hampering their response to neuroinflammation. In conclusion, signaling via three chemokine systems accounts for most of the inflammation-induced, tissue-derived attraction of transplanted NPCs into white matter tracts during EAE.
    Stem Cell Research 09/2014; 13(2). DOI:10.1016/j.scr.2014.06.001 · 3.91 Impact Factor
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    ABSTRACT: In this work, we administered to transgenic mice mimicking a genetic prion disease, which develop a late onset fatal disease, a nanoemulsions formulation of pomegranate seed oil, denominated Nano-PSO. We show in the manuscript that this formulation is successful in inhibiting disease onset when given to still asymptomatic mice and disease progression when given to already sick mice. Nano-PSO treatment reduced brain lipid oxidation and other key neurodegeneration features.Figure optionsDownload full-size imageDownload high-quality image (131 K)Download as PowerPoint slide
    Nanomedicine: nanotechnology, biology, and medicine 08/2014; 10(6). DOI:10.1016/j.nano.2014.03.015 · 5.98 Impact Factor
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    ABSTRACT: Patients with conversion disorder generally suffer from a severe neurological deficit which cannot be attributed to a structural neurological damage. In two patients with acute conversion paraplegia, investigation with functional magnetic resonance imaging (fMRI) showed that the insular cortex, a limbic-related cortex involved in body-representation and subjective emotional experience, was activated not only during attempt to move the paralytic body-parts, but also during mental imagery of their movements. In addition, mental rotation of affected body-parts was found to be disturbed, as compared to unaffected body parts or external objects. fMRI during mental rotation of the paralytic body-part showed an activation of another limbic related region, the anterior cingulate cortex. These data suggest that conversion paraplegia is associated with pathological activity in limbic structures involved in body representation and a deficit in mental processing of the affected body-parts.
    06/2014; 4(2):396-404. DOI:10.3390/brainsci4020396
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    ABSTRACT: Our goals were to explore whether performing computerized tomography angiography (CTA) prior to administration of tissue plasminogen activator (tPA) delays treatment and impacts outcome in patients with proximal middle cerebral artery occlusions (pMCAO). Patients with pMCAO with a National Institutes of Health Stroke scale (NIHSS) score >10 were identified from a prospective Stroke Registry. Patients underwent multi-parametric imaging studies whenever possible. Patients who underwent CTA were compared to those who only had non-contrast CT scan. Disability was measured with the modified Rankin Scale. Logistic regression was used to determine outcome modifiers. We included 73 patients (median age 73years, 52% men) with moderate-severe stroke (median admission NIHSS 14). Of those, 44 underwent CTA and 29 did not. There were no differences between the groups in risk factor profile or baseline characteristics including stroke severity and door to needle, door to imaging or imaging to treatment times. At 90days post-stroke there were no statistically significant differences in outcomes between the groups. On multivariate analysis, performing CTA had no impact on the chance of obtaining favorable outcome. In conclusion, CTA does not have a major impact on outcome in patients with pMCAO treated with tPA. Therefore, performing CTA should be considered on an individual basis prior to administration of tPA.
    Journal of Clinical Neuroscience 05/2014; 21(10). DOI:10.1016/j.jocn.2014.01.013 · 1.32 Impact Factor
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    ABSTRACT: Objective: Transient global amnesia (TGA), an abrupt occurrence of severe anterograde episodic amnesia accompanied by repetitive questioning, has been known for more than 50 years. Despite extensive research, there is no clear evidence for the underlying pathophysiological basis of TGA. Moreover, there is no neuroimaging method to evaluate TGA in real-time. Methods: Here we used resting-state functional MRI recorded in twelve patients during the acute phase of TGA together with connectivity and cluster analyses to detect changes in the episodic-memory network in TGA. Results: Our results show a significant reduction in functional connectivity of the episodic-memory network during TGA, which is more pronounced in the hyper-acute phase than in the post-acute phase. This disturbance is bilateral, and reversible after recovery. While the hippocampus and its connections are significantly impaired, other parts of the episodic-memory network are impaired as well. Similar results were obtained for the analysis of the episodic-memory network whether it was defined in a data-driven or literature-based manner. Interpretation: These results suggest that TGA is related to a functional disturbance in the episodic-memory network, and supply a neuroimaging correlate of TGA during the acute phase. ANN NEUROL 2014. © 2014 American Neurological Association.
    Annals of Neurology 05/2014; 75(5). DOI:10.1002/ana.24137 · 11.91 Impact Factor
  • Tamir Ben-Hur
    Annals of Neurology 03/2014; 75(3):337-8. DOI:10.1002/ana.24118 · 11.91 Impact Factor
  • Muscle & Nerve 03/2014; 49(3). DOI:10.1002/mus.24143 · 2.31 Impact Factor
  • Noa Raz, Michal Hallak, Tamir Ben-Hur, Netta Levin
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    ABSTRACT: In order to follow optic neuritis patients and evaluate the effectiveness of their treatment, a handy, accurate and quantifiable tool is required to assess changes in myelination at the central nervous system (CNS). However, standard measurements, including routine visual tests and MRI scans, are not sensitive enough for this purpose. We present two visual tests addressing dynamic monocular and binocular functions which may closely associate with the extent of myelination along visual pathways. These include Object From Motion (OFM) extraction and Time-constrained stereo protocols. In the OFM test, an array of dots compose an object, by moving the dots within the image rightward while moving the dots outside the image leftward or vice versa. The dot pattern generates a camouflaged object that cannot be detected when the dots are stationary or moving as a whole. Importantly, object recognition is critically dependent on motion perception. In the Time-constrained Stereo protocol, spatially disparate images are presented for a limited length of time, challenging binocular 3-dimensional integration in time. Both tests are appropriate for clinical usage and provide a simple, yet powerful, way to identify and quantify processes of demyelination and remyelination along visual pathways. These protocols may be efficient to diagnose and follow optic neuritis and multiple sclerosis patients. In the diagnostic process, these protocols may reveal visual deficits that cannot be identified via current standard visual measurements. Moreover, these protocols sensitively identify the basis of the currently unexplained continued visual complaints of patients following recovery of visual acuity. In the longitudinal follow up course, the protocols can be used as a sensitive marker of demyelinating and remyelinating processes along time. These protocols may therefore be used to evaluate the efficacy of current and evolving therapeutic strategies, targeting myelination of the CNS.
    Journal of Visualized Experiments 01/2014; DOI:10.3791/51107
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    ABSTRACT: Anti-NMDA receptor (NMDAR) encephalitis is a recently identified autoimmune disorder with prominent psychiatric symptoms. Patients usually present with acute behavioral change, psychosis, catatonic symptoms, memory deficits, seizures, dyskinesias, and autonomic instability. In female patients an ovarian teratoma is often identified. We describe a 32-year-old woman who presented with acute psychosis. Shortly after admission, she developed generalized seizures and deteriorated into a catatonic state. Although ancillary tests including MRI, electroencephalogram, and cerebrospinal fluid (CSF) analysis were unremarkable, the presentation of acute psychosis in combination with recurrent seizures and a relentless course suggested autoimmune encephalitis. The patient underwent pelvic ultrasound which disclosed a dermoid cyst and which led to an urgent cystectomy. Plasmapheresis was then initiated, yielding partial response over the next two weeks. Following the detection of high titers of anti-NMDAR antibodies in the CSF, the patient ultimately received second line immunosuppressive treatment with rituximab. Over several months of cognitive rehabilitation a profound improvement was eventually noted, although minor anterograde memory deficits remained. In this report we call for attention to the inclusion of anti-NMDAR encephalitis in the differential diagnosis of acute psychosis. Prompt diagnosis is critical as early immunotherapy and tumor removal could dramatically affect outcomes.
    01/2014; 2014:868325. DOI:10.1155/2014/868325
  • Tamir Ben-Hur, Nina Fainstein, Yossi Nishri
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    ABSTRACT: The strong rationale for cell-based therapy in multiple sclerosis is based on the ability of stem and precursor cells of neural and mesenchymal origin to attenuate neuroinflammation, to facilitate endogenous repair processes, and to participate directly in remyelination, if directed towards a myelin-forming fate. However, there are still major gaps in knowledge regarding induction of repair in chronic multiple sclerosis lesions, and whether transplanted cells can overcome the multiple environmental inhibitory factors which underlie the failure of endogenous repair. Major challenges in clinical translation include the determination of the optimal cellular platform, the route of cell delivery, and candidate patients for treatment.
    Current Neurology and Neuroscience Reports 11/2013; 13(11):397. DOI:10.1007/s11910-013-0397-5 · 3.67 Impact Factor
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    ABSTRACT: Background: Sandfly viruses (SFV) are a group of closely related viruses which belong to the Bunyaviridae. SVF are transmitted by the Phlebotomine sandflies. The currently known SFV causing human diseases are Sicilian variant (SFSV), Naples variant (SFNV), the Toscana variant (TOSFV), and Cyprus variant (CSFV). The clinical presentation of infection by the sandfly virus group can vary from acute mild influenza-like symptomatology (Papatchi fever) to more severe form that might cause neurological involvement (mainly TOSFV). The neurological manifestations include meningitis, meningo-encephalitis or encephalitis. Methods: All patients with acute seroconversion to SFV at the Hadassah-Hebrew University Medical Centers were allocated and patient's clinical and imaging data was retrospectively collected and analyzed. Results: We identified 11 patients (1.5 to 85 years old) suffering from acute onset neurological symptoms and acute seroconversion to Sandfly virus. Nine had clinical signs of meningitis, meningo-encephalitis, encephalitis or myelitis. Two patients showed signs of myelitis alone without clinical signs of meningitis or encephalitis. In six patients MRI either of the Brain, Spine or both were performed which identified pathological symmetrical changes in the Basal-Ganglia. Three patients had in addition changes consistent with myelitis in the spine. Acute seroconversion to more than single variant of SFV was identified in all. Nine patients had long term follow-up: Three completely recovered and Six patients had gradual recovery with some remaining neurological sequela. Conclusion: Neurological involvement in SFV infections is usually considered to be benign. In our series of patients from Jerusalem, Israel, with acute seroconversion to SFV, 80% of the patients presented with major neurological pathology, including Myelitis and symmetrical Basal-Ganglia involvement, leading to permanent functional damage in some cases. We propose that in the presence of acute neurological symptoms with MRI pathology that included myelitis and/or symmetrical basal ganglia involvement, acute SFV infection should be included in the differential diagnosis.
    IDWeek 2013 Meeting of the Infectious Diseases Society of America; 10/2013
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    ABSTRACT: The clinical evaluation of consciousness in disorder of consciousness (DOC) patients based on their exhibited behavior is difficult and remains erroneous in many cases. Recent studies demonstrated different levels of stimulus processing as well as evidence of some level of awareness in sub-groups of these patients. The aim of the current study was to examine the plausibility and challenges of implementing a clinical service for evaluation of consciousness level in DOC patients. Eleven Patients (ages 11-67) diagnosed as being in vegetative or minimal conscious states were included. Functional MRI evaluations included auditory, language, voice familiarity, imagery, and visual tests. In 9 patients auditory-related activation was found, however only in 5 of the subjects was differential activation found for language. Six patients exhibited differential response to their own name. In three patients a response to visual stimuli was identified. In one patient the auditory and linguistic systems were clearly activated in a hierarchical pattern, and moreover willful modulation of brain activity was identified in the imagery test. We discuss the importance of using a wide battery of tests, the difference between our clinical cohort and previous publications, as well as the challenges of clinically implementing this method. Translating novel imaging methods into the clinical evaluation of DOC patients is essential for better diagnosis and may encourage treatment development.
    Journal of the neurological sciences 08/2013; 334(1-2). DOI:10.1016/j.jns.2013.08.009 · 2.26 Impact Factor
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    ABSTRACT: To identify the source of delayed visual evoked potential (VEP) latencies in the fellow eyes of patients with optic neuritis (ON) and determine whether these latencies stem from clinically silent demyelination or reflect an adaptive process for synchronization with the affected eyes. The study sample comprised 17 patients whom we followed for 12 to 26 months after unilateral first-ever ON diagnosis and 17 age-matched controls. To avoid confounding effects of axonal loss, only intact fellow eyes (except for VEPs) were included. Subjects underwent standard visual evaluation, motion perception, as well as static and time-constrained stereo tasks. Assessments included VEP, optical coherence tomography, high-resolution MRI, and diffusion tensor imaging. We observed delayed VEP peaks (P100) in both affected and fellow eyes. However, while these were derived from prolonged time-to-start in the affected eyes, supporting the existence of demyelination, time-to-start in the fellow eyes was intact. VEP latencies in the fellow eyes could not be explained by demyelinative lesions along postchiasmal pathways (assessed by diffusion tensor imaging). Delayed peaks in fellow eyes resulted from a wider waveform, which evolved over time and occurred with a concomitant decrease in the gap in time between VEP peaks of both eyes. These changes offered a functional advantage; synchronization of inputs highly correlated with improved time-constrained binocular perception. Delayed latencies in the fellow eyes may reflect adaptive mechanisms at the cortical level that improve binocular integration over time to adjust for the damage incurred. These data provide a unique demonstration of temporal reorganization that compensates for delayed transmittal of visual information to the cortex.
    Neurology 07/2013; DOI:10.1212/WNL.0b013e3182a1aa3e · 8.30 Impact Factor
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    ABSTRACT: Emotional processing is lateralized to the non-dominant brain hemisphere. However, there is no clear spatial model for lateralization of emotional domains in the basal ganglia. The subthalamic nucleus (STN), an input structure in the basal ganglia network, plays a major role in the pathophysiology of Parkinson's disease (PD). This role is probably not limited only to the motor deficits of PD, but may also span the emotional and cognitive deficits commonly observed in PD patients. Beta oscillations (12-30 Hz), the electrophysiological signature of PD, are restricted to the dorsolateral part of the STN that corresponds to the anatomically defined sensorimotor STN. The more medial, more anterior and more ventral parts of the STN are thought to correspond to the anatomically defined limbic and associative territories of the STN. Surprisingly, little is known about the electrophysiological properties of the non-motor domains of the STN, nor about electrophysiological differences between right and left STNs. In this study, microelectrodes were utilized to record the STN spontaneous spiking activity and responses to vocal non-verbal emotional stimuli during deep brain stimulation (DBS) surgeries in human PD patients. The oscillation properties of the STN neurons were used to map the dorsal oscillatory and the ventral non-oscillatory regions of the STN. Emotive auditory stimulation evoked activity in the ventral non-oscillatory region of the right STN. These responses were not observed in the left ventral STN or in the dorsal regions of either the right or left STN. Therefore, our results suggest that the ventral non-oscillatory regions are asymmetrically associated with non-motor functions, with the right ventral STN associated with emotional processing. These results suggest that DBS of the right ventral STN may be associated with beneficial or adverse emotional effects observed in PD patients and may relieve mental symptoms in other neurological and psychiatric diseases.
    Frontiers in Systems Neuroscience 01/2013; 7:69. DOI:10.3389/fnsys.2013.00069
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    ABSTRACT: Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by striatonigral degeneration and olivo-pontocerebellar atrophy. The histopathological hallmark of MSA is glial cytoplasmic inclusions (GCI) within oligodendrocytes, accompanied by neuronal degeneration. MSA is a synucleinopathy, and α-Synuclein (α-Syn) is the major protein constituent of the GCI. It is unclear how the neuronal α-Syn protein accumulates in oligodendrocytes. We tested the hypothesis that oligodendrocytes can take up neuronal-secreted α-Syn as part of the pathogenic mechanisms leading to MSA. We report that increases in the degree of α-Syn soluble oligomers or intracellular α-Syn levels, enhance its secretion from cultured MN9D dopaminergic cells, stably expressing the protein. In accord, we show that primary oligodendrocytes from rat brain and oligodendroglial cell lines take-up neuronal-secreted or exogenously added α-Syn from their conditioning medium. This uptake is concentration-, time-, and clathrin-dependent. Utilizing the demonstrated effect of polyunsaturated fatty acids (PUFA) to enhance α-Syn neuropathology, we show an in vivo effect for brain docosahexaenoic acid (DHA) levels on α-Syn localization to oligodendrocytes in brains of a mouse model for synucleinopathies, expressing human A53T α-Syn cDNA under the PrP promoter. Hence, pathogenic mechanisms leading to elevated levels of α-Syn in neurons underlie neuronal secretion and subsequent uptake of α-Syn by oligodendrocytes in MSA.
    PLoS ONE 10/2012; 7(10):e46817. DOI:10.1371/journal.pone.0046817 · 3.53 Impact Factor
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    ABSTRACT: BACKGROUND AND PURPOSE: Our goal was to compare outcomes of patients with proximal middle cerebral artery occlusions treated with intravenous tissue plasminogen activator (tPA) with those of patients treated with stent-based thrombectomy (SBT). METHODS: Patients with proximal middle cerebral artery occlusions included in our prospective stroke registry were identified. Patients presenting with moderate to severe stroke defined as National Institutes of Health Stroke Scale score ≥10 were included. Patients treated with tPA were compared with those treated with SBT. Disability was measured with the modified Rankin Scale and shifts toward favorable outcomes (modified Rankin Scale ≤2) were analyzed. Logistic regression was used to determine outcome modifiers. RESULTS: We included 22 patients treated with SBT and 66 treated with tPA. Patients treated with SBT had higher admission National Institutes of Health Stroke Scale scores (median 21 vs 14.5; P<0.001) and prolonged symptom onset-to-treatment times (median 240 vs 95 minutes; P<0.001). At discharge, the magnitude of change in National Institutes of Health Stroke Scale was larger in the thrombectomy group (median 12 vs 6 points; P<0.001). At 90 days poststroke there was a shift toward favorable outcome in the thrombectomy group (60% vs 37.5%; P=0.001). Treatment allocation did not impact outcome in the regression analysis. CONCLUSIONS: Treatment of patients with proximal middle cerebral artery occlusions with SBT resulted in a shift toward more favorable outcomes compared with tPA. Randomized controlled studies are needed to explore whether treatment with SBT should be used in patients presenting within the first hours after stroke.
    Stroke 10/2012; 43(12). DOI:10.1161/STROKEAHA.112.673665 · 6.02 Impact Factor
  • Nina Fainstein, Mikhal E Cohen, Tamir Ben-Hur
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    ABSTRACT: Fetal neural stem/precursor cells (NPCs) possess powerful neurotrophic properties by which they can facilitate self repair processes in the adult central nervous system. The therapeutic value of NPC therapy in neurodegenerative diseases is critically dependent on their long term survival and enduring functional properties. An important aspect of NPC neurotrophic properties is their ability to support their own survival independent of any exogenous growth factor. Here, we examined whether NPCs survive and maintain their properties for extended periods of time, or become dependent on environmental support. Two months following transplantation to naïve brains, large grafts were detected in the ventricles and hippocampus, but only little survival was evident in the striatum. To point at possible regional characteristics which underlie the differential survival of NPC grafts we performed several manipulations of the brain environment. Acute neurotoxic injury with 6-hydroxydopamine induced a 3-fold increase in striatal graft survival, associated with induction of nestin, CD31, β1-integrin, GFAP and cycling cells. Disruption of the extracellular matrix structure of this reactive niche by continuous blockage of host striatum β1-integrin caused 73% reduction in graft survival. In the hippocampus, NPC graft survival did not correspond to β1-integrin and CD31 expression. This suggests that hippocampal environmental support to graft survival rely on different mechanisms than in the reactive striatum. In correlation with in vivo findings, long term cultured neural precursors exhibited an increase in apoptotic cells and dramatic decline in neurotrophic effects, as indicated by two in vitro functional assays. We conclude that long-term changes in transplanted NPC properties render them dependent on region specific environmental support. The major extracellular matrix protein β1-integrin is essential for providing tissue support for graft survival in the striatum. The neurotrophic properties of transplanted neural stem cells are limited in time, representing a shortcoming which should be taken into consideration when developing clinical transplantation protocols for chronic neurological disorders.
    Neurobiology of Disease 08/2012; 49C:41-48. DOI:10.1016/j.nbd.2012.08.004 · 5.20 Impact Factor
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    ABSTRACT: Neuromyelitis optica (NMO) is an idiopathic demyelinating disease of the CNS that can be clearly distinguished from multiple sclerosis (MS) by clinical, neuroradiogic, and pathologic criteria and the presence of the highly specific serum autoantibodies against the water channel aquaporin-4 (AQP4).(1) Although studies support a central role of the anti-AQP4 antibodies in the pathogenesis of NMO, their exact involvement in the immunopathogenetic cascade of the disease is still not clear, and T cells seem to be equally crucial for the full development of clinical and histopathologic NMO.
    Neurology 08/2012; 79(9):945-6. DOI:10.1212/WNL.0b013e318266fc2b · 8.30 Impact Factor

Publication Stats

5k Citations
674.62 Total Impact Points

Institutions

  • 1992–2014
    • Hadassah Medical Center
      • • Department of Neurology
      • • Liver Unit
      Yerushalayim, Jerusalem District, Israel
  • 1983–2014
    • Hebrew University of Jerusalem
      • • Department of Neurobiology
      • • Department of Ophthalmology
      • • Hadassah Medical School
      • • Faculty of Medicine
      Yerushalayim, Jerusalem District, Israel
  • 2005–2007
    • Johns Hopkins University
      Baltimore, Maryland, United States
  • 2006
    • AHEPA University Hospital
      Saloníki, Central Macedonia, Greece
  • 2002
    • University of Vic
      Vic, Catalonia, Spain
  • 1998–1999
    • Institut Pasteur
      Lutetia Parisorum, Île-de-France, France