The Laboratory for Experimental Neurosurgery main research topics are:
- The role of BBB in CNS diseases
- Pathophysilogy of epilepsy
- Cholinergic transmission in mesial temporal lobe epilepsies
- A Multi-Model Unbiased Algorithm for Reliable Detection of Seizures
Underlie Cortical Injury Under Blood-Brain Barrier Disruption
Many different insults to the brain (including for example trauma, ischemia and infections) are associated with perturbations in neurovascular functional integrity. These perturbations initiate several cascades of injury. Upstream signals such as oxidative stress, together with neurophil and/or platelet interactions with activated endothelium, up regulate matrix metalloproteinases and other proteases, which degrade matrix and lead to blood-brain barrier (BBB) leakage. The development of new imaging methods allowed us to detect subtle BBB leakage in human patients (3 ,7) and confirm the notion that compromised BBB is common in numerous neurological diseases (10,12). Interestingly, we showed that in some patients BBB leakage may last for weeks-months and be associated with clinical signs and symptoms related to cortical dysfunction. These studies have led us to hypothesize that prolonged perturbations in the brain’s “vascular compartment” is tightly associated with neuronal dysfunction. To test this hypothesis, we have established a rat model for isolated BBB lesion with no neuronal injury or hypoperfusion. BBB opening led to a leak of serum proteins from the vascular bed to the brain’s extracellular space. This was followed within hours by activation of neighboring astrocytes leading to abnormal buffering of potassium and NMDA-receptor activation leading to neuronal hyperexcitability. Within few days, abnormal plasticity has developed leading to lower threshold for cortical spreading depression in the affected cortical region (6). Our data shows the tight coupling between abnormal vascular function and long-lasting cortical dysfunction and point to the “neurovascular unit” as an important target in future treatments of neurological disorders.
Epileptic seizures in a synapsin knockout mice (in collaboration with Dr. Danny Gitler) [MOV] , [Quicktime Format]
Temporal Lobe Seizure followed by Status Epilepticus: Intracortical Recording
Cholinergic innervation of the hippocampus and entorhinal
cortex is important in determining neuronal excitability and its proper
function is crucial for higher cognitive processes. Our recent experimental
data show up-regulation of the readthrough, soluble form of the acetylcholinesterase
(AChE-R) mRNA and protein together with cholinergic dysfunction in brains
from pilocarpine-treated epileptic rats. However, the role of these
changes in the development, maintenance and propagation of epileptic
activity as well as in the cognitive deficits described in epileptic
patients is not known. As AChE has been previously shown to induce neuronal
growth in cultures, we hypothesize that its up-regulation in epileptic
rats may be important for axonal sprouting and circuit reorganization.
Furthermore, we hypothesize that the associated cholinergic hypersensitivity
underlies cholinergic-dependent reduction in seizure threshold and propagation
as well as abnormal plasticity and decreased cognitive capabilities.
In our present project we use the pilocarpine- and kainate-models of temporal lobe epilepsy to study changes in (1) gene expression and levels of key cholinergic proteins in the hippocampus and entorhinal cortex; (2) cholinergic-dependent responses in individual neurons of the entorhinal cortex; (3) cholinergic-dependent network activity; (4) cholinergic-associated propagation of seizure like events and (5) AChE-R expression and it’s role in axonal sprouting and epileptogenesis using antisense treatment and transgenic manipulations.
A Multi-Model Unbiased Algorithm for Reliable Detection of Seizures
Epilepsy research in animals often relies on long term intracranial electroencephalographic (iEEG) recordings for studying underlying mechanisms and evaluating the efficacy of new treatments. We developed an un-biased and reliable system for detection of seizures in several animal models of epilepsy, thus replacing manual inspection of iEEG recordings and possibly paving the way towards a variety of automatically triggered treatments. System performance was assessed in three different models of epilepsy, analyzing over 2800 hours of raw iEEG recordings from 15 animals. The developed system achieved sensitivity and positive predictive value of above 98%. Moreover, the system successfully detected seizures in an iEEG recording of an epilepsy patient (data courtesy of the Freiburg Center for Data Analysis and Modeling
).The proposed algorithm proved to be an efficient tool (requiring low computation time and power) for robust seizure detection, with promising potential for real-time implementation and seizure management in humans.
ANN based seizure detection
1) Merav H Shamir, Orit Chi, Alon Friedman, Yael Shilo, Ram Reifen, and Limor Miara. 2008,
Sub-occipital craniectomy in a lion (Panthera Leo) with occipital bone malformation and hypovitaminosis A.
Zoo and Wild Animals Medicine. Journal of Zoo and Wildlife Medicine, 39(3): 455-459.
2) Gabriel Zimmerman, Marleisje Njunting, Sebastian Ivens, Elsa Toner, Christopher J. Behrens, Miriam Gross, Hermona Soreq, Uwe Heinemann and Alon Friedman, 2008. Acetylcholine-Induced Seizure-like Activity and Cholinergic Modified Gene Expression in Chronically Epileptic Rats. European Journal of Neuroscience, 27(4):965-75.
3) Alon Friedman, Daniela Kaufer and Uwe Heinemann, 2009. Blood-Brain Barrier Breakdown-Inducing Astrocytic Transformation: Novel Targets for the Prevention of Epilepsy. Epilepsy research, 85(2-3):142-9. [Impact Factor – 2.41 ]
4) Luisa P Cacheaux, Sebastian Ivens, Yaron David, Alexander J Lakhter, Guy Bar-Klein, Michael Shapira, Uwe Heinemann, Alon Friedman and Daniela Kaufer, 2009. Transcriptome profiling reveals TGF-beta signaling involvement in epileptogenesis. Journal of Neuroscience, 29(28): 8927-8935. [Impact Factor – 7.45 ]
5) Hadar Shalev, Yonatan Serlin and Alon Friedman, 2009. Breaching the Blood-Brain Barrier as a Gate to Psychiatric Disorder. Cardiovascular Psychiatry and Neurology.
6) Ofer Prager, Yoash Chassidim, Chen Klein, Haviv Levi, Ilan Shelef and Alon Friedman, 2010. Dynamic in-vivo imaging of cerebral blood flow and blood-brain barrier permeability. Neuroimage, 49: 337-344. [Impact Factor – 5.694]
7) Yaron David, Luisa P Flores, Sebastian Ivens, Uwe Heinemann, Daniela Kaufer and Alon Friedman. 2009. Astrocytic dysfunction in epileptogenesis: consequences of altered potassium and glutamate buffering? Journal of Neuroscience, 29(34):10588-99. [Impact Factor – 7.45 ]
8) Marco Sifringer, Daniela Braita, Ulrike Weichelta, Gabriel Zimmerman, Stefanie Endesfeldera, Felix Brehmera, Clarissa von Haefen, Alon Friedman, Hermona Soreq, Ivo Bendixg, Bettina Gerstner, Ursula Felderhoff-Muesera, 2010. Erythropoietin attenuates hyperoxia-induced oxidative stress in the developing rat brain. Brain, behavior and immunity, (Epub ahead of print) 24:792-9. Epub 2009 Sep 1 [Impact Factor – 4.91 ]
9) Sebastian Ivens, Szendro Gabriel, Greenberg George, Alon Friedman and Ilan Shelef, 2010. Blood-brain barrier breakdown as a novel mechanism underlying cerebral hyperperfusion syndrome. Journal of Neurology, 257: 615-620. [Impact Factor – 2.54 ]
10) Dan Shlosberg, Mony Benifla, Daniela Kaufer and Alon Friedman. 2010. Blood-Brain Barrier Breakdown as a Therapeutic Target in Traumatic Brain Injury. Nature Reviews Neurology, 6: 393-404. [Impact Factor – 6.98 ]