Biomedical subjects

Alon Friedman

Publications and source records attributed to Alon Friedman.

14 recordsLinked to original sources

PubMed2006

TGF-beta receptor-mediated albumin uptake into astrocytes is involved in neocortical epileptogenesis.

It has long been recognized that insults to the cerebral cortex, such as trauma, ischaemia or infections, may result in the development of epilepsy, one of the most common neurological disorders. Human and animal studies have suggested that perturbations in neurovascular integrity and breakdown of the blood-brain barrier (BBB) lead to neuronal hypersynchronization and epileptiform activity, but the mechanisms underlying these processes are not known. In this study, we reveal a novel mechanism for epileptogenesis in the injured brain. We used focal neocortical, long-lasting BBB disruption or direct exposure to serum albumin in rats (51 and 13 animals, respectively, and 26 controls) as well as albumin exposure in brain slices in vitro. Most treated slices (72%, n = 189) displayed hypersynchronous propagating epileptiform field potentials when examined 5-49 days after treatment, but only 14% (n = 71) of control slices showed similar responses. We demonstrate that direct brain exposure to serum albumin is associated with albumin uptake into astrocytes, which is mediated by transforming growth factor beta receptors (TGF-betaRs). This uptake is followed by down regulation of inward-rectifying potassium (Kir 4.1) channels in astrocytes, resulting in reduced buffering of extracellular potassium. This, in turn, leads to activity-dependent increased accumulation of extracellular potassium, resulting in facilitated N-methyl-d-aspartate-receptor-mediated neuronal hyperexcitability and eventually epileptiform activity. Blocking TGF-betaR in vivo reduces the likelihood of epileptogenesis in albumin-exposed brains to 29.3% (n = 41 slices, P < 0.05). We propose that the above-described cascade of events following common brain insults leads to brain dysfunction and eventually epilepsy and suggest TGF-betaRs as a possible therapeutic target.

Animals↗

PubMed2006

Propagation of interictal discharges in temporal lobe epilepsy: correlation of spatiotemporal mapping with intracranial foramen ovale electrode recordings.

OBJECTIVE: We have investigated intracerebral propagation of interictal epileptiform discharges (IED) in patients with mesial temporal lobe epilepsy (MTLE) by using spatiotemporal source maps based on statistical nonparametric mapping (SNPM) of low resolution electromagnetic tomography (LORETA) values. METHODS: We analyzed 30 patterns of IED recorded simultaneously with scalp and intracranial foramen ovale (FO) electrodes in 15 consecutive patients with intractable MTLE. The scalp EEG signals were averaged time-locked to the peak activity in bilateral 10-contact FO electrode recordings. SNPM was applied to LORETA values and spatiotemporal source maps were created by allocating the t-values over time to their corresponding Brodmann areas. Propagation was defined as secondary statistically significant involvement of distinct cortical areas separated by >15 ms. The results were correlated with intracranial data obtained from FO electrode recordings and with scalp EEG recordings. All patients underwent subsequent amygdalo-hippocampectomy and outcome was assessed one year after surgery. RESULTS: We found mesial to lateral propagation in 6/30 IED patterns (20%, four patients), lateral to mesial propagation in 4/30 IED patterns (13.3%, four patients) and simultaneous (within 15 ms) activation of mesial and lateral temporal areas in 6/30 IED patterns (20%, five patients). Propagation generally occurred within 30 ms and was always limited to ipsilateral cortical regions. Nine/30 IED patterns (30%) showed restricted activation of mesial temporal structures and no significant solutions were found in 5/30 IED patterns (16.7%). There was no clear association between the number or characteristics of IED patterns and the postsurgical outcome. CONCLUSIONS: Spatiotemporal mapping of SNPM LORETA accurately describes mesial to lateral temporal propagation of IED, and vice versa, which commonly occur in patients with MTLE. SIGNIFICANCE: Intracerebral propagation must be considered when using non-invasive source algorithms in patients with MTLE. Spatiotemporal mapping might be useful for visualizing this propagation.

Adult↗

PubMed2006

Coding region paraoxonase polymorphisms dictate accentuated neuronal reactions in chronic, sub-threshold pesticide exposure.

Organophosphate pesticides (OPs), known inhibitors of acetylcholinesterase (AChE), are used extensively throughout the world. Recent studies have focused on the ACHE/PON1 locus as a determinant of inherited susceptibility to environmental OP exposure. To explore the relationship of the corresponding gene-environment interactions with brain activity, we integrated neurophysiologic, neuropsychological, biochemical, and genetic methods. Importantly, we found that subthreshold OP exposure leads to discernible physiological consequences that are significantly influenced by inherited factors. Cortical EEG analyses by LORETA revealed significantly decreased theta activity in the hippocampus, parahippocampal regions, and the cingulate cortex, as well as increased beta activity in the prefrontal cortex of exposed individuals-areas known to play a role in cholinergic-associated cognitive functions. Through neuropsychological testing, we identified an appreciable deficit in the visual recall in exposed individuals. Other neuropsychological tests revealed no significant differences between exposed and non-exposed individuals, attesting to the specificity of our findings. Biochemical analyses of blood samples revealed increases in paraoxonase and arylesterase activities and reduced serum acetylcholinesterase activity in chronically exposed individuals. Notably, specific paraoxonase genotypes were found to be associated with these exposure-related changes in blood enzyme activities and abnormal EEG patterns. Thus, gene-environment interactions involving the ACHE/PON1 locus may be causally involved in determining the physiological response to OP exposure.

Acetylcholinesterase↗

PubMed2006

Source localization of interictal epileptiform discharges: comparison of three different techniques to improve signal to noise ratio.

OBJECTIVE: To investigate the localization accuracy of low-resolution electromagnetic tomography (LORETA) for mesial temporal interictal epileptiform discharges (IED) using a new relative averaging (RELAVG) technique for noise reduction. METHODS: We analyzed 19 patterns of mesial temporal IED recorded simultaneously with scalp and foramen ovale (FO) electrodes in 15 consecutive patients who underwent presurgical assessment for intractable temporal lobe epilepsy. The scalp signals were time-locked to the peak activity in the FO electrode recordings and source modeling was performed using the RELAVG technique. Random noise of various amounts was then applied. The results were compared to intracranial data obtained from the FO electrode recordings and to LORETA source solutions obtained using two other approaches to improve signal to noise ratio (SNR): statistical non-parametric mapping (SNPM) and the commonly applied averaging (AVG) technique. RESULTS: The RELAVG technique allowed for reasonable mesial temporal localization in 52.6% (10/19) of IED patterns, compared with 73.7% (14/19) using SNPM. The AVG technique provided no strictly mesial temporal solutions. Nine of the IED patterns revealed relative current density quotient changes >10; all of these were accurately localized by RELAVG into mesial temporal structures. Increasing amounts of white and physiological noise had no influence on the accuracy of RELAVG and SNPM solutions, whereas AVG source reconstructions became progressively spurious. CONCLUSION: The RELAVG technique and SNPM, but not the commonly used AVG technique, allow for reasonable source localization of mesial temporal IED. SNPM is the most accurate but also the most time-consuming noise reduction technique. SIGNIFICANCE: The RELAVG LORETA technique might provide a simple and fast semi-quantitative alternative for localizing IED with low single to noise ratio.

Adult↗

PubMed2006

Motor inhibition and learning impairments in school-aged children following exposure to organophosphate pesticides in infancy.

Despite the critical role of acetylcholinesterase (AChE) in cortical function and development, no long-term studies have been conducted in humans on the long-term sequelae of the disruption of the cholinergic system in early childhood. We report a neuropsychological assessment of healthy school-aged children, who had been hospitalized in infancy following exposure to organophosphate pesticides, compared with children exposed to other toxins such as kerosene, and age- and sex-matched non-exposed children. Although overall, the children seem to have overcome the acute one-time exposure incident, and they all attend regular schools, a finer assessment of specific cognitive abilities indicates they are impaired compared with the matched controls. Specifically, the children who had been exposed to organophosphate pesticides had a deficit in inhibitory motor control. Children with pesticide or kerosene poisoning had a retrieval deficit on the acquisition phase of a verbal learning task.

Case-Control Studies↗

PubMed2005

Source localization of mesial temporal interictal epileptiform discharges: correlation with intracranial foramen ovale electrode recordings.

OBJECTIVE: We have investigated the localization accuracy of low-resolution electromagnetic tomography (LORETA) for mesial temporal interictal epileptiform discharges (IED) on a statistical basis by using clinical electroencephalographic (EEG) data of simultaneous scalp and intracranial foramen ovale (FO) electrode recordings. METHODS: We retrospectively analyzed the IED of 15 patients who underwent presurgical assessment for intractable temporal lobe epilepsy. All patients have subsequently undergone amygdalohippocampectomy. The scalp signals were averaged time-locked to the peak activity in bilateral 10-contact FO electrode recordings. Source modeling was carried out by using statistical non-parametric mapping (SNPM) of LORETA values and by calculating raw LORETA values of averaged IED. The results were compared to intracranial data obtained from FO electrode recordings. RESULTS: Two thousand six hundred and fifteen discharges could be attributed to 19 different patterns of intracranial mesial temporal IED. SNPM of LORETA revealed confined ipsilateral mesial temporal solutions for 14 (73.7%) and no significant solutions for five (26.3%) of these patterns. Raw LORETA current density distributions of the 19 averaged IED patterns revealed ipsilateral basal to lateral temporal solutions for the 14 IED patterns with a sufficient signal to noise ratio (SNR), but spurious results for those five IED with a low SNR. CONCLUSIONS: SNPM of LORETA but not LORETA analysis of averaged IED patterns accurately localizes the source generators of mesial temporal IEDs. SIGNIFICANCE: SNPM of raw LORETA values might be appropriate for localizing restricted mesial temporal lobe sources.

Adult↗

PubMed2005

Induction of sharp wave-ripple complexes in vitro and reorganization of hippocampal networks.

Hippocampal sharp wave-ripple complexes (SPW-Rs) occur during slow-wave sleep and behavioral immobility and are thought to represent stored information that is transferred to the neocortex during memory consolidation. Here we show that stimuli that induce long-term potentiation (LTP), a neurophysiological correlate of learning and memory, can lead to the generation of SPW-Rs in rat hippocampal slices. The induced SPW-Rs have properties that are identical to spontaneously generated SPW-Rs: they originate in CA3, propagate to CA1 and subiculum and require AMPA/kainate receptors. Their induction is dependent on NMDA receptors and involves changes in interactions between clusters of neurons in the CA3 network. Their expression is blocked by low-frequency stimulation but not by NMDA receptor antagonists. These data indicate that induction of LTP in the recurrent CA3 network may facilitate the generation of SPW-Rs.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed2005

Acetylcholinesterase/paraoxonase interactions increase the risk of insecticide-induced Parkinson's disease.

Exposure to agricultural insecticides, together with yet incompletely understood predisposing genotype/phenotype elements, notably increase the risk of Parkinson's disease. Here, we report findings attributing the increased risk in an insecticide-exposed rural area in Israel to interacting debilitating polymorphisms in the ACHE/PON1 locus and corresponding expression variations. Polymorphisms that debilitate PON1 activity and cause impaired AChE overproduction under anticholinesterase exposure were strongly overrepresented in patients from agriculturally exposed areas, indicating that they confer risk of Parkinson's disease. Supporting this notion, serum AChE and PON1 activities were both selectively and significantly lower in patients than in healthy individuals and in carriers of the risky polymorphisms as compared with other Parkinsonian patients. Our findings suggest that inherited interactive weakness of AChE and PON1 expression increases the insecticide-induced occurrence of Parkinson's disease.

Acetylcholinesterase↗

PubMed2005

Persistent BBB disruption may underlie alpha interferon-induced seizures.

Generalized seizures during Interferon-alpha (IFN-alpha) therapy have been repeatedly described in about 1%-4% of patients. However, the mechanisms underlying IFN-alpha induced seizures are not known. We describe a patient who developed partial and secondary generalized seizures during IFN-alpha therapy while displaying a focal disruption of her blood-brain barrier (BBB) corresponding with pathological electroencephalography (EEG). To test our hypothesis that IFN-alpha induces seizure activity, we exposed rat somatosensory cortices to clinically relevant concentrations of IFN-alpha in the acute in-vitro slice preparation or in-vivo. While acute exposure did not induce epileptic activity, recordings from slices exposed to IFN-alpha in-vivo one week prior to recordings revealed pronounced epileptiform activity in > 80% of the slices. We propose that cortical exposure to IFN-alpha leads to the generation of an epileptic cortex, which explains the weeks of latency in patients from initial treatment to seizures, and stressing the importance of identifying possible BBB disruption among high-risk patients administered peripherally acting drugs.

Action Potentials↗

PubMed2004

Lasting blood-brain barrier disruption induces epileptic focus in the rat somatosensory cortex.

Perturbations in the integrity of the blood-brain barrier have been reported in both humans and animals under numerous pathological conditions. Although the blood-brain barrier prevents the penetration of many blood constituents into the brain extracellular space, the effect of such perturbations on the brain function and their roles in the pathogenesis of cortical diseases are unknown. In this study we established a model for focal disruption of the blood-brain barrier in the rat cortex by direct application of bile salts. Exposure of the cerebral cortex in vivo to bile salts resulted in long-lasting extravasation of serum albumin to the brain extracellular space and was associated with a prominent activation of astrocytes with no inflammatory response or marked cell loss. Using electrophysiological recordings in brain slices we found that a focus of epileptiform discharges developed within 4-7 d after treatment and could be recorded up to 49 d postoperatively in >60% of slices from treated animals but only rarely (10%) in sham-operated controls. Epileptiform activity involved both glutamatergic and GABAergic neurotransmission. Epileptiform activity was also induced by direct cortical application of native serum, denatured serum, or albumin-containing solution. In contrast, perfusion with serum-adapted electrolyte solution did not induce abnormal activity, thereby suggesting that the exposure of the serum-devoid brain environment to serum proteins underlies epileptogenesis in the blood-brain barrier-disrupted cortex. Although many neuropathologies entail a compromised blood-brain barrier, this is the first direct evidence that it may have a role in the pathogenesis of focal cortical epilepsy, a common neurological disease.

2-Amino-5-phosphonovalerate↗

PubMed2003

Pyridostigmine enhances glutamatergic transmission in hippocampal CA1 neurons.

Pyridostigmine, a carbamate acetylcholinesterase (AChE) inhibitor, is routinely employed in the treatment of the autoimmune disease myasthenia gravis. Due to its positively charged ammonium group, under normal conditions pyridostigmine cannot cross the blood-brain barrier (BBB) and penetrate the brain. However, several studies have suggested that under conditions in which the BBB is disrupted, pyridostigmine enters the brain, changes cortical excitability, and leads to long-lasting alterations in gene expression. The aim of this study was to characterize the mechanisms underlying pyridostigmine-induced changes in the excitability of central neurons. Using whole cell intracellular recordings in hippocampal neurons we show that pyridostigmine decreases repetitive firing adaptation and increases the appearance of excitatory postsynaptic potentials. In voltage clamp recordings, both pyridostigmine and acetylcholine (ACh) increased the frequency but not the amplitude of excitatory postsynaptic currents. These effects were reversible upon the administration of the muscarinic receptor antagonist, atropine, and were not blocked by tetrodotoxin. We conclude that pyridostigmine, by increasing free ACh levels, causes muscarinic-dependent enhancement of excitatory transmission. This mechanism may explain central side effects previously attributed to this drug as well as the potency of AChE inhibitors, including nerve-gas agents and organophosphate pesticides, in the initiation of cortical synchronization, epileptic discharge, and excitotoxic damage.

Acetylcholine↗

PubMed2003

Long-term seizure outcomes following amygdalohippocampectomy.

OBJECT: Analyses of the results of surgery for epilepsy are hindered by inconsistent classifications of seizure outcome, small numbers of patients, and short postoperative follow-up periods. The authors conducted a retrospective study with a reassessment of the long-term seizure outcomes in patients who underwent selective amygdalohippocampectomy (SelAH) for pharmacotherapy-resistant mesial temporal lobe epilepsy (MTLE) at the Zurich University Hospital from 1975 to 1999. METHODS: Year-by-year data and the last available data on seizure outcomes were retrospectively assessed for 369 consecutively surgically treated patients who had participated in a follow-up period longer than 1 year as of 1999 and whose outcomes were classified according to the Engel scale and the proposed new International League Against Epilepsy (ILAE) scale. Patients were grouped into nonlesional and lesional MTLE groups depending on whether they harbored a gross anatomical lesion that caused the MTLE. Differentiation was made between curative and palliative operations. Complications related to surgery are reported for 453 patients who underwent SelAH and participated in more than 3 months of follow-up review. The last available outcome data according to the Engel scale were found to be generally similar to those of the new ILAE classification, with 66.9% of patients free from disabling seizures (Engel Class I) compared with 57.1% who were completely seizure and aura free (ILAE Class 1). The last available data on seizure outcome were not significantly different between patients in the lesional and nonlesional MTLE groups. In the lesional group, seizure outcomes were significantly better when patients underwent surgery early in the course of the disease. Overall, 70% of the patients received reductions in their antiepileptic drug treatment at the time of the last available follow-up review. Complications related to the surgical procedures were rare. CONCLUSIONS: The authors conclude that SelAH is a safe and effective surgical procedure for MTLE.

Adult↗

PubMed2002

Alternative splicing and neuritic mRNA translocation under long-term neuronal hypersensitivity.

To explore neuronal mechanisms underlying long-term consequences of stress, we studied stress-induced changes in the neuritic translocation of acetylcholinesterase (AChE) splice variants. Under normal conditions, we found the synaptic AChE-S mRNA and protein in neurites. Corticosterone, anticholinesterases, and forced swim, each facilitated a rapid (minutes), yet long-lasting (weeks), shift from AChE-S to the normally rare AChE-R mRNA, promoted AChE-R mRNA translocation into neurites, and induced enzyme secretion. Weeks after stress, electrophysiological measurements in hippocampus slices displayed apparently normal evoked synaptic responses but extreme hypersensitivity to both anticholinesterases and atropine. Our findings suggest that neuronal hypersensitivity under stress involves neuritic replacement of AChE-S with AChE-R.

Acetylcholine↗

PubMedDate not supplied

Focal cortical dysfunction and blood-brain barrier disruption in patients with Postconcussion syndrome.

Postconcussion syndrome (PCS) refers to symptoms and signs commonly occurring after mild head injury. The pathogenesis of PCS is unknown. The authors quantitatively analyzed EEG recordings, localized brain sources for abnormal activity, and correlated it with imaging studies. Data from 17 patients with neurologic symptomatology consistent with ICD-10 criteria for PCS was analyzed. Normalized quantitative EEG (QEEG) revealed significantly higher power in the delta band and lower power in the alpha band compared with matched controls. The generators for the abnormal rhythms were focally localized in neocortical regions. Brain computerized tomography and/or MRI did not reveal focal abnormality at the time of diagnosis. Single photon emission computed tomography (SPECT) after 99mTc-ethylcysteinate dimer administration showed a focal reduction in perfusion in 85% (n = 11) of the patients, and abnormal blood-brain barrier (BBB) after 99mTc-diethylenetriaminepentaacetic acid administration in 73% (n = 8). In 75% of these patients, low-resolution brain electromagnetic tomography analysis showed that the generators for abnormal rhythms were closely related to the anatomic location of the BBB lesion. These data point to focal cortical dysfunction in conjunction with BBB disruption and hypoperfusion as a possible mechanism of pathogenesis in at least some PCS patients, and offer QEEG and SPECT as important tools in evaluating these patients.

Adolescent↗